Nuclear Magnetic Resonance

Nuclear Magnetic Resonance Volume 36 A Specialist Periodical Report Nuclear Magnetic Resonance Volume 36 A Review of ...

Author: Graham A Webb

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Nuclear Magnetic Resonance Volume 36

A Specialist Periodical Report

Nuclear Magnetic Resonance Volume 36 A Review of the Literature Published between June 2005 and May 2006 Editor G.A. Webb, formerly Department of Chemistry, University of Surrey, Guildford, UK Authors A.E. Aliev, University College London, UK N. Asakawa, Tokyo Institute of Technology, Tokyo, Japan A.C. de Dios, Georgetown University, Washington, DC, USA H. Fukui, Kitami Institute of Technology, Kitami, Japan E.F. Hounsell, Birkbeck University of London, UK C.J. Jameson, University of Illinois at Chicago, USA K. Kamien´ska-Trela, Polish Academy of Sciences, Warszawa, Poland S. Kuroki, Tokyo Institute of Technology, Tokyo, Japan H. Kurosu, Nara Women’s University, Nara City, Japan R.V. Law, Imperial College of Science and Technology, London, UK R. Ludwig, University of Rostock, Germany S.J. Matthews, Imperial College London, UK M. Monduzzi, University of Cagliari, Italy S. Murgia, University of Cagliari, Italy D. Nietlispach, University of Cambridge, UK M.J.W. Prior, University of Nottingham, UK W. Schilf, Polish Academy of Sciences, Warszawa, Poland T. Watanabe, Aoyama Gakuin University Women’s College, Tokyo, Japan J. Wo´jcik, Polish Academy of Sciences, Warszawa, Poland T. Yamanobe, Nara Women’s University, Nara City, Japan H. Yasunaga, Kyoto Institute of Technology, Kyoto, Japan

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ISBN-10: 0-85404-362-4 ISBN-13: 978-0-85404-362-0 ISSN 0305-9804 A catalogue record for this book is available from the British Library r The Royal Society of Chemistry 2007 All rights reserved Apart from any fair dealing for the purpose of research or private study for non-commercial purposes, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act, 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Typeset by Macmillan India Ltd, Bangalore, India Printed and bound by MPG Books Ltd, Bodmin, Cornwall, UK

Preface G. A. Webb DOI: 10.1039/b615948f It is a pleasure for me to introduce Volume 36 of the Specialist Periodical Reports on NMR which comprises the familiar comprehensive annual coverage of the appropriate literature. In this case that appearing between June 2005 and May 2006. Three changes to the reporting team are noted with this volume. M. Monduzzi and S. Murgia, who have been covering Liquid Crystals and Micellar Solutions, and S. J. Matthews who has reported on NMR of Proteins and Nucleic Acids, are retiring. At the same time D. Nietlispach is joining the team with his account of Multiple Resonance. It is my pleasure to thank them, and all the other reporters for their timely and interesting accounts.

Royal Society of Chemistry, Burlington House, Piccadilly, London, UK W1J 0BA. E-mail: [email protected]

Nucl. Magn. Reson., 2007, 36, 7 | 7 This journal is

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The Royal Society of Chemistry 2007

CONTENTS Cover 3D illustrated atom. Image courtesy of Bruker BioSpin Ltd.

Preface

7

G. A. Webb

NMR books and reviews

22

W. Schilf Books Regular reviews series Edited books and symposia Reviews in periodicals Reviews and books in foreign languages

22 22 22 22 22

Theoretical and physical aspects of nuclear shielding

50

Cynthia J. Jameson and Angel C. de Dios Theoretical aspects of nuclear shielding Physical aspects of nuclear shielding

50 58

Nucl. Magn. Reson., 2007, 36, 9–21 | 9 This journal is

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Applications of nuclear shielding

72

Shigeki Kuroki, Naoki Asakawa and Hidekazu Yasunaga Introduction Shielding of particular nuclear species

72 72

Theoretical aspects of spin–spin couplings Hiroyuki Fukui Introduction NMR spectroscopy and chirality Relativistic calculation of spin–spin coupling constants Relationships between spin–spin coupling constants and structures Assessment of density functional theory Hydrogen bonding effects on nuclear spin–spin coupling constants Conformational analysis

113 113 113 114 116 121 122 123

Applications of spin–spin couplings

131

Krystyna Kamien´ska-Trela and Jacek Wo´jcik Introduction New methods One-bond couplings to hydrogen One-bond couplings not involving hydrogen Two-bond couplings to hydrogen Two-bond couplings not involving hydrogen Three-bond hydrogen–hydrogen couplings Three-bond couplings to hydrogen Three-bond couplings not involving hydrogen Couplings over more than three bonds and through space Couplings through hydrogen bonds Residual dipolar couplings

131 132 134 135 141 142 143 147 151 152 154 154

10 | Nucl. Magn. Reson., 2007, 36, 9–21 This journal is

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Nuclear spin relaxation in liquids and gases R. Ludwig Introduction General, physical and experimental aspects of nuclear spin relaxation Selected applications of nuclear spin relaxation Nuclear spin relaxation in gases Self-diffusion in liquids

170 170 171 183 186 188

Solid-state NMR spectroscopy A. E. Aliev and R. V. Law Introduction Reviews Experimental developments Distance and angle measurements by solid-state NMR NMR parameters: experimental and theoretical studies Applications

196

Multiple pulse NMR

244

Daniel Nietlispach Introduction General methods and theoretical developments Fast multidimensional methods Spin relaxation methods Diffusion experiments Coupling constant measurement Residual dipolar couplings Homonuclear spectroscopy Inverse proton detected correlation spectroscopy

244 244 245 249 252 253 254 255 256

NMR of proteins and nucleic acids S. J. Matthews Introduction New methodology Macromolecular structures Protein folding

196 196 200 207 209 212

262 262 262 270 278


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NMR of carbohydrates, lipids and membranes

285

Elizabeth Hounsell Introduction Glycosylated protein conformation and folding Studies of proteins and small molecules in membranes Oligosaccharide conformation, recognition and function Metabolomic studies and hyphenated techniques Bacterial polysaccharides Phytotherapeutics Other natural products Materials science

285 285 287 291 293 295 297 299 300

Synthetic macromolecules Hiromichi Kurosu and Takeshi Yamanobe Introduction Primary structure Liquid crystalline polymers Imaging and diffusion Characterization of the synthetic macromolecules Polymer blend of the synthetic macromolecules Dynamics of the synthetic macromolecules

309

NMR in living systems

344

Malcolm J. W. Prior General applications and methodologies Cells Plants Tissues Clinical

344 348 350 351 355


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309 309 309 318 319 326 328

Nuclear magnetic resonance imaging

363

By Tokuko Watanabe Introduction Introductory articles and reviews Instruments Pulse sequences and data processing Other nuclei Dynamics: diffusion, flow, and velocity Polymer Plant, seed, fruit Food In vivo application

363 363 365 370 373 376 382 384 385 387

NMR of liquid crystals and micellar solutions

397

Maura Monduzzi and Sergio Murgia Introduction General articles: reviews, methods, models Liquid crystals Micellar solutions

397 398 399 408


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Symbols and Abbreviations These lists contain the symbols and abbreviations most frequently used in this volume, but they are not expected to be exhaustive. Some specialized notation is only defined in the relevant chapter. An attempt has been made to standardize usage throughout the volume as far as is feasible, but it must be borne in mind that the original research literature certainly is not standardized in this way, and some difficulties may arise from this fact. Trivial use of subscripts etc. is not always mentioned in the symbols listed below. Some of the other symbols used in the text, e.g. for physical constants such as h or p, or for the thermodynamic quantities such as H or S, are not included in the list since they are considered to follow completely accepted usage.

Symbols aN A

B

B0 B1, B2 Cx CJ, C> D D DJ, D> Dint D0 E En g G Hij H Ii Iix, Iiy, Iiz

hyperline (electron–nucleus) interaction constant (i) hyperfine (electron–nucleus) interaction constant (ii) parameter relating to electric field effects on nuclear shielding (i) magnetic induction field (magnetic flux density) (ii) parameter relating to electric field effects on nuclear shielding static magnetic field of NMR or ESR spectrometer r.f. magnetic fields associated with n1, n2 spin-rotation coupling constant of nucleus X 2 (used sometimes in tensor form): C 2 ¼ 1=3ðCJ2 þ 2C> Þ components of C parallel and perpendicular to a molecular symmetry axis (i) self-diffusion coefficient (ii) zero-field splitting constant rotational diffusion tensor components of D parallel and perpendicular to a molecular symmetry axis internal diffusion coefficient overall isotropic diffusion coefficient electric field ^ (or a contribution to H) ^ eigenvalue of H nuclear or electronic g-factor magnetic field gradient element of matrix representation of H Hamiltonian operator–subscripts indicate its nature nuclear spin operator for nucleus i components of Ii


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I n

J

Jr J n K mi M0 M x , M y, M z Mn PA Pi Puv q Q sA 2 SA (0) S

t T Tc Tg TX 1 TX 2 T 02 T2 T3 X TX 1p ,T 2p T1D Xi ZA

(i) ionization potential (ii) moment of inertia nuclear spin–spin coupling constant through n bonds (in Hz). Further information may be given by subscripts or in brackets. Brackets are used for indicating the species of nuclei coupled, e.g. J (13C, 1H) or additionally, the coupling path, e.g. J(POCF) reduced splitting observed in a double resonance experiment rotational quantum number reduced nuclear spin–spin coupling constant (see the notes concerning nJ) eigenvalue of Iiz (magnetic component quantum number) equilibrium macroscopic magnetization of a spin system in the presence of B0 components of macroscopic magnetization the number of average mol. wt. valence p orbital of atom A fractional population (or rotamers etc.) element of bond-order, charge-density matrix electric field gradient (i) nuclear quadrupole moment (ii) quality factor for an r.f. coil valence s-orbital of atom A electron density in SA at nuclear A (i) singlet state (ii) electron (or, occasionally, nuclear spin) cf. I (iii) ordering parameter for oriented systems (iv) overlap integral between molecular orbitals elapsed time (i) temperature (ii) triplet state coalescence temperature for an NMR spectrum the glass transition temperature (of a polymer) spin–lattice relaxation time of the X nuclei (further subscripts refer to the relaxation mechanism) spin–spin relaxation time of the X nucleus (further subscripts refer to the relaxation mechanism) inhomogeneity contribution to dephasing time for Mx or My total dephasing time for Mx or My; (T2*)1¼T21 þ (T2 0 )1 decay time following 900t9090 pulse sequences spin–lattice and spin–spin relaxation time of the X nuclei in the frame of reference rotating with B1 dipolar spin–lattice relaxation time mole fraction of compound atomic number of atom A


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a

b gX dX

dij d(rKA) D DJ Dn Dd Dn 12 Ds Dw er e0 Z

m m0 mB mN ni n0 n1 n2 si

sJ,s> sd sp t tc

(i) nuclear spin wavefunction (eigenfunction of Iz) for a spin 12 nucleus (ii) polarizability nuclear spin wavefunction (eigenfunction of Iz) for a spin 12 nucleus magnetogyric ratio of nucleus X chemical shift of a nucleus of element X (positive when the sample resonates to high frequency of the reference). Usually in p.p.m. Kronecker delta (¼1 if i ¼ j, and ¼0 otherwise) Dirac delta operator (i) time between field gradient pulses (ii) spectral width anisotropy in J (DJ ¼ JJJ>, for axial symmetry) population difference between nuclear states change of difference in d full width (in Hz) of a resonance line at half-height (i) anisotropy in s(Ds ¼ sJs>, for axial symmetry) (ii) differences in s for two different situations (i) susceptibility anisotropy(Dw ¼ wJw>, for axial symmetry) (ii) differences in electronegativities relative permittivity permittivity of a vacuum (i) nuclear Overhauser effect (ii) asymmetry factor (e.g. in e2 qQ=h) (iii) refractive index (iv) viscosity magnetic dipole moment permeability of a vacuum Bohr magneton nuclear magneton Larmor precession frequency of nucleus i (in Hz) (i) spectrometer operating frequency (ii) Larmor precession frequency (general, or of bare nucleus) frequency of ‘observing’ r.f. magnetic field frequency of ‘irradiating’ r.f. magnetic field shielding parameter of nucleus i (used sometimes in tensor form). Usually in p.p.m. Subscripts may alternatively indicate contributions to s. components of s parallel and perpendicular to a molecular symmetry axis diagrammatic contribution to s paramagnetic contribution to s (i) pre-exchange lifetime of molecular species (ii) time between r.f. pulses (general symbol) correlation time


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tcoll tj tp tt w o oi, o0, o1, o2 om or

mean time between molecular collisions in the liquid state angular momentum correlation time pulse duration translational magnetic relaxation correlation time (i) magnetic susceptibility (ii) electronegativity (iii) nuclear quadrupole coupling constant (¼ e2 qQ=h) carrier frequency in rad s1 as for n i , n 0 , n 1 , n 2 but in rad s1 modulation angular frequency (in rad s1) sample rotation (rad s1)

Abbreviations (a) Physical properties a.f. audiofrequency a.u. atomic unit a.m. amplitude modulation b.c.c. body-centred cubic c.m.c. critical micelle concentration e.d. electron diffraction e.f.g. electric field gradient f.c.c. face-centred cubic f.m. frequency modulation h.c.p. hexagonal close-packed h.f. hyperfine i.d. inside diameter i.f. intermediate frequency l.c. liquid crystalline mol.wt. molecular weight o.d. outside diameter p.p.m. parts per million r.f. radiofrequency r.m.s. root mean square s.h.f. super-high frequency u.h.f. ultra-high frequency ADC analogue-to-digital converter AEE average excitation energy approximation AQ acquire ARP adiabatic rapid passage BIRD bilinear rotation decoupling CCPPA coupled cluster polarization propagator approximation CH-COSY carbon-hydrogen correlation spectroscopy CHESS chemical shift selection


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CHF CIDEP CIDNP COSY CP CPMG CSA CSI CW DAC DD DEPT DLB DNP DQ DQF ECOSY EHT ENDOR EOM ESR EXSY FC FID FLASH FPT FT GIAO HMQ HOHAHA HRPA IDESS IGLO INADE-QUATE INDO INDO/S INDOR INEPT IR ISIS LIS

coupled Hartree–Fock molecular orbital calculations chemically induced dynamic electron polarization chemically induced dynamic nuclear polarization correlation spectroscopy cross polarization Carr–Purcell pulse sequence. Meiboom–Gill modification chemical shielding anisotropy chemical shift imaging continuous wave digital-to-analogue converter dipole-dipole (interaction or relaxation mechanism) distortionless enhancement by polarization transfer differential line broadening dynamic nuclear polarization double quantum double quantum filter exclusive correlation spectroscopy extended Hu¨ckel molecular orbital theory electron–nucleus double resonance equations of motion electron spin resonance exchange spectroscopy Fermi contact free induction decay fast low angle shot finite perturbation theory Fourier transform gauge included atomic orbitals heteronuclear multiquantum homonuclear Hartman–Hahn higher random phased approximation improved depth selective single surface coil spectroscopy individual gauge for different localized orbitals incredible natural abundance double quantum transfer experiment intermediate neglect of differential overlap intermediate neglect of differential overlap calculations for spectroscopy internuclear double resonance insensitive nuclei enhanced by polarization transfer infrared image selected in vivo spectroscopy lanthanide induced shift


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LORG LSR MASS MBPT MEM MINDO MQ MQC MQF NMR NOE NOESY NQCC NQR PFG PRE QF QPD REX

local origin lanthanide shift reagent magic angle sample spinning many body perturbation theory maximum entropy method modified INDO multiple quantum multiple quantum coherence multiple quantum filter nuclear magnetic resonance nuclear Overhauser enhancement nuclear Overhauser enhancement spectroscopy nuclear quadrupole coupling constant nuclear quadrupole resonance pulsed field gradient proton relaxation enhancement quadrupole moment/field gradient quadrature phase detection relativistically extended Hu¨ckel molecular orbital theory rotating frame Overhauser enhancement spectroscopy random phase approximation self consistent perturbation theory spin dipolar spin echo correlation spectroscopy spin echo Fourier transform slice interleaved depth resolved surface coil spectroscopy second order polarization propagator approach selective population inversion selective population transfer spin rotation (interaction or relaxation mechanism) tip angle reduced T1 imaging total correlation spectroscopy ultraviolet Waugh, Huber and Ha¨berlen (cycle of pulses) zero quantum zero quantum coherence

ROESY RPA SCPT SD SECSY SEFT SLITDRESS SOPPA SPI SPT SR TART TOCSY UV WAHUHA ZQ ZQC (b) Chemical speciesa acac ACTH ADP a

acetylacetonato adrenocorticotropic hormone (corticotropin) adenosine diphosphate

Lower case initials are used when the species is a ligand.


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AMP ATP BSA CMP cp DAP DME DMF DML DMS DMSO DNA DPG DPI dpm DPPH DSS DTBN EBBA EDTA EVA fod HAB HMPA HOAB IHP KDP MBBA NADH(P) NMF PAA PBA PBLG PC PCB PDMS PMA PMMA POM PS PTFE PVC

adenosine monophosphate adenosine triphosphate bovine serum albumin cytidine monophosphate cyclopentadienyl dodecylammonium propionate 1,2-dimethoxyethane dimethylformamide dimyristoyl-lecithin dimethylsiloxane dimethyl sulfoxide deoxyribonucleic acid 2,3-diphosphoglycerate dipalmitoyl-lecithin dipivaloylmethanato diphenylpicrylhydrazyl 2,2-dimethyl-2-silapentane-5-sulfonate (usually as the sodium salt) di-t-butyl nitroxide N-(p-ethoxybenzylidene)-p-butylaniline ethylenediaminetetra-acetic acid ethylene-vinyl acetate 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4, 6-dionato 4,4 0 -bis(heptyl)azoxybenzene hexamethylphosphoramide p-n-heptyloxyazoxybenzene inositolhexaphosphate potassium dihydrogen phosphate N-(p-methoxybenzylidene)-p-butylaniline nicotinamide adenine dinucleotide (phosphate) N-methylformamide p-azoxyanisole pyrene butyric acid poly(L-benzyl m-glutamate) phosphatidyl choline (lecithin) polychlorinated biphenyl polydimethylsiloxane poly(methacrylic acid) poly(methyl methacrylate) poly(oxymethylene) phosphatidylserine polytetrafluoroethylene poly(vinyl chloride)


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PVF PVP RNA SDS TAB TCNQ TFA THF TMS UTP

poly(vinyl fluoride) poly(vinyl pyrrolidone) ribonucleic acid (tRNA, transfer RNA) sodium dodecyl sulfate trimethylammonium bromide tetracyanoquinodimethane trifluoroacetic acid tetrahydrofuran tetramethylsilane uridine triphosphate

Amino-acid residues Ala alanine Arg arginine Asn asparagine Asp aspartic acid Cys cysteine Gln glutamine Glu glutamic acid Gly glycine His histidine Hyp hydroxyproline Ile isoleucine

Leu Lys Met Phe Pro Ser Thr Trp Tyr Val

leucine lysine methionine phenylalanine proline serine threonin tryptophan tyrosine valine


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NMR books and reviews W. Schilf DOI: 10.1039/b618335m

1

Books

See ref. 1–3.

2

Regular reviews series

See ref. 4–118.

3

Edited books and symposia

See ref. 119–264.

4

Reviews in periodicals

See ref. 265–525.

5

Reviews and books in foreign languages

See ref. 526–656. Czech See ref. 526. Chinese See ref. 527–554. Croat See ref. 555. Danish See ref. 556–557. French See ref. 558–562. German See ref. 563–566. Greek See ref. 567. Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw 42, POB 58, Poland


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Hungarian See ref. 568–572. Japanese See ref. 573–634. Polish See ref. 635–650. Russian See ref. 651–653. Slovakian See ref. 654. Spanish See ref. 655–656.

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Theoretical and physical aspects of nuclear shielding Cynthia J. Jamesona and Angel C. de Diosb DOI: 10.1039/b618338g

1. Theoretical aspects of nuclear shielding 1.1 General theory Relativistic effects on molecular magnetic properties, in particular the nuclear magnetic shielding tensor, can be significant in molecules containing heavy atoms. Many approaches have been put forward. One approach is to append the spin–orbit interaction to the non-relativistic theory. Nakatsuji et al. presented an ab initio UHF formalism for calculating the spin–orbit (SO) effect without electron correlation1 and applied it to many systems,2–5 while Malkin et al. presented a density functional theory (DFT) formalism,6 and Vaara et al., on the other hand, used multi-configuration self consistent field (MCSCF).7,8 While these works showed the importance of including the spin orbit effects, particularly to understanding the observed ‘‘normal halogen dependence’’, this approach clearly is insufficient for the nuclear shielding of heavy nuclei. Several methods have been proposed to reduce the fourcomponent Dirac equation to two-component equations. The most successful twocomponent relativistic method to date starts with the no-pair formalism and external field projectors, as developed by Douglas and Kroll and Hess. Nakatsuji and coworkers used a two-component quasi-relativistic (QR) theory based on the DouglasKroll-Hess transformation,9,10 included the change of picture effect which ensures consistency with the Hellmann-Feynman theorem for the QR theory,9 adopted gauge-including atomic orbitals (GIAO) method for gauge origins,10 and incorporated electron correlation at the MP2 level in this reporting period.11 Fukui and Baba developed a two-component method that derived the expression for the nuclear shielding from the Douglas-Kroll-Hess (DKH) transformation of the nopair equation for a molecule bearing a nuclear moment and is placed in a magnetic field; they used common origin coupled Hartree–Fock to begin with,12 later introduced GIAOs.13,14 In these earlier works, the finite perturbation method was used to compute nuclear shielding values. In this reporting period, Kudo and Fukui derived expressions for the shielding tensor by analytically differentiating the electronic energy of a system based on the Douglas-Kroll-Hess approach.15 Earlier, Fukui, Baba and Inomata had derived a two-component formalism using the Breit-Pauli approach; the magnetic vector potential is added to the canonical momentum in the Breit-Pauli Hamiltonian in order to get a gauge-invariant scheme up to order c4.16,17 In the process, a mass correction term in the shielding became apparent for the first time, arising from a second order expression containing the Fermi contact terms and the kinetic energy operators. The same approach was carried out more completely by Manninen et al., avoiding some of the approximations introduced by Fukui et al.18–20 Another alternative two-component approach to NMR properties begins with the zeroth order regular approximation (ZORA) Hamiltonian; an external magnetic field and nuclear moment are introduced. Wolff and Ziegler derived the equations for calculating the nuclear shielding tensor in the ZORA formulation and implemented them within an existing density functional program for which the ZORA a b

University of lllinois at Chicago, Department of Chemistry, 845 W, Taylor Street, Chicago, IL, 60607-7061, USA Department of Chemistry, Georgetown University, Washington, DC, 20057-2222, USA


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part had already been developed by van Lenthe et al.21 This version of the twocomponent approach has been applied to many molecular systems involving heavy atoms by Ziegler and others.21–24 Fukui et al. have also derived a ZORA version, but without electron correlation.25 A third approach which leads to a two-component method of calculating nuclear shielding is the linear response within the elimination of small components (LR-ESC), introduced by Melo et al.26 They start with a four-component Rayleigh-Schrodinger perturbation theory formalism, and construct a two-component theory by using the elimination of small component scheme, thereby obtaining formal expressions for operators previously neglected.26 They arrive at expressions similar to Fukui et al.16,17 plus some additional terms correcting both the diamagnetic and paramagnetic parts of the shielding. Thus, the formal relation between the Breit-Pauli approach of Fukui et al. and the LR-ESC approach of Melo et al. had been shown.26 Yet another formalism is Kutzelnigg’s minimal coupling approach.27 He developed two-component expressions of magnetic properties starting from the Dirac equation in the presence of a magnetic field and using direct perturbation theory. By carrying out a double perturbation expansion (in c1 and in the magnetic vector potential) he arrived at formal perturbative expressions based on the Levy-Leblond Hamiltonian.27 Are these two-component approaches equivalent to each other? It is difficult to ascertain the answer to this question, in part because basis set incompleteness errors do not impact contributions in different approaches uniformly and in part because two-body contributions which are difficult to calculate are sometimes not included. A full four-component treatment is to adapt Ramsey’s theory to the fourcomponent Dirac equation. In a four-component context all relativistic corrections are included from the beginning.28,29 Within the random phase approximation (RPA) method, four-component relativistic calculations of nuclear shielding have been derived by Visscher et al.30 Four-component calculations have been carried out on small molecular systems.19,28–33 where it should be noted that refs. 30 and 31 have an error in having neglected positronic excitations in RPA calculations and refs. 28, 32 and 33 have used modest basis sets. It seems natural to identify the paramagnetic contribution as that originating in operators linear in the magnetic vector potential A, and to identify the diamagnetic contribution as that from operators linear in A. With this definition, various approaches to the calculations of relativistic effects on nuclear magnetic shielding yield different decompositions into para- and diamagnetic components of magnetic properties. There are different definitions of para- and diamagnetic contributions at the four component level yielding the same para- and diamagnetic separation in the non-relativistic limit. In a very useful paper in this reporting period, Zaccari et al.34 attempts to clear up the situation by analyzing the formal relations connecting the different para- and diamagnetic contributions of three approaches: the Breit-Pauli, the LR-ESC, and the minimal coupling approaches, as they were presented in refs. 19, 26 and 27, respectively. In the process, the equivalence of these three approaches within the elimination of the small component approximation is proven and verified numerically for the HX series of molecules (X ¼ Br, I). Formal relations are presented proving the gauge origin invariance of the full relativistic effect on the nuclear shielding tensor within the LR-ESC approach. Only one-body terms are included in the analysis by Zaccari et al.34 Finally, these three equivalent approaches, represented by the Breit-Pauli approach,20 can be compared to the Douglas-Kroll Hess,15 and three other twocomponent methods, and also with the non-relativistic values and the benchmark full 4-component Dirac-Fock with an analytical linear response approach.19,29 Table 1 is a comparison of the calculated results for the isotropic nuclear shieldings for noble gas atoms, HX (X ¼ F, Cl, Br, I), and H2X (X ¼ O, S, Se, Te) molecules. Presented in Table 2 are the anisotropies of the shielding in HX (X ¼ F, Cl, Br, I), and H2X (X ¼ O, S, Se, Te) molecules. Kudo and Fukui also developed a second Nucl. Magn. Reson., 2007, 36, 50–71 | 51 This journal is

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Table 1 Calculated results for isotropic nuclear magnetic shieldings (in ppm) for noble gas atoms (Ne to Xe), HX (X ¼ F, Cl, Br, I), and H2X (X ¼ O, S, Se, Te) molecules. All calculations are at the Hartree–Fock level

O in H2O S in H2S Se in H2Se Te in H2Te F in HF Cl in HCl Br in HBr I in HI H in HF H in HCl H in HBr H in HI Ne Ar Kr Xe

NonRel15

4-component DHF19,29

BreitPauli20

Douglas-KrollHess15

IOTCCHF15

NESCZORA36

NESCSORA36

327.7 719.2 2153.4 3463.5 412.0 953.1 2615.9 4752.4 26.72 30.05 29.70 35.33 551.5 1237.7 3234.7 5590.7

330.7 738.3 2441.4 4806.7 418.4 984.5 2959.4 5913.7 28.03 31.18 35.86 47.05 561.3 1274.3 3579.5 6965.2

330.8 737.3 2406.2 4569.4 418.1 977.1 2922.0 5598.2 28.60 31.78 36.93 50.65 556.6 1273.3 3553.8 6718.5

331.1 747.0 2463.2 4668.4 417.1 988.3 2982.1 6303.4 26.92 30.51 35.45 44.18 558.3 1280.3 3631.8 7177.9

331.1 746.6 2454.8 4626.5 417.0 987.8 2972.2 6245.0 26.92 30.51 35.46 44.20 558.3 1279.7 3621.1 7120.6

421.0 994.4 3011.5 5924.5 28.17 31.37 36.10 48.11

421.0 994.3 3023.3 6192.4 28.17 31.37 36.10 48.08

expression based on the method of Barysz-Sadlej-Snijders, in which the off-diagonal block terms in the transformed Dirac Hamiltonian are completely eliminated with respect to purely electrostatic nuclear attraction potential and the magnetic vector potential A. This is an infinite order two-component DKH method (IOTC). They carried out calculations using the same basis sets for the same molecular systems,15 and these results are included in Tables 1 and 2 with the label IOTC. In addition to these two-component methods already discussed above, Filatov and Cremer35 recently introduced a normalized elimination of small component (NESC) method which Kudo et al. have extended to include magnetic interactions.36 Filatov and Cremer have developed the regular approximation to the normalized elimination of the small component (NESC) to the Dirac equation and this was used as a starting point for the development of a second order regular approximation to NESC, with the acronym NESC-SORA. The NESC method corresponds to the projection of the Dirac Hamiltonian onto a set of positive-energy (electronic) states, which guarantees its variational stability. NESC-ZORA and NESC-SORA can easily be implemented in any non-relativistic quantum mechanical program. Both methods have been applied by Kudo et al. to the same set of molecular systems and these results are compared with the other methods in Tables 1 and 2. Incidentally, what is typically called ZORA is the lowest order regular approximation to the equation for the unnormalized elimination of the small component. We note that of the two-component methods, those which gave the best agreement with the benchmark four-component calculations are the IOTC, NESC-ZORA and NESC-SORA methods. The Breit-Pauli, which has been shown to be formally analytically equivalent to the LR-ESC, gives a poorer result for the full shielding tensor, as shown by the too large anisotropies of I in HI and Te in H2Te, for example. The Douglas-Kroll-Hess fails to give a good account of the anisotropy of the shielding of both I and H nuclei in the HI molecule. The last three columns in Tables 1 and 2 seem to indicate that the two component methods can give results which are reasonably close to the four-component calculations. These are all largebasis-set calculations which do not include electron correlation. Correlated relativistic calculations are, so far, available in the form of DFTZORA21 and the recently introduced DKH-MP2 by Fukuda and Nakatsuji.11 The latter has been applied to Te shielding calculations, using only modest basis sets, 52 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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Table 2 Calculated results for the anisotropy of nuclear magnetic shieldings (in ppm) for HX (X ¼ F, Cl, Br, I), and H2X (X ¼ O, S, Se, Te) molecules. All calculations are at the Hartree– Fock level. Ds ¼ s8 s> for HX molecules, and Ds ¼ s33 (s11 þ s22)/2 for H2X molecules

O in H2O S in H2S Se in H2Se Te in H2Te F in HF Cl in HCl Br in HBr I in HI H in HF H in HCl H in HBr H in HI

NonRel15

4-component DHF19,20

BreitPauli20

Douglas-KrollHess15

IOTC15

NESCZORA36

NESCSORA36

58.0 319.6 685.7 1463.0 100.3 287.2 722.6 872.9 24.28 21.73 28.19 42.75

57.1 317.1 668.5 1232.4 100.7 288.2 664.0 1025.2 23.80 21.32 18.11 0.39

57.8 317.5 747.9 1692.1 103.1 408.5 792.6 1627.1 23.14 20.51 17.45 1.21

58.6 317.4 659.4 1216.0 98.9 285.6 641.4 651.2 23.96 20.85 18.60 26.57

57.8 317.3 658.4 1212.6 99.0 285.7 641.7 981.0 23.96 20.85 18.59 2.18

99.0 286.7 647.8 1033.5 23.80 20.97 17.93 3.19

99.0 286.7 647.8 1033.9 23.80 20.97 17.93 3.20

however, and it is not clear whether all relativistic terms have been included. For example, the non-relativistic and DKH isotropic shielding values calculated for Te in H2Te were, respectively 3644 and 5094 ppm11 which can be compared to the values 3463.5 and 4569.4 ppm in the Table 1. There have been other correlated relativistic calculations such as those using MCSCF functions, but which only included spin orbit contributions.7,8 A new two-component method has been developed which solves the Dirac equation at the Kohn–Sham level of theory using a basis for the large component only and avoids some of the approximations used in the standard ZORA method.37 This is related to the widely used ZORA approach in that it is an unnormalized elimination of small component method, and that it is density functional theory based rather than ab initio. This new approach, labeled DKS2RI (Dirac-Kohn–Sham with resolution of identity approximation), employs the resolution of identity approach to reformulate the basic Dirac-Kohn–Sham equations before elimination of the small component. No picture-change problems arise in electronic property calculations by this method. The first applications of the method are to calculations of hyperfine constants for atoms. The differences between ZORA and this method are small for Cu and Ag and larger for Au: 6750 vs. 6737; 1909 vs. 1967; and 3134 vs. 2986 all in MHz for ZORA vs. DKS2-RI methods, respectively.37 The method has also been applied to calculations of hyperfine constants of Hg in HgH, HgF and HgCN. The new DKS2-RI method gives uniformly smaller values than ZORA, and the agreement with experiment is worse for DKS2-RI, except in the case of HgH and Au. Spin–orbit contributions to the hyperfine tensor can be substantial and in the examples calculated to date, it looks like they tend to decrease the magnitude of the isotropic contact hyperfine, while the dipolar part of the hyperfine tensor remains the same. DFT calculations of the 13C hyperfine tensors in metallocenes with and without inclusion of spin–orbit contributions reveal that, depending on the metal atom, the calculated 13C contact hyperfine is 74 to 84% of that obtained without including SO.38 In a particular nitroxide radical where both signs of contact hyperfine are observed, the magnitudes of the 13C contact hyperfine of the eight inequivalent carbons are all smaller when SO is included in the calculations. As discussed in vol. 34 of this series, the remarkable experimental values of the shielding tensors measured for the XeF2 molecule23 provide the clear indication that insights we have derived from mathematical identities which relate one molecular electronic property to another based on non-relativistic Hamiltonians are completely overturned in systems involving very heavy atoms, since the same identities do not Nucl. Magn. Reson., 2007, 36, 50–71 | 53 This journal is

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hold in the relativistic case. The DFT-ZORA calculations which accompanied the experimental report gave anisotropies of 4469 ppm and 277 ppm for Xe and F nuclei.23 A recent IOTC-CHF (see above for description of this method) calculation by Kudo et al.39 gave 4276 and 115 ppm, which can be compared with the experimental values 4245 ppm and 150 ppm, respectively. The isotropic shielding values for Xe and F nuclei are, respectively, 3007 and 339 ppm from DFT-ZORA while they are 3570 and 415 ppm from IOTC-CHF. Differences may be due to neglect of electron correlation in the one case and the real differences between t he unnormalized elimination of small component ZORA method compared to the infinite order two component formalism based on the Barysz-Sadlej-Snijders method. The search for better approximations to exchange correlation functionals for use in DFT calculations continues in this reporting period. What is the optimum admixture of exact exchange? To find this, hybrids, such as Becke3, have been parametrized on sets of thermochemical data, properties which are directly associated with the total energy.40 On the other hand, it has been found that relatively large admixtures of exact exchange give better values in shielding calculations.41 Another approach is to convert non-local and non-multiplicative hybrid exchange– correlation potentials into local and multiplicative Kohn–Sham potentials. To do this, Wilson and Tozer used the iterative approach of Zhao, Morrison and Parr (ZMP),42 to convert a given electron density to a multiplicative KS potential, which was then applied to the calculation of nuclear shieldings.41 The advantage of this method is that electron densities derived from any, even non-DFT methods, can be used as the starting point. On the other hand, instead of this ZMP approach, Arbuznikov and Kaupp43–45 construct the Kohn–Sham potential by applying the socalled localized Hartree–Fock approximation to the optimized effective potential method.46 The resulting localized hybrid exchange–correlation potentials provide improved performance at very nearly the same amounts of admixture of exact exchange (close to 0.5) and nearly independent of which standard DFT functional is used (LYP, or PW91, or PBE).44,45 These conclusions are based on results for nuclear shielding in 22 light main-group molecules. Furthermore, they find that an adaptable formulation of local hybrid functionals with position-dependent exact exchange admixture enhances flexibility. At every point in space, a local mixing function determines the amount of exact exchange admixture.47 This has been tested with thermochemical properties but remains to be tried on shielding calculations. Actually, the concept of position-dependent local mixing functions had been proposed first by Becke when he proposed his hybrid functionals.40,48 The performance of CAM-B3LYP, a hybrid exchange correlation energy functional based on the Coulomb-attenuating method (CAM), is compared with standard B3LYP.49 While it gives improvement in long-range properties, for isotropic nuclear shielding the results are comparable to B3LYP. It has been demonstrated with self-consistent field calculations that the basis-set dependence of magnetic properties can be characterized by a parameter t, that describes the deviation of the basis set from completeness in the exponent range (which corresponds to distance from the nucleus) relevant for the property of interest.50 The completeness profile concept introduced by Chong51 is particularly useful for molecular properties that may be dominated by phenomena occurring close to atomic nuclei, which are then best described by high-exponent basis functions, or for those dominated by the valence regions farther away from nuclei, which are best described by diffuse basis functions. Based on this a scheme for designing Gaussian-type orbital basis sets is proposed. Instead of optimizing the parameters of the basis sets with respect to electronic energy, a primitive set is constructed at the outset so as to be complete for a range of exponents relevant for the specific property. This has been illustrated for nuclear shielding;50 completeness profiles of existing basis sets and code for generating completeness-optimized basis sets are made available at http://www.chem.helsinki.fi/Bmanninen/kruununhaka. 54 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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NMR can distinguish diastereomers but conventional NMR spectroscopy is blind to a full mirror image; that is, it is unable to distinguish between the two mirrorimage forms of a chiral molecule. It has been shown that the shielding tensors for the left and right-handed enantiomers are identical except for the antisymmetric parts, whose off-diagonal components differ only in sign. Nevertheless, A. D. Buckingham has shown that52 in principle, chirality may be directly observable in NMR spectroscopy without the need for a chiral auxiliary, although not in conventional NMR spectroscopy. The manifestation of chirality in the chemical shift can be proved using simple symmetry arguments.53 The effective Hamiltonian for nuclear spins can be obtained from the ground state energy of the electronic and nuclear system in which they are embedded. This energy must be time even and an overall scalar. In the presence of a static electric field E, static magnetic field B, and nuclear spin operator S, for an isotropic system the only scalar that may be formed from these three vectors is a pseudoscalar, PS ¼ S . B E, which is time even. Hence the contribution to the ground state energy may be written as EG ¼ s S . B þ schiral S . B E, Under parity, EG is unchanged; however, schiral goes into-schiral, so schiral must be a pseudoscalar. Hence the chiral portion of the chemical shift for each enantiomer is schiral for the left-handed enantiomer and—schiral for the right-handed enantiomer. Buckingham and Fischer54 suggest three experiments which can lead to observables only for chiral molecules. A laser polarized in the plane perpendicular to the field of the magnet may in principle give rise to chiral chemical shifts. The coherent precession of nuclear spins following application of a p/2 pulse to an optically active liquid will lead to a rotating macroscopic electric polarization. In a chiral liquid, the application of an oscillating electric field at right angles to the magnetic field of the spectrometer may give rise to a magnetization oscillating at a unique frequency in the direction of the permanent magnetic field. Of course NMR without electric fields, without diastereomers, is not totally blind to chirality. Parity is not conserved, so there is a tiny pseudoscalar component to the shielding.55,56 In this reporting period, parity violation effects in the nuclear magnetic shielding are evaluated using analytical linear-response theory in the framework of the Breit-Pauli Hamiltonian, based on Hartree–Fock and DFT reference states.57 The calculated splitting in the 19F NMR spectrum between the left and right-handed CHFClBr molecules in vacuum is 2.34 1010 ppm (using Hartree–Fock) or 3.52 1010 ppm (using DFT-B3LYP). The order of magnitude of these effects is in agreement with earlier estimates.58,59 1.2 Ab initio and DFT calculations Calculations of shielding tensors for heavy nuclei such as 183W and 129Xe require relativistic treatment,39,60,61 as do nuclei having neighbors which are heavy atoms, such as 19F in XeF2,39 and in uranium complexes,62 17O in polyoxotungstates,60,61 31P and 15N in a lead (II) complex,63 and the interstitial 13C in an octahedral gold cluster.64 The XeF2 molecule has been discussed above. DFT-ZORA calculations of 183W and 17 O shielding in polyoxotungstate ions having as many as 18 W atoms in the cluster have been carried out.60,61 Relativistic core potentials were used for the internal or core electrons and Slater-type orbitals (STO) for the rest. The valence orbitals are kept orthogonal to the core orbitals by means of a single-z Slater type coreorthogonalization basis set. Optimization of structure results in a unique configuration of a cluster anion. Solvation effects are not included. A linear correlation of calculated and experimental values of chemical shifts for 17O gives a slope of 1.0623, Nucl. Magn. Reson., 2007, 36, 50–71 | 55 This journal is

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but for 183W shifts the best-fit line has a slope of 0.7854, although both have R2 better than 0.98. The calculated 183W shifts permit assignments of non-equivalent W nuclei, albeit the calculated chemical shift range is substantially expanded compared to experiment. The 17O chemical shift range is well-reproduced by the calculations. The relationships between structure and chemical shift are discussed, and the calculations provide a means of understanding the nature of the bonding in these clusters. The 19F shielding in the uranium complexes UFnCl6n have previously been calculated by all-electron ZORA and Pauli methods by Schreckenbach.65,66 In this reporting period, DFT calculations were carried out with various functionals using a relativistic small core pseudopotential on uranium.62 These authors claim that the DFT results can be of comparable quality to those obtained previously by relativistic calculations; instead of the usual effective core potentials, they recommend using a small inner core. However, there is large dependence on the type of functional used. There is only a 40.3 ppm range in the experimental chemical shifts for all nonequivalent 19F sites, while there is a 124 ppm range for one 19F site (UF6) in the DFT-calculated values, depending on which functional is used. The interstitial 13C in an octahedral gold cluster is in a unique bonding situation, surrounded by six Au atoms having phosphine-type ligands.64 The 13C nuclei in interstitial transition metal carbides are known experimentally to be greatly deshielded, with chemical shifts as large as 450 ppm, for example. On the other hand the 183W nucleus in the WAu12 cluster is greatly shielded. DFT-ZORA calculations find the interstitial carbon in an octahedral gold cluster [(Ph3PAu)6C]21 to have a chemical shift of 99.6 to 128.7 ppm relative to TMS, depending on the functional and basis set used. The experimental value is 135.2 ppm. The strongly shielding spin–orbit contribution from the Au cage is suppressed due to electronic effects from the phosphine ligands. Without the phosphine ligands the calculated chemical shift is around 300 ppm.64 All-electron DFT-ZORA calculations, including spin–orbit coupling, of 119Sn in SnH4, Me4Sn, Me4n SnXn (X ¼ Cl, Br, I, n ¼ 1 3) and SnH31 (stannyl cation) find that calculated shifts correlate well with experimental values only when spin orbit terms are included.67 The observed chemical shift of the stannyl cation does not correspond to a bare cation but rather one that is strongly coordinated to a partner such as FSO3H. 99Ru shielding calculations at the DFT level using B3PW91 hybrid functional and small basis sets (3-21G* on Ru and 6-21G* on all other atoms) correlate well (one could say fortuitously) with experimental chemical shifts.68 DFT calculations of 77Se shielding were carried out using B3LYP and GIAO with basis sets 6-311þG(3df) for Se and 6-311þG(3d,2p) for other nuclei in order to understand the relationship of the chemical shift to the orientation of the Aryl group in ArSeR (RQH, Me, Ph) compounds, where Ar ¼ p-YC6H4, (Y ¼ COOEt, CN, NO2).69 It would have been more enlightening to have looked at the full tensor instead of just the isotropic value. Nevertheless, the authors found that a molecular orbital analysis of the contributions to the Se shielding was helpful in understanding the orientation dependence. Phosphorus shielding has been investigated in phosphoranes,70 in the reference liquid, concentrated phosphoric acid.71 chiral phosphorus sulfide cages,72 and bimetallic diphenylphosphinopyridine compexes where the metals are Ru and either Zn, Cd, or Hg.73 It has been known experimentally that phosphoranes, with rare exceptions, have chemical shifts well upfield of the common reference 85% phosphoric acid, mostly in the range d ¼ 50 to 100 ppm, and this generalization has been employed in many cases to decide if a structure is truly a phosphorane, or is the 4-coordinate phosphonium ion (with positive shifts of d ¼ þ15 to þ20 ppm). Chesnut has been using his estimated infinite order Møller–Plesset and scaled DFT for several systems, with reasonable success. In this work, he also employed the conductor like solvaton model (COSMO) to take care of solvent effects in aqueous solution and finds a good correlation with experiment except for multiple chloro compounds, (which should of course be treated relativistically, at least to include the spin–orbit contributions).70 The calculation of the shielding of a liquid reference 56 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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compound is particularly problematic in the case of 31P, because many ionic and molecular species are in equilibrium with each other in a polyprotic acid such as phosphoric acid. Chesnut considered clusters which are hydrated versions of these species, at optimized geometries with one or two waters, as well as dimers and trimers of H3PO4.71 Solutions of naturally occurring phosphates, while occurring in an equilibrium mixture of undissociated, partially dissociated, and completely dissociated species nevertheless span a narrow chemical shift range of 0.1 to 2.6 ppm. Calculations of gas phase species, even hydrated ones, give a much larger range which is about one order of magnitude larger. So it remains an open question what gives rise to the narrow chemical shift range. Perhaps, there is fast exchange between the various species so that calculations of individual static species cannot duplicate experimental observations. The calculations in the bimetallic complexes are not particularly convincing, since the experimental range for the three compounds is only 11 ppm and the errors in the shielding calculations when the method gives optimized bond lengths which are in error by more than 0.1 A˚.73 The 31P calculations in the diastereomers of closo-derivatives of P4S3 cages point towards absolute configurations, but since many rotamers are possible and the diastereomeric shift is not large, assignment of configuration by computations is not certain.72 29 Si shielding in disilynes have been analyzed in terms of the MO contributions.74 17 O shielding in crystalline tellurites do not depend on whether the oxygen is at a bridging or non-bridging position.75,76 This is very surprising since the two sites differ formally by a full electronic charge, and is in contrast to the clear differences observed in the case of silicates. An understanding of this similarity in shielding is gained by a study using plane waves and pseudopotentials.76 11B chemical shifts have been calculated in various compounds using DFT-GIAO methods.77–79 In the case of halogen-substituted compounds, the spin–orbit contribution needs to be included.77 A systematic study of basis sets in reproducing by Hartree–Fock and DFT-B3LYP calculations the experimental 13C shielding tensors obtained from single crystal experiments included 102 tensors from 14 organic crystals and examined 81 combinations of basis functions.80 The correlation between calculated and experimental values is perfect when the slope is unity and the intercept is consistent with the deduced absolute shielding of liquid TMS. The calculations did not include vibrational averaging or neighbor effects, The general findings are as follows: (a) Hartree–Fock leads to consistently too shielded values, whereas DFTB3LYP leads to consistently too deshielded values. It had previously been found that aromatic carbon shielding tensors are particularly sensitive to the technique used to describe electron correlation. This is borne out in this study. (b) The intercept for Hartree–Fock is consistently 20 ppm higher, consistent with the sign of the electron correlation contribution. (c) The slope is particularly sensitive to the description of the valence region. A large increase is observed going from the ‘21’ split valence to the ‘31’ as well as to the ‘311’ valence triple zeta. This increase leads toward better overall results in the DFT method. (d) Going from double to triple to quadruple zeta using the Hartree–Fock method leads to apparently worse slope. There is a mix of carbon chemical sites in the systems studied; the sites which have larger electron correlation contributions are at the ones which appear at the least shielded end of the range of experimental values. Not including electron correlation therefore leads to the wrong slope. (d) A balance between the polarization added to both heavy atoms and hydrogens must be kept. (e) At least one d function on the heavy atoms must be included to obtain good slope values as well as acceptable rmsd values. (f) Diffuse functions have less of an impact than polarization functions. The r3 in the operators leads to greater sensitivity to the description close to the nucleus, whereas diffuse functions extend further in space. For this aspect, Chong’s completeness profile concept,51 discussed above, would be useful. The basis-set dependence of magnetic properties can be characterized by the parameter t which describes the deviation of the basis set from completeness in the exponent range (which corresponds to distance from the nucleus) relevant for the property of interest; Manninen et al. Nucl. Magn. Reson., 2007, 36, 50–71 | 57 This journal is

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have applied Chong’s concept to testing basis sets for nuclear shielding calculations.50 The study by Sefzik et al.80 was a very useful study in that the quality of the data from single crystal experiments is very high and consistently from the same highly expert laboratory, the full tensor information was available for comparisons, the availability of X-ray data meant that the geometries used in the calculations were reliable. There is the remaining problem that since the calculations did not include neighbor effects, the missing ring current contributions and hydrogen bonding effects which differentially impact the accuracy of the calculations for aromatic carbons and the saccharides, respectively, could affect the validity of the conclusions. DFT/GIAO Calculations of 13C shielding in particular compounds have been used (a) to assign the experimental peaks in several studies, such as for free-base porphine, porphyrazine, phthalocyanin and napththalocyanin and their metal complexes,81 (3aminopropyl)guanidine and (trans-4-aminocycloexyl)guanidine,82 N-substituted pyrazoles and indazoles,83 a cycloheptenone derivative,84 substituted 3-nitropyridines,85 chloropyrimidines,86 (b) to assign the structure of newly isolated metabolites from marine animals,87 of benzothiazepines and benzothiazines,88 of hexacyclinol,89 of the products of condensation of hydroxylamine with trifluoromethyl-b-diketones,90 of some new 4-heteroarylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives,91,92 (c) to find the preferred conformers of chlorobornenes in solution,93 of the bicyclic pheromone from a beetle,94 (d) to distinguish between macrocyclic ligands, the smaller and larger sized cucurbit[n]urils, (n ¼ 5 to 8),95 (e) to investigate the changes to the principal components of the shielding tensor upon N-oxidation of quinolines which are anti-malarial drugs,96 (f) to study the influence of axial or equatorial Br substitution on 13C chemical shifts in spirostanes and furostanes,97 (g) to study the dependence of the shielding on the angle between the planes of the two aromatic or heteroaromatic rings in Tro¨ger’s bases,98 and (h) to study the equilibrium between tautomers of triketones 2-acylcyclohexane-1,3-diones.99 1.3 Semi-empirical calculations A review of prediction of chemical shifts using semi-empirical models, with particular applications to the 1H chemical shifts in proteins has appeared.100 The isotropic chemical shift is considered to be a sum of through-bond and through space contributions, with the through space contributions including the electric field effects, magnetic anisotropy effects, ring-current effects, and solvent effects.

2. Physical aspects of nuclear shielding 2.1 Anisotropy of the shielding tensor We begin this section by citing the single crystal studies of peptide 15N shielding tensors by Waddell et al. 101 These studies focus on the central peptide (Gly and Pro) in three tripeptides GGV, AGG and APG. In all cases, the least shielded component s11 of the tensor 15N shielding is found to lie about 20–231 from the N–H vector in Gly and from the N–Cd bond in Pro. In addition, the s22 component, which is usually assumed to be normal to the amide plane, is observed to deviate from this orientation. These results are in general agreement with previous experimental powder-NMR studies 102 and predictions from theoretical work.103 The recent work likewise explores theoretical calculations and found, that in DFT calculations, results on amide 15N shielding tensors, obtained with 6-311þþG(d,p) are already comparable to those of a larger basis set (aug-cc-pv5z). In accordance with earlier tensor calculations in hydrogen-bonded systems, the use of dimer and trimer clusters, which incorporate hydrogen bond partners, is shown to be important in quantitatively predicting the orientation of the 15N shielding tensor. Wylie et al.104 have determined the 15N shielding anisotropy in the solid state for 51 backbone amide sites of the 56-residue b1 immunoglobulin binding domain of protein G 58 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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(GB1). By employing the recoupling of chemical shift anisotropy (ROCSA) method developed by Chan and Tycko,105 combined with specific polarization transfer to either 13Ca or C0,106 3D 15N–15N–13C sets of data have been collected, from which amide 15N shielding tensor data could be extracted. The new shielding tensor data reveal that 15N sites in a-helical segments of a protein have a higher anisotropy (by about 6 ppm) compared to those in b-sheet regions. 13 C shielding tensor measurements continue to play a significant role in the elucidation of structures and dynamics of biologically relevant molecules. Ying et al.107 have measured the 13C shielding anisotropy in DNA bases by taking advantage of NMR relaxation rates measured at two different magnetic fields (500 and 800 MHz proton frequency). In a related study, Hansen and Al-Hashimi have shown that incorporation of residual chemical shift anisotropy of 13C sites in nucleobase carbons in a weakly aligned stem-loop RNA provides additional restraints for structure determination.108 Recoupling of anisotropy information (RAI) 109 has also been applied to the solid state NMR study of Bombyx mori silk fibroin protein.110 Lastly, Hall and Fushman111 have used a combination of relaxation and cross-correlation measurements at five different magnetic fields to measure the amide 15N shielding tensors in protein G in solution. Their findings of a significant variability in the 15N shielding tensor throughout the protein illustrate the importance of using site specific 15N shielding tensors (instead of a uniform 15N shielding tensor for all residues) in analyzing protein dynamics from 15N relaxation measurements. The intimate relationship between electronic structure and the magnitude of shielding tensor components is once again illustrated in the work of Strohmeier et al.112 on tetracyanoethylene (TCNE) and its dianion, p-(TCNE)22. The dianion is formed via a 2.9 A˚ bond between the two monomeric units. The interaction between the monomers, expected to be a combination of Coulomb and van der Waals forces, as well as a singlet coupling of the two unpaired electrons of the monomer anions, is examined through the metric of the magnitudes of the principal components of the 13C shielding tensors in TCNE. The ethylenic C sites show dramatic changes upon dimer formation in their in-plane shielding components. These are the components that lie perpendicular to the line of approach between the two TCNE units. Likewise, similar changes are observed for the cyano C sites. In a related study, keeping track not only of the magnitude but also the orientation of the principal components of 13C shielding in an alkene and an alkyne proves to be important in analyzing Z2–bonding to transition metals.113 If one examines only the values of the shielding components of 13C in the acetylene sites of (Z2–diphenylacetylene)Pt(PPh3)2, a quick conclusion can be easily drawn indicating that the least and most shielded components decrease by 60 ppm, while the intermediate component s22 changes only slightly. However, by keeping track of the orientation of the shielding tensor in free diphenylacetylene (DPA) and how this changes with the formation of the complex, it becomes evident that the changes in the acetylene 13C shielding principal components upon Z2-coordination to Pt are less than straightforward. There are dramatic changes in the orientation of the tensor. In free DPA, the most shielded component, s33, lies along the triple bond, and upon coordination to Pt, this component decreases by about 200 ppm, making it the new intermediate component, s22, in (Z2-DPA)Pt(PPh3)2. The intermediate component, s22, in DPA lies perpendicular to the triple bond, along the same plane defined by the aromatic rings. Upon coordination, the shielding in this direction increases by about 130 ppm, rendering this component the most shielded (s33) in (Z2-DPA)Pt(PPh3)2. The least shielded component, s11, bears the same orientation (normal to the plane defined by the atoms in DPA) in free and coordinated DPA, except that upon complexation this component becomes further deshielded by about 70 ppm. These changes are markedly different from the ones observed for 13C shielding in an alkenyl ligand, as exemplified by (Z2-trans-stilbene)Pt(PPh3)2. In stilbene, in contrast to acetylene, coordination leads to a shielding increase in all directions, thereby conserving the Nucl. Magn. Reson., 2007, 36, 50–71 | 59 This journal is

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orientation of the tensor. Exploring the relationship between electronic structure and the principal components of the 13C shielding tensor in aromatic quinolines, Casabianca and de Dios114 have found an interesting correlation between the magnitude of the least shielded component of these tensors, s11, in 7-subsituted quinolines and their binding strength to heme. In examining the orientation of the principal axis system of 31P shielding in Pt(II)-phosphine complexes, it has been suggested that the tensor orientation is more likely to follow a pseudo plane defined by the P atom and the two other atoms attached to it rather than the directions of the bonds to the P atom.115 The 15N and 31P shielding tensors have been reported for the adduct between silver nitrate and triphenyl phosphine.116 Due to a relatively large quadrupolar coupling in asymmetric environments and low sensitivity, 39K solid state NMR spectroscopy is challenging. With the use of a quadrupolar Carr-Purcell Meiboom-Gill (QCPMG) method developed by Larsen et al.,117,118 Widdifield and Schurko119 have measured the solid state 39K NMR parameters in the polymeric cyclopentadienyl complex of potassium. The contribution of chemical shift anisotropy to the powder pattern of 39K NMR spectrum of polymeric potassium metallocenes is found to be insignificant. Theoretical calculations indicate a possible range of 9–63 ppm (170–1200 Hz in a 9.4 Tesla magnet) for the shielding tensor span, relatively small compared to the observed quadrupolar coupling constant of 2.6 MHz. Half-sandwich cyclopentadienyl complexes of niobium(I) and niobium(V) have been the subject of recent solid state 93Nb and 13 C NMR studies.120 The change in oxidation state of Nb from I to V leads to an appreciable increase (about 50 times) in the quadrupole coupling constant. The span of the 93Nb shielding tensor in CpNb(CO)4 is found experimentally to be 35 ppm, while B3LYP/6-311G**(16s10p7d on Nb) calculations predict a much larger value, 479 ppm. Similarly, calculations likewise overestimate the shielding tensor span in CpNbCl4, 468 ppm, to be compared with 150 ppm from experiment. In both cases, theory underestimates s11 and overestimates s33, leading to a much higher tensor span. Various lanthanum(III) coordination compounds have been examined by solid state 139La NMR spectroscopy and relativistic DFT calculations.121 In this set of compounds, the range of 139La quadrupolar coupling constants is found to be within 10–36 MHz, and the span of the 139La shielding tensor encompasses 50–260 ppm (3500–18600 Hz in an 11 Tesla magnet). The range of isotropic 139La NMR chemical shifts is about 250 ppm. In order to extract this information, accurate simulation of spectra obtained at two different fields, 11.75 and 17.60 Tesla) is critical. The shielding anisotropy contribution to the line shape is obviously smaller than that of the quadrupolar coupling, thus, requiring a second higher magnetic field measurement. An interesting trend seen in this set of lanthanum compounds is the observed correlation between the isotropic 139La NMR chemical shift and the coordination number around La. As the coordination number around Lanthanum increases, so does the shielding. Comparison between ZORA-DFT calculated shieldings and experimental 139La NMR chemical shifts yields a slope of 0.89 with an R2 of 0.89, indicating modest agreement between theory and experiment. A slope smaller than 1.0 was also found for 183W calculations (0.75) in another study.60,61 Similar to the 93Nb study, the 139La shielding tensor spans appear to be overestimated in the calculations. Using multiple magnetic fields (7.0, 9.4, 11.7, 14.1 and 17.6 Tesla), 139La shielding tensors have been measured for anhydrous lanthanum(III) halides.122 Referenced to a 1.0M LaCl3 (aq), the measured isotropic shifts in the anhydrous halides are: 135 ppm (LaF3), 305 ppm (LaCl3), 400 ppm (LaBr3), and 700 ppm (LaI3). The spans are likewise increasing with increasingly heavier halogen: 35 ppm (LaF3), 50 ppm (LaCl3), 100 ppm (LaBr3), and 650 ppm (LaI3). ZORA-DFT calculations agree qualitatively with these measured tensors. Titanium NMR presents a bigger challenge as two isotopes, 47Ti and 49Ti, both quadrupolar, share almost identical frequencies (45.102 and 45.112 MHz, respectively) even at 18.8 Tesla. By taking advantage of the difference in spin quantum number (I ¼ 5/2 for 47Ti and I ¼ 7/2 for 49Ti), pulse sequences can be employed to select a given 60 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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isotope.123 Applying this new experimental procedure, a small anisotropy (about 30 ppm) has been observed for the 49Ti shielding in the rutile form of titanium dioxide. The sensitivity of both shielding and quadrupolar coupling to symmetry enables the use of these NMR parameters in probing the geometries of transition metal complexes. In a solid state 95Mo NMR study by Forgeron and Wasylishen,124 dodecahedral (D2d) and square antiprismatic (D4d) geometries can be distinguished by examining both shielding and electric field gradient tensors. K4Mo(CN)8 2H2O, which exhibits approximate dodecahedral symmetry, provides a 95Mo shielding tensor span of about 1160 ppm. On the other hand, Tl4Mo(CN)8, which crystallizes in a square antiprismatic form, exhibits a span of about 1350 ppm. Lastly, a recent review and compilation of solid state NMR data of quadrupolar halogens; 35/37Cl, 79,81 Br and 127I, has been written by Bryce and Sward.125 2.2 Shielding surfaces and rovibrational averaging Huda´ky and Perczel have recently added histidine to the list of amino acid residues, whose 13C shielding surfaces have been theoretically constructed as a function of protein dihedral angles.126 In this latest work, a closer inspection of backbone 1H and 13C chemical shifts reveals the possibility of extracting additional detailed structural information, such as the position of the histidine residue in a helix or sheet region of a protein. It appears that the chemical shifts of residues near the ends of these secondary structures exhibit greater variation from the values predicted by the dihedral angles alone. The dependence of 13C chemical shifts on conformation has been examined in two aryltetralin lignan lactones, polygamain and morelensin.127 These two lactones differ from each other in terms of conformational rigidity, polygamain being the more rigid of the two. Morelensin owes its flexibility to the two methoxy groups (ortho to each other) bound to the aromatic ring. In polygamain, a five-membered di-ether ring replaces the two methoxy groups, which leads to a restricted geometry. A conformational search for both lactones yields 4 energy minima for polygamain and 12 for morelensin. Calculated chemical shifts weighted by a Boltzmann distribution over these minimum structures are shown to compare favorably with experiment. Proposed structures for the cucurbit[6]uril-sperminecomplex have been validated by 1H shielding calculations.128 Calculating NMR chemical shifts on structures suggested by conformational searches have been applied to elucidate the structure of the natural products jungianol and mutisianthol.129 Likewise, 13C NMR shielding calculations have found application in the conformational study of liquid crystalline polymers that contain an ester functional group in its mesogenic unit.130 In this work, the shielding of the carbonyl C is predicted to be affected by its conjugation with the phenyl ring ester and by the dihedral angle of the ring–ring linkage. A similar conformational analysis in combination with calculations of chemical shifts has been performed on N-substituted derivatives of piperidine and pyrrolidine.131 The conformers that lead to a better agreement between calculated and observed NMR chemical shifts reveal specific weak hydrogen bonding of the type C–H O. Another set of compounds in which 13C and 1H chemical shifts have been explored as a function of dihedral angles are the calix[n]arenes.132 The two dihedral angles in these systems define the conformation around the CH2 group that joins the two phenyl rings. These dihedral angles determine whether the two aromatic rings are syn- or anti- with respect to each other. Using a model structure that involves two p-methoxytoluene groups connected at C-3 by a single methylene, the two dihedral angles were systematically varied by 301 and chemical shifts were calculated at each conformation, producing a shielding surface of the two dihedral angles. With this surface, it is now possible to explain the chemical shifts observed for larger calixarenes that exhibit unusual orientation of two adjacent aromatic rings. An interesting 1H shielding surface has been calculated for the reaction coordinate that involves a proton transfer from His57 to Asp102 in serine protease trypsin.133 This shielding surface shows Nucl. Magn. Reson., 2007, 36, 50–71 | 61 This journal is

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maximum deshielding for the 1H nucleus when the proton is near the midway point between the two residues. These results are similar to the 1H shielding surfaces constructed for the proton-exchange pathway in porphyrin and porphycene.134 In addition to 1H shielding, 15N shielding surfaces are likewise calculated for porphyrin and porphycene, but in contrast to 1H, the 15N shielding is monotonic, with the N losing the proton becoming deshielded, while the N gaining the proton becoming shielded with the proton transfer. 2.3 Isotope shifts Secondary isotope effects on NMR chemical shifts are due to slight differences in the rovibrationally averaged geometry. These effects on shielding generally diminish as one goes farther from the site of isotopic substitution. Hence, in the Schiff bases of gossypol the significant deuterium-induced isotope effects observed for the 13C shielding (about 0.34 ppm) of the carbon directly attached to an N atom indicate that these Schiff bases of gossipol are mostly enamines, the form that contains an exchangeable proton on the nitrogen.135 Similarly, from deuterium-induced isotope shifts, it is likewise suggested that the proton transferred N–H form is the dominant species in lithium salts of amino acid-derivatized Schiff bases.136 Long-range deuterium isotope effects (in the range 0.036 to 0.106 ppm) on a 13C site that resides five single bonds away from the site of deuteration have been observed for a series of thioanilides.137 In these compounds, the hydrogen replaced by deuterium is participating in an intramolecular hydrogen bond. Deuterium isotope effects in systems involving intramolecular hydrogen bonds have found application in characterizing b-diketones.138 It is a common assumption that differences in observed secondary isotope effects on two carbonyl carbons at various temperatures can be used to assess if one is dealing with a single-well or a double-well potential surface for the intramolecular hydrogen bond in these systems. As yet, this has not been rigorously demonstrated. Three factors have been suggested as responsible for the variations observed in deuterium isotope effects on 13C NMR chemical shifts in o-hydroxy Schiff bases,139 namely the nature of the substituents on the aromatic ring, the substituent on the enamine carbon, and whether the nitrogen atom is bound to an aromatic or aliphatic group. Finally, recent 1H, 13C and 19F NMR measurements on CHF3 in the gas phase have yielded the following secondary isotope effects: 1 19 D F(13/12C) ¼ 0.126 ppm and 2D19F(2/1H) ¼ 0.812 ppm.140 These values are in the limit of zero density at 300 K. 2.4 Intermolecular effects on nuclear shielding A recent review on the effects of non-covalent interactions on NMR parameters has been made available.141 Included in this review is a survey of quantum chemical methods as well as supermolecule and molecular dynamics approaches for calculating solvent effects on nuclear shielding. Oldfield142 presents a review on electrostatic effects on NMR parameters and discusses how recent developments in the field can be used to explore various aspects of protein structures and electrostatic properties. For intermolecular effects on NMR shielding, 129Xe NMR spectroscopy continues to be an area of active research. Vukovic et al.143 have performed the first calculation of the intermolecular shielding of a Xe atom in the presence of a paramagnetic species, an O2 molecule. In contrast to diamagnetic linear molecules such as CO and N2, interaction with O2 leads to extrema at y ¼ 451 and 1351 (where y is the angle that Xe, the center of mass of O2 and one of the O atoms make). The explanation provided for this behavior is drawn from the fact that the spin density comes mainly from the antibonding p orbital of O2, which consists of a nodal plane passing through the center of the O2 molecule. Therefore, the greatest interaction between Xe and the spin density of O2 occurs at the orientations, y ¼ 451 and 1351. With 62 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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diamagnetic systems, 129Xe maintains its role as an important probe in characterizing porous materials. Shape-persistent macrocyles are among the porous materials that can be studied with 129Xe nuclei as probes, and with hyperpolarized 129Xe, a quick and sensitive characterization of the porosity in these materials has become possible.144 Ooms et al.,145 for example, have used 129Xe NMR spectroscopy in investigating potentially porous organic macrocyclic materials. The specific systems examined in this recent study consist of ordered solid materials derived from conjugated pyridine-containing macrocycles. Several resonances are observed for Xe in these materials. A broad peak near 190 ppm (referenced from the gas peak of 7 Torr of Xe in 7 Torr of N2 and 686 Torr of He) is assigned to Xe atoms occupying sites near the end of the channel, thereby interacting more with phenyl groups of the macrocycle. This interaction is supposed to lead to greater deshielding of the 129Xe nucleus. A peak observed near 130 ppm is assigned to Xe atoms inside the cavity site, which is less confined compared to the end of the channels. Changing the pyridine into a phenyl group in these macrocycles leads to a greater deshielding of the peak near 130 ppm. This difference is explained by a comparison between ab initio calculations performed on a Xe atom interacting with benzene and with pyridine. The differences in chemical shifts observed are in the same direction as those predicted by the model calculations, in which a C–H (in benzene) causes greater deshielding of Xe than an N (in pyridine) atom does. However, calculations of Xe shieldings at particular locations next to the model fragment cannot be used to compare with experiments; averaging over all Xe positions in a grand canonical scheme is necessary. Sears et al.146 have extended the use of hyperpolarized 129Xe NMR spectroscopy to monitoring the formation of microporous AlPO4-5 and AlPO4-18. By following the changes in the 129Xe NMR chemical shifts, one is able to see that beginning with an amorphous phase, AlPO4-5 is first formed, which is then converted to AlPO4-18. 129Xe inside AlPO4-5 has a chemical shift of 63 ppm (referenced to Xe gas at zero density), while those inside AlPO4-18 have a chemical shift of 74 ppm. A combination of grand canonical Monte Carlo (GCMC) simulations and 129Xe shielding surfaces has also been successfully applied to Xe atoms adsorbed in nanochannels of ionic crystals of ()-[Co(en)3]Cl3.147 In this particular case, the calculated span for an axially symmetric 129Xe shielding tensor is 105 ppm, in close agreement to the observed value of 100 ppm. In this example, Xe in the channels did not exhibit the expected changes in line shape with increasing Xe occupancy. GCMC simulations revealed that Xe–Xe contributions are minimal in these channels since Xe singly occupy cell-like pores rather than uniform-diameter channels.147 Telkki et al. in a series of studies148–150 have illustrated the use of variable temperature 129Xe NMR spectroscopy in determining and characterizing pore sizes and volumes in controlled pore glasses. Work on optimizing Xe biosensors for detecting protein interactions continues.151 The new biosensors consist of a Xe-binding cryptophane-A cage, a short peptide to make the sensor water-soluble, and a moiety that specifically binds to a target protein molecule. In this study, a biotinylated sensor is used and the target protein is avidin. The spacing between biotin and the crytophane-A cage can be controlled by a linker, whose length plays a significant role in the line width of the observed 129Xe resonance. Furthermore, the dependence of the Xe chemical shift upon binding on the linker length is totally consistent with the sensing mechanism via mechanical cage deformation proposed earlier.152 The study shows that a flexible linker of moderate length (about 12–30 bonds) leads to reasonably narrow lines in the 129Xe spectrum, thus, increasing its signal-to-noise ratio and sensitivity. Hilty et al.153 have demonstrated that such biotinylated Xe biosensors could also be used for magnetic resonance imaging. Lastly, due to the sensitivity of 129Xe NMR chemical shifts to the environment, an NMR thermometer based on 129Xe NMR spectroscopy has been proposed.154 Gas phase NMR measurements enable the extrapolation of measured resonances to zero density, thereby providing the chemical shifts for an isolated molecule. In Nucl. Magn. Reson., 2007, 36, 50–71 | 63 This journal is

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addition to specific studies on the molecule sevoflurane ((2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether)155 and benzene,156 Jackowski157 has recently compiled NMR chemical shifts for a variety of gas phase molecules, extrapolated to the isolated molecule limit. This recent work also includes the gas phase density dependence of the NMR parameters. Since hydrogen bonding plays an important role in a wide array of systems, the study of its effects on NMR chemical shifts remains a vigorous area of research. For instance, one can take advantage of the effects of hydrogen bonding on chemical shifts to discriminate between water molecules in hydrophilic and hydrophobic environments in bone tissue.158 By closely deciphering the observed 1H and 13C chemical shifts in anomeric maltose, Yates et al.159 have found a quantitative correlation between the NMR chemical shifts and the geometry (distance and angle) of weak CH O hydrogen bonds. In a recent work on crystalline uracil, Ida et al.160 have determined that 17O NMR shielding tensors are more difficult to reproduce theoretically when the O site is involved in weak CH O hydrogen bonding as opposed to the stronger NH O arrangement. A similar situation is apparent with the electric field gradient tensors. This difficulty is attributed to the uncertainty in the hydrogen atom positions and it appears that partial geometry optimizations of cluster models derived from X-ray structures are necessary. This part of the computational protocol has been in use for some time in many other hydrogenbonded systems, as reported in this series of volumes. A comparison between CH O and NH O hydrogen bonds and their effects on 1H NMR chemical shifts in monohydrated 2,4-dithiothymine has been reported by He et al.161 Focusing on typical hydrogen bonds, OH O, Wong et al.162 have used 17O NMR spectroscopy to characterize hydrogen bonds in carboxylic solids. Their findings indicate that the 17 O nucleus in O–H becomes deshielded with shorter hydrogen bond distances while that of CQO becomes shielded. Balandina et al.163 have used model hydrogenbonded dimer structures to reproduce the observed 1H, 13C and 15N NMR chemical shifts in functionalized derivatives of quinoxalines. 1H and 13C NMR chemical shifts, as expected, are also useful in determining which tautomeric form is dominant in N-substituted acridin-9-amines.164 13C NMR shielding tensors have been utilized to characterize the hydrogen bonded structures of amino acids that have been crystallized in the presence of inorganic acids.165 This recent work suggests that the observed and calculated 13C shielding principal components (mainly the difference between s11 and s22) could be used to distinguish between four different types of interactions possible for amino acid—inorganic acid complexes. These four categories are: (1) the amino acid is formally a carboxylate, COO H–X, (2) the proton is localized at the carboxylate, COOH X, (3) the proton resides at the central region, and (4) there is a low barrier hydrogen bond with disordered proton positions. Similar work has been done on 2-amino-pyridine betaine166 and 3-(2amino-pyridinium)-proprionate monohydrate.167 Kolehmainen et al.168 have incorporated explicit acetone molecules in their calculation of 13C chemical shifts in polychlorinated biphenyl (PCB)-derived carboxylic acids. This model provides one acetone molecule as a hydrogen bonding partner for each proton in the PCB-derived carboxylic acid molecule. It has been known for some time that a cluster that includes all surrounding hydrogen bond partners are necessary to provide calculated NMR chemical shifts that agree with experiment. A recent example is the calculation of 13C chemical shifts observed for the imidazole carbon sites in various histidinecontaining dipeptides.169 Instead of using molecular clusters to calculate shielding tensors in solids and extended networks, one could use the method devised by F. Mauri et al.170 To reproduce the 13C, 14N, 15N, and 17O shielding tensors in amino acids, Gervais et al.,171 have employed the plane-wave pseudopotential approach in the solid state. The results are satisfactory even for the sites that participate in hydrogen bonding. The number of hydrogen bonds is particularly important in interpreting the quadrupolar coupling constants as well as the shielding tensors for Cl ions172 in various amino acid—HCl salts. 31P NMR chemical shift tensors have 64 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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been measured and calculated for hypervalent oxyphosphoranes and polymeric orthophosphates.173 Based on the computational portion of this work, solvents effects on 31P shieldings in pentaoxyphosphoranes are found to be very small (o0.5 ppm). Proton NMR shielding computations have been performed on the hydrogen molecule to see if its chemical shift would be able to distinguish between small and large cages in structure II clathrates.174 The results suggest that the difference is in the order of 0.1 to 0.2 ppm. Alkali metal-reduced mesoporous titanium oxides have been examined by solid state 23Na and 7Li NMR spectroscopy.175 The chemical shifts and line widths of the observed resonances provide information regarding the reduction level of these materials. Other alkali nuclei (39K and 87Rb) have been used to characterize Gquadruplex structures.176,177 The effects of Mg21 coordination to the NMR shielding tensors of nuclei in nucleotides have been calculated.178,179 195Pt NMR shielding calculations are found to be challenging not only because of the large basis set, relativistic and electron correlation requirements, but also solvent effects.180 As in other nuclei, the solvent can affect the chemical shift via two ways, perturbing the electronic structure of the solute and/or altering its geometry. A lighter nucleus, 59 Co, poses similar challenges. The electronic structure of the transition metal complex depends on the metal ligand distance (which changes with temperature). This has been known from the early days of crystal field and ligand field theory. Neither this nor the abovementioned 195Pt study includes these vibrational-electronic effects. Rovibrational corrections bring calculated 59Co shieldings closer to experiment but not when the data were obtained in aqueous solution.181 In these calculations the mean absolute deviations between theory and experiment is in the order of 500–760 ppm, to be compared with the observed chemical shifts range of almost 20 000 ppm. 93Nb NMR spectra of a series of inorganic niobates have been reported.182 In this set of niobates, the isotropic 93Nb NMR chemical shift offers clues with regard to the coordination number around Nb. An accompanying increase in 93Nb shielding is observed with increasing number of O atoms bound to Nb. Ring-current effects in porphyrins have been explored by several studies during this reporting period. First, Steiner et al.183 have demonstrated through an ipsocentric-orbital based model that the central charge in metalloporphyrins changes the pathway of global p currents. Starting with a neutral cation (Z ¼ 0), the global p current takes an inner pathway, and as the charge at the center becomes more positive (Z ¼ 2), the current becomes bifurcated, and with Z ¼ 4, the current already takes an outer path. The same model has been applied to visualize the ring currents in an extended porphyrin, amethyrin.184 In this expanded porphyrin, the internal NH protons are deshielded while the bridge CH protons are shielded, suggesting the presence of a global paratropic ring current. The recent work shows that indeed there is a dominant paratropic current concentrated on the inner 20-site cycle, but there is also a weaker diatropic circulation on the outer 24-site pathway plus a combination of local 5-site diatropic current on the six pyrollic rings. By fusing 10 pentagons around a central decagon, as in [5,10]-coronene (C30H10), it has been demonstrated via an ipsocentric ab initio mapping of currents that this molecule can support diatropic currents on the inner part (hub) and paratropic currents on the outer pathway (rim).185 Calculated magnetic field-induced current densities have also been used to verify the aromaticity or anti-aromaticity in heteropentalenes formed by two phosphole units,186 and in fullerenes and other curved carbon networks.187 Soncini et al.188 have verified the independence in choice of gauge origin of the continuous transformation of the origin of the current density (CTOCD) method. The paramagnetic zero (PZ2) variant of CTOCD has been used to characterize the magnetic and electronic properties of dicyclopenta-fused pyrene congeners.189 Sebastiani 190 has developed a current density calculation based on a pseudo-potential plane-wave approach. This method is then applied to current density and NICS calculations in the solid state. Examples of systems in which a Nucl. Magn. Reson., 2007, 36, 50–71 | 65 This journal is

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successful plane-wave current density calculation has been implemented are calixhydroquinone, graphite and various types of carbon nanotubes. The gauge-including projector augmented-wave (GIPAW) approach has also been used successfully to explain the observed 13C solid state NMR spectra of carbon nanotubes.191 Static and magic-angle spinning 13C NMR spectra have been measured for carbon nanohorn aggregates.192 Two distinct resonances are observed. The first one, with an isotropic shift of 124 ppm, has a short longitudinal relaxation time, and is assigned to the nanotubelike horns on the surface of the particles. The second peak is around 116 ppm and exhibits a longer relaxation time, and is assigned to the graphite-like regions of the aggregate. Visualizing ring currents is more reliable than the use of isotropic NMR chemical shifts in gauging whether a system is aromatic or anti-aromatic. In the absence of induced ring current pictures, as Faglioni et al.193 have demonstrated on unsaturated polycyclic compounds, the out-of-plane component of the shielding tensor is a more reliable measure of aromaticity, compared to nucleus-independent chemical shifts (NICS). NICS being average isotropic quantities, provide less complete information about the effects of ring currents compared to current density maps. Still, NICS do offer a qualitative indication of the presence of ring currents. For example, four porphyrin groups have been made to fuse, forming a planar cyclooctatetraene core.194 This compound, as characterized by NICS calculations, is shown to exhibit strong paratropic shifts around the cyclooctatetraene core and weak diatropic shifts inside each of the porphyrin cores. NICS are likewise useful for predicting intermolecular effects on NMR chemical shifts that arise from nearby aromatic rings. Facelli195 has constructed a three dimensional grid above the molecular plane of systems like benzene, naphthalene and coronene. The NICS evaluated at these grid points are then fitted to a dipolar type function ((1–3 cos2y)/r3). The computation of NICS has also been utilized in characterizing dimer structures of quinolinebased antimalarial drugs.196 Murata et al.197 have managed to encapsulate a hydrogen molecule inside the fullerene C60. The synthesis involves a 4-step closure of a 13-membered ring opening. The 1H NMR chemical shift of the encapsulated hydrogen molecule is measured for each of the intermediates. A gradual downfield shift is observed as the fullerene cage is closed. The calculated NICS agree qualitatively with this experimental trend. In the case of N-phenyl amino-substituted thio(seleno) acrylamides, in addition to the ring current effects from the phenyl substituent, the anisotropic effects of either CQS or CQSe are equally important in differentiating conformers.198 Lastly, 1H nuclear magnetic shielding tensors have been carefully measured for the biphenyl molecule.199 In this recent work, assignment is obtained by utilizing semiempirical and quantum chemical calculations of intermolecular shielding contributions. These contributions are then subtracted from the measured tensors to extract the shielding components for the isolated molecule. The correctness of the calculations is gauged by evaluating how well the resulting tensors obey the molecular symmetry relations. Expressed in icosahedral tensor representation, the error is found to be under 0.5 ppm. It has been suggested that more accurate values of nuclear magnetic dipole moments may be obtained from measurements of resonance frequencies in the same sample containing a very dilute gas consisting of molecules having two or more NMR-active nuclei. The frequencies can be extrapolated to zero density to eliminate intermolecular effects. The ratios of experimental frequencies and accurate calculations of the isotropic shielding for the two nuclei permit the ratio of magnetic dipole moments to be checked for accuracy.200

2.5 Absolute shielding scales There are no papers in this area in this reporting period. 66 | Nucl. Magn. Reson., 2007, 36, 50–71 This journal is

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146 D. N. Sears, B. A. Demko, K. J. Ooms, R. E. Wasylishen and Y. N. Huang, Chem. Mat., 2005, 17, 5481. 147 D. N. Sears, R. E. Wasylishen and T. Ueda, J. Phys. Chem. B., 2006, 110, 11120. 148 V. V. Telkki, J. Lounila and J. Jokisaari, Phys. Chem. Chem. Phys., 2006, 8, 2072. 149 V. V. Telkki, J. Lounila and J. Jokisaari, J. Chem. Phys., 2006, 124, 034711. 150 V. V. Telkki, J. Lounila and J. Jokisaari, J. Phys. Chem. B, 2005, 109, 24343. 151 T. J. Lowery, S. Garcia, L. Chavez, E. J. Ruiz, T. Wu, T. Brotin, J. P. Dutasta, D. S. King, P. G. Schultz, A. Pines and D. E. Wemmer, Chembiochem, 2006, 7, 65. 152 D. N. Sears and C. J. Jameson, J. Chem. Phys., 2003, 119, 12231. 153 C. Hilty, T. J. Lowery, D. E. Wemmer and A. Pines, Angew. Chem. Intl. Ed., 2006, 45, 70. 154 J. Saunavaara and J. Jokisaari, J. Magn. Reson., 2006, 180, 58. 155 E. Maciega, W. Makulski, K. Jackowski and B. Blicharska, J. Mol. Struct., 2006, 785, 139. 156 K. Jackowski, E. Maciaga and M. Wilczek, J. Mol. Struct., 2005, 744, 101. 157 K. Jackowski, J. Mol. Struct., 2006, 786, 215. 158 V. V. Turov, V. M. Gun’ko, V. I. Zarko, R. Leboda, M. Jablonski, M. Gorzelak and E. Jagiello-Wojtowicz, Coll. Surf. B, 2006, 48, 167. 159 J. R. Yates, T. N. Pham, C. J. Pickard, F. Mauri, A. M. Amado, A. M. Gil and S. P. Brown, J. Am. Chem. Soc., 2005, 127, 10216. 160 R. Ida, M. De Clerk and G. Wu, J. Phys. Chem. A, 2006, 110, 1065. 161 W. D. He, Y. Xue, H. Zhang, A. M. Tian and N. B. Wong, J. Phys. Chem. B, 2006, 110, 1416. 162 A. Wong, K. J. Pike, R. Jenkins, G. J. Clarkson, T. Anupold, A. P. Howes, D. H. G. Crout, A. Samoson, R. Dupree and M. E. Smith, J. Phys. Chem. A, 2006, 110, 1824. 163 A. Balandina, A. Kalinin, V. Mamedov, B. Figadere and S. Latypov, Magn. Reson. Chem., 2005, 43, 816. 164 Y. Ebead, A. Wroblewska, K. Krzyminski, J. Rak and J. Blazejowski, J. Phys. Org. Chem., 2005, 18, 870. 165 M. Ilczyszyn, D. Godzisz, M. M. Ilczyszyn and K. Mierzwicki, Chem. Phys., 2006, 323, 231. 166 M. Szafran, I. Kowalczyk and J. Koput, J. Mol. Struct., 2005, 754, 85. 167 M. Szafran, I. Kowalczyk and A. Katrusiak, J. Mol. Struct., 2006, 786, 25. 168 E. Kolehmainen, K. Tuppurainen, S. A. Lanina, E. Sievanen, K. Laihia, V. P. Boyarskiy, V. A. Nikiforov and T. E. Zhesko, Chemosphere, 2006, 62, 368. 169 F. Cheng, H. H. Sun, Y. Zhang, D. Mukkamala and E. Oldfield, J. Am. Chem. Soc., 2005, 127, 12544. 170 F. Mauri, B. G. Pfrommer and S. G. Louie, Phys. Rev. Lett., 1996, 77, 5300. 171 C. Gervais, R. Dupree, K. J. Pike, C. Bonhomme, M. Profeta, C. J. Pickard and F. Mauri, J. Phys. Chem. A, 2005, 109, 6960. 172 D. L. Bryce, G. D. Sward and S. Adiga, J. Am. Chem. Soc., 2006, 128, 2121. 173 Y. Zhang and E. Oldfield, J. Phys. Chem. B, 2006, 110, 579. 174 S. Alavi, J. A. Ripmeester and D. D. Klug, J. Chem. Phys., 2005, 123, 051107. 175 A. Y. H. Lo, R. W. Schurko, M. Vettraino, B. O. Skadtchenko, M. Trudeau and D. M. Antonelli, Inorg. Chem., 2006, 45, 1828. 176 A. Wong, R. Ida and G. Wu, Biochem. Biophys. Res. Commun., 2005, 337, 363. 177 R. Ida and G. Wu, Chem. Commun., 2005, 4294. 178 M. Monajjemi, M. A. S. Sajadi, R. Sayadia, M. Kia and G. Ghasemi, Main Group Metal Chem., 2005, 28, 71. 179 M. Monajjemi, R. Sayyadia, G. Ghasemi, K. Lalateh, A. Nouria and F. Naderi, Main Group Metal Chem., 2005, 28, 247. 180 M. Sterzel and J. Autschbach, Inorg. Chem., 2006, 45, 3316. 181 S. Grigoleit and M. Buhl, J. Chem. Theory Comput., 2005, 1, 181. 182 O. B. Lapina, D. F. Khabibulin, K. V. Romanenko, Z. H. Gan, M. G. Zuev, V. N. Krasil’nikov and V. E. Fedorov, Solid State Nucl. Magn. Reson., 2005, 28, 204. 183 E. Steiner, A. Soncini and P. W. Fowler, Org. Biomol. Chem., 2005, 3, 4053. 184 E. Steiner and P. W. Fowler, Org. Biomol. Chem., 2006, 4, 2473. 185 G. Monaco, R. G. Viglione, R. Zanasi and P. W. Fowler, J. Phys. Chem. A, 2006, 110, 7447. 186 I. G. Cuesta, A. M. J. S. De Meras and P. Lazzeretti, J. Comput. Chem., 2006, 27, 344. 187 A. Soncini, R. G. Viglione, R. Zanasi, P. W. Fowler and L. W. Jenneskens, Compt. Rend. Chim., 2006, 9, 1085. 188 A. Soncini, P. Lazzeretti and R. Zanasi, Chem. Phys. Lett., 2006, 421, 21. 189 M. J. Otero-Lobato, C. A. van Walree, R. W. A. Havenith, L. W. Jenneskens, P. W. Fowler and E. Steiner, Tetrahedron, 2006, 62, 5510. 190 D. Sebastiani, Chemphyschem, 2006, 7, 164.


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Applications of nuclear shielding Shigeki Kuroki,a Naoki Asakawab and Hidekazu Yasunagac DOI: 10.1039/b601639c

1. Introduction The report covers and introduces studies on the application of nuclear shielding and related NMR chemical shifts, which were made in the world from 1 June 2005 to 31 May 2006. The shieldings of particular nuclear species are described in the following section according to their position in the periodic table. Although there is a great number of articles on NMR spectroscopy during the period of this review, the coverage of this chapter is restricted to widely available and common journals, which are published in English as a general rule, due to space limitation. The report also introduces a couple of topics, which should have been mentioned in the volume 35 of this book.

2. Shielding of particular nuclear species The NMR experiments for most elements contained in molecules were made in the course of physical, chemical or biological studies during the period covered by the report. The simple chemical structure determination and related studies of synthesised and natural products are excluded in the report, and the review articles are given as necessity requires. 2.1 Group 1 (1H, 2H, 3H,

6,7

Li,

23

Na,

39

K,

87

Rb,

133

Cs)

2.1.1 Hydrogen (1H) (I =1/2). The proton shielding tensors for a spherical crystal of biphenyl compound were determined by using line-narrowing multiple pulse techniques.1 The assignment of the measured tensors to the corresponding proton sites was given and intermolecular shielding contributions were calculated. The isolated-molecular shielding tensors obtained from experiments and calculated intermolecular contributions were compared with isolated-molecular quantum chemical results. It was found that the least shielded direction of all protons is the perpendicular to the molecular plane for the compound. Solution-state 1H and 13C NMR spectroscopy and density functional theory quantum mechanic conformational modeling were combined with solid-state cross-polarization/magic angle spinning (CP/MAS) 13C NMR spectroscopy for the research of cis-cyclooctene and cis-cyclononene medium ring stereochemistry.2 The theoretical possibility of stereochemically labeled chiral medium rings having diastereomeric conformational subtypes was shown to exist in practice for some of the 2,5-benzoxazocine and 2,6benzoxazonine skeletons. The structure of 3-hydroxy-3-methyl-pyrido [2,1-c][1,4]dihydrooxazinium chloride and 3-hydroxy-3-phenyl-pyrido[2,1-c][1,4] dihydrooxazinium bromide was determined by using 1H and 13C NMR spectroscopy.3,4 Correlations between the experimental 1H and 13C NMR chemical shifts and the GIAO/B3LYP/6-31G(d, p) calculated magnetic isotropic shielding tensors were a

Tokyo Institute of Technology, Department of Chemistry and Materials Science, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8552, Japan. E-mail: [email protected]; Tel: +81-3-5734-2880 b Tokyo Institute of Technology, Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, 4259 Nagatsuda, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan. E-mail: [email protected]; Tel: +81-45-924-5796 c Kyoto Institute of Technology, Department of Chemistry & Materials Technology, Kyoto Sakyo-ku Matugasaki Gosyokaido-tyo, 606-8585, Japan. E-mail: [email protected]; Tel: +81-75-724-7562


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reported. A good linear relationship between the experimental and calculated data for carbons was obtained. The interaction between Rh or Pt and H–C or H–N was investigated.5 There are large downfield 1H NMR chemical shift changes on metal bonding, accompanied by changes in shielding tensor orientations. The NMR signal assignments for (di-)cyclopenta-fused pyrene congeners, cyclopenta[cd]-, dicyclopenta[cd, fg]-, dicyclopenta[cd, jk]- and dicyclopenta[cd, mn]pyrene were achieved using two-dimensional (2D) NMR spectroscopy.6 Substituent-induced chemical shifts in the pyrene core induced by annelation of cyclopenta moieties were discussed and effects of dicyclopenta topology on electronic structure were illustrated. The comparative study of the calculated ab initio 17O and 1H shielding constants for hypothetical water clusters (H2O) n (n = 2 – 6, 12 and 17) was reported.The densityfunctional theory (DFT)(B3LYP)/aug-cc-pCVDZ calculations of shielding constants were performed for all clusters and the correlation of the changes in the 1H shielding constants on intra- and intermolecular distances was observed.7 The NMR-shielding of cucurbit[5]uril, decamethylcucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril and cucurbit[8]uril were studied by DFT calculations.8 All the molecules were found to be highly symmetric with a distinct geometric flexibility and their chemical complex building ability was discussed. The authors also reported the NMR-shielding of cucurbit[6]uril-spermine host-ligand complexes investigated by DFT calculations and measurements.9 Cucurbit[6]uril and spermine can form complexes with two different minimum energy geometries having a perfect inversion symmetry and they show corresponding characteristic differences in NMR shielding. The conformational properties of the aldol adducts of some N4-isopropyl-oxadiazinones were studied by 1H NMR spectroscopy and the shielding aspect observed clearly suggested the presence of the anti-parallel arrangement.10 It was found that solution state conformation of the N4-Me and N4-isopropyl-oxadiazinones involves anti-parallel carbonyls in contrast to the solid state evidence of the X-ray crystallographic data of oxadiazinone. Three Rh phosphinite complexes with the general structural formula [RhCl(i-Pr2POXy)(L)]2 (Xy = 2, 3-xylyl; L = PPh3, PMe3, t-BuNC) were synthesised and characterised.11 The 1H NMR chemical shielding calculations on a geometry-optimized model complex were used for assignments. The effectiveness of a calix[4]resorcarene prepared from N-methyl-L-alanine as a chiral NMR discriminating agent was studied comparing to the L-prolinylmethyl derivative.12 Aromatic resonances of the substrates show substantial upfield shifts because of shielding from the aromatic rings of the calix[4]resorcarene. The several resonances in the 1H NMR spectra exhibit enantiomeric discrimination. The extent of enantiomeric discrimination depends on interactions of the substituent groups of the substrates with the prolinylmethyl groups of the calix[4]resorcarene. The NMR spectra of the Diels-Alder adducts from 3,6-dibromophencyclone reacted with Nethylmaleimide, N-n-propylmaleimide and N-n-butylmaleimide were studied by 1H and 13C NMR and rigorous assignments for protonated carbons were obtained with the heteronuclear chemical shift correlation spectra (HETCOR).13 Endo Diels-Alder adduct stereochemistry was supported by substantial magnetic anisotropic shielding effects in the 1H NMR spectra of the alkyl groups. Alkyl proton NMR shielding magnitudes in the adducts were evaluated and the relation between the adduct geometries and the observed shielding magnitudes was derived by using ab initio Hartree-Fock level calculations. The adducts obtained from phencyclone and Nalkylmaleimides were studied by 1H and 13C NMR and substantial magnetic anisotropic shielding effects in the 1H spectra of the N-alkyl groups of the adducts were revealed.14 Magnetic anisotropic shielding magnitudes for alkyl group protons in the adducts were calculated relative to corresponding proton chemical shifts in the maleimides. The existence of different contributing conformers for the adducts was discussed with respect to implications regarding experimental observed anisotropic shielding magnitudes and their calculated energies. The charges on methyl-4acetoxybenzothiophene-6-carboxylate and 4-hydroxybenzothiophene-6-carboxylic acid were calculated by the parametric quantum mechanic molecular model AM1 Nucl. Magn. Reson., 2007, 36, 72–112 | 73 This journal is

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and PM3 and were correlated with 1H NMR chemical shifts.15 Thermodynamic functions (heats of formation, enthalpy and entropy) of these molecules were calculated in the temperature range 100–1000 K. It was shown that the difference in the 1H NMR chemical shift of a protic hydrogen in DMSO and CDCl3 solvents is directly related to the overall hydrogen bond acidity for a wide range of solutes.16 The NMR method allows the determination of the Abraham solute hydrogen bond acidity parameter for individual protic hydrogens in multifunctional solutes. The behaviour of water at mosaic hydrophilic/hydrophobic surfaces of different silicas and in biosystems was studied in different dispersion media over wide temperature range using 1H NMR spectroscopy.17 It was found that there are weakly associated interfacial water (1H NMR chemical shift delta(H) = 1.1–1.7 ppm), strongly associated interfacial water (delta(H) = 4–5 ppm) and continuous interfacial layer. Hydrogen-bonding effects in the real crystalline structure of 9-methyladenine were studied using calculated electric field gradient (EFG) and chemical shielding (CS) tensors for 1H, 2H, 14N and 15N via density functional theory.18 The chemical shielding anisotropy (Ds) and chemical shielding isotropy (s iso) were also reported for 1H and 15N. The results indicated that N(10) (imino nitrogen) has a major role in H-bonding interactions, whereas that of N(9) is negligible. 1H NMR shielding constants and chemical shifts for hydrogen guests in the cages of structure II clathrates were calculated using density functional theory and the gauge-invariant atomic-orbital method.19 The calculated chemical shifts of single hydrogen molecules in the small and large structure II cages are 4.94 and 4.84 ppm, respectively. Multiple occupancy of the guests in the cage changes the chemical shift of the guests by approximately 0.2 ppm. Porphyrin and porphycene was studied using DFT for both the spin–spin coupling constants and the shielding constants paying attention to their changes during the process of proton exchange.20 The calculated nuclear spin–spin coupling constants and shielding constants were analyzed as functions of the progress of the proton transfer between two nitrogen atoms. The isotropic shielding constant shows a strong deshielding of the nitrogen nuclei when the proton migrates away by the exchanging. It can be said that both the isotropic shielding of the exchanged protons and the shielding anisotropy exhibit a minimum close to the transition states. The presence of intermolecular hydrogen bonds between the adducts of formula [N(CH2CH2)3N]–H–[OOC(CH2)nCOOH] (n = 1–7) was studied by 1H MAS and 15 N CP/MAS spectroscopy.21 Correlations among isotropic 1H and 15N chemical shift data and the N–O distances of the atoms involved in the hydrogen bond interaction were found for the adducts. Density functional theory was applied to explore changes upon hydrogen bonding in the 1H and 15N shielding parameters and it was also found that the calculated values agree with the experimental value. Hydrogen/deuterium isotope effects on the 15N NMR chemical shifts were also investigated. 2.1.2 Deuterium (2H) (I = 1). The 2H–15N and 2H–1H NMR chemical-shift correlations and distance measurements were made for cytosine monohydrate, whose acidic protons can readily be replaced by deuterons by recrystallisation from D2O.22 The 2H NMR spectroscopy provides information complementary to 1H NMR data and can be performed in full analogy to 1H spectroscopy in solid-state NMR, when the NMR experiments are conducted in a ‘‘rotor-synchronized’’ fashion under fast MAS. 2H and 13C MAS correlation experiments were made for a uniformly 2H, 13C and 15N labeled Nac-Val and 2H and 15N labeled dipeptide NacVal-Leu-OH.23 The experiments involve the measurement of the 2H tensor parameters by evolution of the 2H chemical shift. A novel two-dimensional 2H NMR technique was introduced for determination of both quadrupole and chemical/ paramagnetic shift tensors and their relative orientation.24 The properties of the novel technique were demonstrated using computer simulation. The technique was 74 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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applied to benzoic acid-d1 (C6H5CO2D) and copper(II) chloride dihydrate-d4 (CuCl2 2D2O). Hydrogen-bonding effects in the real crystalline structure of 9methyladenine were studied using calculated EFG and CS tensors for 1H, 2H, 14N and 15N via density functional theory as described in 2.1.1 Hydrogen.18 2H NMR was examined in order to determine 1H chemical shifts in solids.25 It was shown that the sensitivity can be enhanced by applying 1H to 2H cross polarization and by adding spinning-sideband spectra, then 2H natural-abundance MAS spectra revealing highly resolved 2H signals can be obtained. The second-order quadrupole effects of 2H were also studied. 2.1.3 Tritium (3H) (I =1/2). The structure of complex 3H-labeled molecules was understood by complete assignment of their 1H and 3H solution-state NMR spectra with the aide of the detection of heteronuclear chemical shift correlations between 1 H and 3H nuclei.26 Heteronuclear correlation (HETCOR) experiments were demonstrated for 1H–3H systems and 2nd HETCOR experiment using the heteronuclear Overhauser effect to obtain through-space correlations between nearby nuclei was also made. The experiments were used to analyze 3H incorporation in sub-milligram quantities of 3H-labeled pharmaceutical derivatives. The (N-CHDT)(a)-isosparteinium ditosylamide >I N-(SO2C6H4Me-4)2] was studied by 3H NMR spectroscopy to assign the configuration of an intact stereogenic Me group.27 It was found that the S-CHDT group has a 3H chemical shift that is 49 ppb downfield of the R-CHDT resonance. The sign and magnitude of this chemical shift difference of these diastereotopic tritium nuclei were found to be in agreement with predictions obtained by ab initio calculations. 2.1.4 Lithium (6,7Li) (I = 1, 3/2). High-resolution solid-state 7Li NMR was used to characterize the structure and dynamics of lithium ion transport in monoclinic Li3V2(PO4)3 and three resonances were clearly resolved and assigned to the three kinds of crystallographic sites.28 The Li[Ni1/3Mn1/3Co1/3]O2 samples prepared under six different conditions were compared using high-resolution solid-state 6Li NMR.29 It was established that chemical shift trends to high frequency with decreasing degrees of disorder among this family of samples and this was explained according to the orbital overlap experienced by Li nuclei in the two environments. The local ordering observed in the dominant NMR resonance of Li is pervasive affecting the majority of the NMR nuclei. The condensation of BuLi on o-tolualdehyde in the presence of a chiral 3-aminopyrrolidine Li amide was studied by 6Li NMR.30 The interaction between a mixed aggregate and the aldehyde was discussed on the basis of a theoretical analysis of the solvation energies of the two Li atoms by three different ethers. The CP NMR experiments with spin state mixing under radio frequency irradiation and MAS were made for glasses in the system [(Li2O)x (Na2O)1x]0.3[B2O3]0.7 to discriminate between alkali ions by virtue of different heteronuclear 7Li–23Na dipole–dipole coupling strengths.31 Cation–cation interactions play a significant role in shaping the nonlinear compositional dependence of ionic condition (mixed-alkali effect: MAE) in glassy solid electrolytes. Mesoporous titanium oxide treated with 0.2, 0.6 and 1.0 equiv of Li- or Na-naphthalene were characterised by solid-state 23Na and 7Li NMR spectroscopy.32 23Na NMR spectra indicated that the relative population of the framework site increases with increased reduction levels and 7Li NMR spectra display a single broad resonance, which increases in breadth with increased reduction levels. The obtained 7Li chemical suggests that an anatase-like structure with no long-range order in the least-reduced samples but a lithium titanate-like structure with no long-range order in the higher reduced materials. 2.1.5 Sodium (23Na) (I =3/2). Diphenylmethylsodium, diphenylmethylsodium and fluorenylsodium were studied by 13C and 23Na solid-state NMR spectroscopy.33 Nucl. Magn. Reson., 2007, 36, 72–112 | 75 This journal is

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The chemical shifts d(13C) and d(23Na) as well as 23Na quadrupole coupling constants w(23Na) were analysed. The stability of Na+ ion complexes with 18crown-6 (18C6), dicyclohexyl-18-crown-6 (DC18C6), dibenzo-18-crown-6 (DB18C6), 15-crown-5 (15C5) and benzo-15-crown-5 (B15C5) in binary acetonitrile-dimethylformamide mixtures were monitored by 23Na NMR measurements.34 The variation of 23Na chemical shift with [crown]/[Na+] mole ratios indicates the formation of 1:1 complexes and the formation constants of the resulting complexes were evaluated. It was found that the stabilities of the complexes vary in the order 15C5 4 DC18C6 4 B15C5 4 18C6 4 DB18C6 in pure acetonitrile, while DC18C6 4 18C6 4 15C5 4 B15C5 4 DB18C6 in pure DMF. Metal-ligand complexation systems were studied NMR chemical shift titration and the results for LiClO4:12crown-4 system in acetonitrile and the NaClO4:12-crown-4 system in methanol were reported.35 Mesoporous titanium oxide treated with 0.2, 0.6 and 1.0 equiv of Li- or Na-naphthalene were characterised by solid-state 23Na and 7Li NMR spectroscopy as described in 2.1.4 Lithium.32 The dynamic behaviour of Na+ in NaCl-exchanged polyamide (PA) films comparable to those of the active skin layer of many reverse osmosis (RO) membranes was studied by 23Na NMR spectroscopy.36 The 23Na NMR spectra for freshly made polymer samples exchanged in 1 M NaCl solution show significant relative humidity (RH) dependence. The solution-diffusion model for RO membranes transport was provided and the capabilities of multi-nuclear NMR methods to investigate molecular-scale structure and dynamics of the interactions between dissolved species and RO membranes were demonstrated. The susceptibility to ischemia-reperfusion in isolated hearts from diabetic db/db and control db/+ mice was studied by 23Na and 31P NMR spectroscopies.37 The higher duration of ventricular tachycardia and the degeneration of ventricular tachycardia into ventricular fibrillation were observed upon reperfusion in db/db hearts. 2.1.6 Potassium (39K) (I = 3/2). The quadrupolar Carr-Purcell Meiboom-Gill (QCPMG) and double frequency sweep (DFS)/QCPMG pulse sequences were applied for acquiring solid-state 39K NMR spectra of organometallic complexes. Ab initio carbon chemical shielding anisotropy (CSA) calculation and 39K electricfield gradient (EFG) measurements were made in order to correlate the experimental NMR parameters with the molecular. 39K DFS/QCPMG and 13C CP/MAS experiments proved invaluable for probing molecular structure, temperature-dependent structural changes and the presence of impurities in these systems.38 The efflux of K+ from suspensions of human erythrocytes [red blood cells (RBCs)], which is occurred in response to the calcium ionophore and calcium ions, was studied by 39K NMR and the velocity of the K+ efflux mediated by the Gardos channel was determined.39 Signals from the intra—and extracellular populations of 39K+ were differenciated by T1. The effect of nitrate uptake on the subcellular distribution of tissue nitrate in maize root tips was investigated by 39K and 133Cs NMR.40 2.1.7 Rubidium (87Rb) (I = 3/2). A complex of 1,6-anhydro-b-maltose with rubidium and that of 1,6-anhydro-b-D-glucopyranose with rubidium were investigated by use of 87Rb NMR spectroscopy and diffusion-ordered NMR spectroscopy (DOSY).41 The complex formation with rubidium was identified for 1,6-anhydro-bD-glucopyranose using NMR and electrospray ionization mass spectrometry techniques. The ordered state of Na5RbCu4(AsO4) Cl2 was characterize by 87Rb NMR and the properties of Rb nuclear site and the structural phase transitions around 74 and 110 K were discussed.42 Mesoporous tantalum oxide rubidium fulleride composites were studied by solid-state 87Rb and 13C NMR.43 Solid-state 87Rb NMR experimental results indicated the presence of two Rb environments associated with the walls or channels of the mesostructure as well as several resonances associated with various fulleride species. 76 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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2.1.8 Cesium (133Cs) (I =7/2). The crystal structure and properties of lithium (cryptand[2.1.1]) ceside (Li+(C211)Cs) and cesium (cryptand[2.2.2]) ceside (Cs+(C222)Cs) were studied by 133Cs NMR and large paramagnetic chemical shifts were observed.44 Ab initio multiconfiguration SCF calculations were also made. The effect of nitrate uptake on the subcellular distribution of tissue nitrate in maize root tips studied by 39K and 133Cs NMR was described in 2.1.6 Potassium.40 2.2 Group 2 (9Be,

25

Mg,

43

Ca,

87

Sr,

137

Ba)

2.2.1 Beryllium (9Be) (I = 3/2). The interaction between a dicarboxyimidazolebased polymer and Be(II) was studied by 1H and 9Be NMR and DFT calculations.45 Differences in the binding modes of the mononuclear and polymeric species are discussed. DFT calculations using the GIAO-based method were performed on 16 cation-p complexes formed by cations of Li+, Na+, Be2+ and Mg2+, and p systems of benzene, 1,3,5-trifluorobenzene (TFBZ), 1,3,5-trimethylbenzene and 1,3,5-trimethoxybenzene (TMOBZ).46 The calculations revealed that the cation-p interaction has a remarkable effect on NMR chemical shifts. 2.2.2 Magnesium (25Mg) (I = 5/2). The temperature dependence of 17O and Mg NMR chemical shifts in solid MgO were calculated to describe the motion of the nuclei and to compute the NMR chemical shifts, which were obtained using the gauge-including projector augmented wave method.47 The chemical shift behaviour with temperature cannot be explained by thermal expansion alone. Vibrational corrections due to the fluctuations of atoms around their equilibrium position are crucial to reproduce the experimental results. 25

2.2.3 Calcium (43Ca) (I = 7/2). A correlation of the 43Ca NMR isotropic chemical shift with Ca–O distance in biomolecules was found by solid-state 43Ca NMR spectroscopy.48 The 43Ca shift increases as the mean Ca–O distance decreases, with a strong deshielding being observed for calcium with strong Ca–O bonds. 43Caenriched model slags were studied by 43Ca 3QMAS NMR spectroscopy to know the local environments of Ca2+ ions in slow- and rapid-quench slags.49 The slow-quench slag has well-defined CaO8 polyhedra in a crystalline form, while the rapid-quench slag may have CaO6 octahedral species. 2.2.4 Strontium (87Sr) (I = 9/2). Powder samples possessing either simple cubic (SrO) or fluorite-analog (SrCl2 and SrF2) structures were studied by 87Sr MAS NMR.50 The MAS spectra of these samples reveal a sideband pattern resulting from first order quadrupolar broadening of the outer transitions brought about by imperfections in the crystal structure. The chemical sifts for SrO, SrCl2 and SrF2 were discussed. The Sr sites in the natural minerals strontianite (SrCO3) and celestine (SrSO4) were characterised by using quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) pulse sequence.51 The quadrupolar parameters of 87Sr obtained by simulations of the experimental spectra appear to be highly sensitive to the symmetry of the Sr coordination environment. A fully strontium-exchanged synthetic mica of Na4Mg6Al4Si4O20F4 was studied by solid-state 87Sr NMR and 87Sr NMR spectrum of the heat-treated mica shows a single strontium environment with a quadrupolar coupling constant of 9.02 MHz and a quadrupolar asymmetry parameter of 1.0.52 The strontium cations in the proton-free interlayer are bound through electrostatic interactions as nine coordinate inner-sphere complexes sitting in the ditrigonal holes. The results demonstrated that structural details of strontium binding by phyllosilicate minerals are provided by modern pulsed NMR techniques and high fields. SrTinO3 (n = 16, 18) was measured by 87Sr quadrupole perturbed NMR spectroscopy and this showed that local symmetry breaking takes place at the A site of the ABO3 perovskite lattice in the cubic phase and not only at the B site.53 The start of Nucl. Magn. Reson., 2007, 36, 72–112 | 77 This journal is

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the antiferrodistortive transition around Ta = 105 K is accompanied by a large splitting of the 87Sr NMR line due to formation of macroscopic 901 domains and an anomalous shortening of the T2 of the quadrupole satellite transitions. 2.2.5 Barium (137Ba) (I = 3/2). The effect of the particle size of BaTiO3 and PbTiO3 on the material properties was investigated 137Ba NMR spectroscopy and typical changes in the fine structure tensor and the quadrupole coupling tensor were observed.54,55 The structure model for very small grains in the ferroelectric tetragonal phase was proposed. 2.3.

Group 3 (45Sc,

89

Y,

139

La,

171

Yb,

235

U)

2.3.1 Scandium (45Sc) (I = 7/2). Solid-state MAS and static 45Sc NMR spectroscopies, ab initio calculations and X-ray crystallography were applied to study the relationships between 45Sc NMR interactions and molecular structure and symmetry for Sc(acac)3, Sc(TMHD)3, Sc(NO3)3 5H2O, Sc(OAc)3, ScCl3 6H2O, ScCl3 3THF and ScCp3.56 These systems provide a variety of scandium coordination environments yielding an array of distinct 45Sc chemical shielding and electric field gradient tensor parameters. The first observations of scandium chemical shielding anisotropy were obtained from the spectra at two distinct magnetic fields. The structures of the microcrystalline Sc(OTf)3 were characterised by solid-state 45Sc, 13C and 19F NMR. 45 Sc NMR isotropic chemical shifts and quadrupole coupling constants of scandium-containing solid oxides were measured.57 The 45Sc isotropic chemical shift appears to be dominated by the first neighbor coordination number and the difference in the isotropic shifts between six-coordinated and eight-coordinated scandium is more than 150 ppm. The chemical shift correlation was applied to (ZrO2)0.92(Sc2O3)0.08 and the mean coordination number was obtained. 2.3.2 Yttrium (89Y) (I = 1/2). [Y(CH2SiMe3)(12-crown-4)(THF)3]2+[BPh4]2 and a series of similar compounds were studied by NMR spectroscopies including 89 Y NMR.58 The 1JYC coupling constants for yttrium nuclear at the Y-CH2 group and the 89Y chemical shift values were discussed. 2.3.3 Lanthanum (139La) (I = 7/2). Solid LaIII coordination compounds were measured by 139La NMR at applied magnetic fields of 11.75 and 17.60 T.59 The values obtained by the 139La NMR measurements were as follows: the 139La quadrupolar coupling constants range from 10.0 to 35.6 MHz, the spans of the chemical shift tensor range from 50 to 260 ppm and the isotropic chemical shifts range from 80 to 178 ppm. The breadth and shape of the 139La NMR spectra of the central transition are dominated by the interaction between the 139La nuclear quadrupole moment and the electric field gradient. Magnetic-shielding tensors, which was calculated by using relativistic zeroth-order regular approximation density functional theory (ZORA-DFT) and incorporating scalar only or scalar plus spin-orbit relativistic effects, reproduce the experimental chemical shift tensors. Results from a solid-state 139La NMR spectroscopic measurements of the anhydro lanthanum(III) halides (LaX3, XQF, Cl, Br and I) were reported and the 139La quadrupolar coupling constants were found to range from 15.55 to 24.0 MHz for LaCl3 and LaI3, respectively.60 The lanthanum isotropic chemical shifts exhibit an inverse halogen dependence and the spans of the magnetic shielding tensors vary widely. DFT calculations of the 139La electric field gradient and magnetic shielding tensors were also made. LaHx (2.0 r x r 3.0) samples were characterised by 139La NMR spectroscopy and the temperature and composition dependence of all quantities was determined.61 The chemical shift is larger than the Knight shift for 139 La in the LaHx samples. It was found by 139La- and 55Mn NMR measurements 78 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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that the ground state of the A-site-ordered perovskite manganite LaBaMn2O6 is a spatial mixture of the ferromagnetic and antiferromagnetic regions.62 2.3.4 Ytterbium (171Yb) (I = 1/2). Charge ordering of Yb ions in the quantum spin chain system Yb4As3 was studied by 171Yb NMR and the clear evidence for the existence of 4f holes on Yb2+ sites was obtained from the non-monotonic T-dependence of the resonance shift K.63 2.3.5 Uranium (235U) (I = 7/2). 235U antiferromagnetic NMR (AFNMR) signal was resolved by using 235U-enriched samples of USb2.64 The U hyperfine field and coupling constant were estimated for USb2. The chemical shifts of UF6nCln were investigated by 235U and 19F NMR and DFT calculation and 235U NMR shieldings was also calculated.65 2.4 Group 4 (47,

49

Ti,

91

Zr)

47, 49

Ti) (I = 5/2, 7/2). The separation of the spectroscopic 2.4.1 Titanium ( contribution from both 47Ti and 49Ti in solid-state NMR spectra was reported for TiO2 polymorphs as anatase and rutile.66 The separation of the two isotopes for anatase at high field facilitated accurate determination of the electric field gradient and chemical shift anisotropy tensors. The rutile sample was measured by 49Tiselective NMR at different magnetic fields and the spectra with different scalings of the two anisotropic tensors were obtained. A small chemical shielding anisotropy (CSA) of 30 ppm was also determined. 2.4.2 Zirconium (91Zr) (I = 5/2). The crystalline phase of ZrSiO4 was studied by 29Si, 17O and 91Zr NMR and computational calculation.67 The NMR spectra were calculated by means of first principles density functional methods to find an additional evidence for the presence of high concentrations of defects in irradiated zircon. The influence of the substitution pattern on steric and electronic parameters for a series of borazirconocenophanes in the Ziegler-Natta ethene polymerisation behaviour was studied by 91Zr NMR spectroscopy and X-ray diffraction analyses.68 The stability of the species after activation was also studied by aging and interrupting the polymerisation and borazirconocenophanes proved to form a stable species after activation with MAO. It was shown that an application of 47Ti, 49Ti and 91Zr NMR is extremely useful in controlling the microscopic structure of semi-Heuslertype intermetallics for TiPtSn, ZrPtSn, HfPtSn and ThPtSn.69 However, no valuable information on structural order/disorder in MPtSn compounds can be directly obtained from static NMR spectra of 117Sn, 119Sn and 195Pt nuclei. Since the observed spectra are broadened far beyond the rigid-lattice dipolar width due to indirect spin couplings of these heavy nuclei through the chemical bondings. 2.5 Group 5 (51V,

93

Nb)

51

2.5.1 Vanadium ( V) (I = 7/2). A single crystal of b-Na0.33V2O5 was measured by 51V NMR to study the local magnetic susceptibility and the electronic structure at the vanadium sites.70 The 51V Knight shift and the electric field gradient tensors at the vanadium sites were determined and the temperature dependence of principal components of the 51V Knight shift and the electric field gradient tensors were also obtained. The orbital ordering of Lu2V2O7 was investigated by 51V NMR measurements and a characteristic angle dependence reflecting V 3d orbital states was found.71 It was found by the temperature dependence of the NMR spectra that the magnitude of the quadrupole moment is almost invariant below TC and that the orbital ordering would probably persist above TC. A 1-dimensional Heisenberg antiferromagnet LiCuVO4 was studied by 7Li and 51V NMR and both the results Nucl. Magn. Reson., 2007, 36, 72–112 | 79 This journal is

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were compared to theoretical predictions.72 The 51V solid-state NMR spectroscopy for the 67.5 kDa vanadium chloroperoxidase was performed and the quadrupolar and chemical shift anisotropy tensors were determined by simulations of the spinning sideband envelopes and the line shapes of the individual spinning sidebands corresponding to the central transition.73 With the quadrupolar coupling constant Cq of 10.5 1.5 MHz and chemical shift anisotropy Ds of 520 13 ppm, the information on the geometric and electronic structure of the vanadium center was obtained. The quasi-one-dimensional BaCu2V2O8 was studied by 51V NMR measurements and the two 51V NMR lines that are associated with two vanadium crystallographic sites were resolved.74 The temperature-dependent NMR shift for each site shows low-dimensional magnetism with a broad maximum at Tmax. The NMR chemical shifts and spin-lattice relaxation rates below Tmax indicate activated behaviour confirming the spin gap formation in BaCu2V2O8. The BixV8O16 (1.72 r x r 1.80) that shows a temperature-induced metal-insulator transition (MIT) was studied by 51V NMR.75 Observation of the 51V-NMR signal below the MIT temperature (TMIT) indicates the existence of non-magnetic V sites and the decrease in the Knight shift at low temperatures suggests the spin-singlet nature of the ground state. 2.5.2 Niobium (93Nb) (I = 9/2). The 93Nb solid-state NMR spectra of a series of inorganic niobates with Nb in different oxygen coordination environments were measured and their chemical shielding and quadrupole tensor parameters were determined using conventional and ultrahigh speed MAS, DQ STMAS, solid-echo NMR and computer simulation.76 It was demonstrated that the 93Nb isotropic chemical shift is sensitive to the coordination number of Nb sites. The possible correlation between the value of the isotropic chemical shift and the ionic character of the NbOx–MOy polyhedra association was suggested. A mixed KTa1xNbxO3 single crystal with x = 15% was measured by 93Nb NMR and an unresolved quadrupole-induced 1st-order satellite background was observed.77,78 It demonstrates that the Nb ions occupy off-center positions rather than the high symmetry central perovskite site. Half-sandwich niobium metallocenes Cp 0 Nb(I)(CO)4 and CpNb(V)Cl4 (Cp = C5H5 and Cp 0 = C5H4R with R = COMe, CO2Me, CO2Et and COCH2Ph) were studied by solid-state 93Nb and 13C NMR, in combination with theoretical calculations of NMR tensors.79 Anisotropic quadrupolar and chemical shielding parameters were estimated from 93Nb MAS and static NMR spectra for seven different complexes. The calculated chemical shielding parameters and electric field gradient tensors were used to determine relations between tensor orientations, the principal components and molecular structures for the niobium metallocenes. 2.6 Group 6 (53Cr,

95,97

Mo,

183

W)

2.6.1 Chromium (53Cr) (I = 3/2). The 53Cr chemical shifts of CrO42, Cr2O72, CrO3X, CrO2X2 (X = F, Cl) and Cr(CO)5L (L = CO, PF3, CHNH2, CMeNMe2) were calculated, using geometries optimized with the gradient-cor. BP86 density functional, at the gauge-including AOs (GIAO)-, BPW91- and B3LYP levels and comparing with those obtained by 53Cr NMR experiments.80 For selected cases, 53Cr NMR line widths can be rationalized in terms of electric field gradients computed with the BPW91 or molecular correlation times. The 53Cr chemical shifts and electric field gradients were predicted for CrO3, Cr(C6H6)2 and Cr(C6H6)CO3 and for Cr2(m2-O2CH)4 with reduced reliability. The behaviour that ferromagnetic ordering temperature of SrRu1xCrxO3 increases to 175 and 186 K for x = 0.05 and 0.12, respectively, from 162 K for SrRuO3 (x = 0) was investigated by 53Cr and 99, 101Ru NMR. The study revealed that Cr is in a ‘valence state’ of Cr3+ (t2g3m), and Ru is in a mixed valence state of Ru4+ (t2g3m1k) and Ru5+ (t2g3m).81 80 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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2.6.2 Molybdenum (95, 97Mo) (I = 5/2, 5/2). Photolysis of Mo(CO)6 in nheptane Solution with Et2SiH2 was studied by 1H, 29Si and 95Mo NMR spectroscopy.82 The 95Mo NMR spectrum showed a resonance at d = 3785 at high field, which is characteristic for seven-coordinate molybdenum compounds. The diamagnetic octacyanomolybdate(IV) anions, Mo(CN)84, of approximately dodecahedral and square antiprismatic symmetry were investigated by solid-state 95Mo NMR spectroscopy.83 Quantum chemical calculations of the Mo s and EFG tensors, using zeroth-order regular approximation density functional theory and RHF methods, were carried out and the results were compared with those obtained by the experiments. 95Mo quadrupole couplings in molydbates were measured by MAS NMR and ab initio density functional theory calculations of the electric field gradient were also performed.84 It was predicted that 95Mo MAS NMR could evolve as a routine characterization tool for ill-defined structures such as supported molybdates in catalysis when the experiments would be made 417 T. The (A, A 0 )2FeMoO6 (A, A 0 = Ca, Sr, Ba) ferromagnetic oxides with double perovskite structure were studied by 95, 97Mo and 57Fe NMR spectroscopy.85 The NMR experiments provided clear evidence that the magnetic moment at Mo sites is not constant but varies sensitively with the size of the ions and the 95, 97Mo frequency and the electronic charge at Mo ions are smaller in Ba and Ca than in Sr-based oxides. 2.6.3 Tungsten (183W) (I = 1/2). A phosphane sulfate relativistic DFT method was employed to calculate the 183W and 17O NMR chemical shifts for large polyoxotungstates, such as W6O192, CH3OTiW5O183, W5O18WIINO3, W10O324, a-d-g-XW12O40n, b-PW9O28Br63, P2W18O626, PW2O143 and W7O246.86 The analysis of the components of the paramagnetic shielding showed that the most significant change in both 183W and 17O NMR chemical shifts for anions consisting of tungsten and oxygen atoms are the occupied-occupied and not the occupied-virtual ones. The same authors also studied W5O18WIINO3, g-SiW12O406, P2W18O628 and W10O326 by the same methods.87 2.7 Group 7 (55Mn,

99

Tc)

55

2.7.1 Manganese ( Mn) (I = 5/2). Bi0.125Ca0.875MnO3 and CaMnO3 were studied by 55Mn NMR measurements and NMR signals observed at 4.2 K for Bi0.125Ca0.875MnO3 around 100 and 605 MHz were ascribed to regions with ferromagnetic spin structure from their behaviour in external magnetic fields.88 La2/3Ca1/3MnO3 epitaxial films on (001) and (110) SrTiO3 substrates were measured by 55Mn NMR and it was shown that the (110) films do not show traces of electronic phase separation, in contrast to (001) films.89 The results provided evidence that no weakening of double exchange coupling at interfaces takes place in (110) films. A single crystal of YMn4Al3 was studied by using 55Mn and 27Al NMR measurements. Two sets of NMR resonance peaks were assigned to the respective Al sites based on the difference in NMR shift, linewidth and relaxation rates.90 NMR shift and linewidth for 55Mn and 27Al NMR follow temperature dependence of the susceptibility, confirming that the hyperfine field from Mn 3d spins dominates local electronic structures at both Al and Mn sites. The Mn12 single-molecular magnet (SMM) in truly axial (tetragonal) symmetry and the complex [Mn12O12(O2CCH2Br)16(H2O)4] 4CH2Cl2 (2 4CH2Cl2 or Mn12–BrAc) was studied by 55Mn NMR spectroscopy and the quadrupole coupling parameters (e2qQ) was determined.91 It was found that crushing crystals of Mn12–BrAc into a microcrystalline powder causes severe broadening and shifts of the NMR resonances. La0.67Sr0.33MnO3 thin films were studied by 55Mn NMR and two distinct lines were observed at 322 and 380 MHz corresponding to the interface with localized charges and to the film bulk with itinerant carriers.92 The field dependence of the NMR signal intensity above the effective anisotropy field agrees with a model of Nucl. Magn. Reson., 2007, 36, 72–112 | 81 This journal is

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magnetically homogeneous sample. La0.7Sr0.3MnO3 particles were studied by 55Mn NMR and temperature dependences of the NMR spectra to understand the magnetic properties of its fine-particle ensembles.93 The low-temperature blocking of its magnetic moments was clearly observed and it was found that the blocking temperature depends on the measuring frequency. La0.67Ca0.33Mn0.9757Fe0.03O3 was measured by means of zero field 55Mn and 57Fe NMR and it was found that the 55 Mn NMR spectra exhibit a single double exchange line up to the magnetic ordering temperature.94 Application of a molecular field model to the temperature dependence of the 55Mn and 57Fe hyperfine field allows to estimate values of the Mn–Mn and the Fe–Mn exchange integrals. The 55Mn NMR study of the La0.75Sr0.25MnO3 particles was reported and a dominant signal from the double exchange controlled metallic ferromagnetic interior of the grains and a small signal from insulating ferromagnetic regions were observed.95 The double exchange line in the NMR spectrum shows a frequency shift with applied field according to a full 55 Mn gyromagnetic ratio. La0.6Sr0.3Mn1.1xFexO3d(x = 0, 0.04) samples were studied by 55Mn NMR.96 Their broad asymmetric 55Mn NMR spectra support the high-frequency electron-hole exchange between Mn3+ and Mn4+ and the fact that their environments are different due to a high defect concentration and high structural inhomogeneity. The single crystal 55Mn NMR studies of Mn12O12(CH2BrCOO)16(4H2O)-4CH2Cl2 indicate that the highly symmetric lattice may be an improved model for studying single-molecular magnetism.97 The 55Mn NMR spectra from single crystal yield much-enhanced NMR data such as 55Mn hyperfine and quadrupole couplings as compared to magnetically oriented powders. The single crystals of [Mn12O12(O2CMe)16(H2O)4]-2MeCO2H-4H2O and [Mn12O12(O2CCH2Br)16(H2O)4]-4CH2Cl2 were studied by 55Mn NMR spectroscopy and their single crystal spectra gave a dramatic improvement in the spectral resolution over oriented powder spectra, allowing the determination of quadrupole coupling parameters.98 2.7.2 Technetium (99Tc) (I = 9/2). Time-dependent analyses of the formation reactions of mixed dicarbonyl-mononitrosyl complexes from the organometallic precursor, [MX3(CO)3]+, (M = 99Tc, X = Cl, Br) by 99Tc NMR spectroscopy and HATR-IR were made and it was revealed that the almost quantitative substitution of one CO ligand by NO+ is caused and (NEt4)[TcCl3(CO)2NO] and [TcCl (m-Cl)(CO)2NO]2 are produced.99 The isolated complexes and their potential facial isomers were further investigated by DFT calculations. The 99Tc NMR data for Tc compounds in various oxidation states are summarized in a review.100 2.8 Group 8 (57Fe,

99

Ru)

57

2.8.1 Iron ( Fe) (I = 1/2). The intramolecular dynamic behaviour of the tetrahedron-type cluster [Fe2(CO)6(m-SNH)] was studied by 13C NMR spectroscopy, and the 57Fe chemical shift and the coupling constants J(57Fe,13C) were measured.101 Density-functional-based Car-Parrinello and Born-Oppenheimer molecular dynamics simulations were presented for ferrocene, FeCp2 and its protonated form, FeCp2H+, in the gas phase, employing BP86 and B3LYP functionals, and thermally averaged chemical shifts were computed from snapshots along the trajectory, where 1 H and, in particular, 57Fe chemical shifts in FeCp2H+ are sensitive to the location of the proton.102 2.8.2 Ruthenium (99Ru) (I = 3/2). The computed chemical shifts of transitionmetal complexes with dimetridazole (=1,2-dimethyl-5-nitro-1H-imidazole; (1), a prototypical nitro-imidazole-based radiosensitizer, were reported at the GIAOBP86 and -B3LYP levels for BP86/ECP1-optimised geometries, and the 195Pt chemical shifts of cis- and trans-[PtCl2(1)2] are well-reproduced using the zero-order 82 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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regular approximation including SO coupling (ZORA-SO), and predictions are also reported for 99Ru and 103Rh chemical shifts, which suggest that these metal centers could be used as additional, sensitive NMR probes in their complexes with nitroimidazoles.103 2.9 Group 9 (59Co,

103

Rh)

2.9.1 Cobalt ( Co) (I = 7/2). 59Co chemical shifts were computed at the GIAOB3LYP level for [Co(CN)6]3, [Co(H2O)6]3+, [Co(NH3)6]3+ and [Co(CO)4] in water.104 A chemical shielding calculation using density functional theory at the BP86/AE1 level was presented for the Co bis(dicarbollide) ion [3-Co-(1, 2C2B9H11)2] (1) and selected isomers and rotamers thereof.105 The synthesis and characterisation (X-ray crystallography, UV/visible spectroscopy, electrochemical, ESI-MS and 1H, 13C and 59Co NMR) of [Co(L)(O2CO)]ClO4 xH2O (L = tpa = tris(2-pyridylmethyl)amine (x = 1), pmea = bis((2-pyridyl)methyl)-2-((2-pyridyl)ethyl)amine (x = 0), pmap = bis(2-(2-pyridyl)ethyl)(2-pyridylmethyl)amine (x = 0), tepa = tris(2-(2-pyridyl)ethyl)amine (x = 0)) which contain tripodal tetradentate pyridyl ligands and chelated carbonate ligands are reported.106 59

2.9.2 Rhodium (103Rh) (I = 1/2). Using 103Rh[1H] cross-polarisation (CP) methods, solid-state 103Rh NMR spectra for diamagnetic Rh(III) compounds were obtained, and the isotropic chemical shift and chemical shift anisotropy (CSA) are reported for a crystalline form of the dihydroxy-bridged Rh(III) dimer and for a salt of the oxo-centered acetate-bridged Rh(III) trimer, from analysis of conventional CP/MAS spectra.107 2.10 Group 10 (195Pt) 2.10.1 Platinum (195Pt) (I = 1/2). Variable low-frequency 15N coordination shifts (ca. 70–140 ppm) were noted for a number of chloride complexes of Pd(II), Pt(II), Au(III), Pd(IV), Pt(IV), Co(III), Rh(III) and Zn(II) with pyridine, 2, 2 0 -bipyridine, 1, 10-phenanthroline, 2, 2 0 -biquinoline, purine and 1, 2, 4-triazolo-[1, 5a]-pyrimidine(s), and some dependencies between the magnitude of the shielding effect and such features of the concerned complex as the type of central ion, its electron configuration (oxidation state) and the coordination sphere geometry were discussed.108 195Pt chemical shifts and 1JPtPt coupling constants were measured for a series of head-to-head (HH) and head-to-tail (HT) amidato-bridged cis-diammineplatinum(III) dinuclear complexes involved in the axial water substitution reactions with halide ions (X = Cl, Br): HH-[Pt2(NH3)4(m-amidato)2L1L2]n+, [L1Pt(N2O2)-Pt(N4)-L2]n+ (amidato = alpha-pyridonato, alpha-pyrrolidonato and pivalamidato) and HT-[Pt2(NH3)4(mu-alpha-pyridonato)2L1L2]n+, [L1-Pt(N3O)Pt(N3O)-L2]n+; the diaqua (L1, L2 = H2O, n = 4), the aquahalo (L1 = X, L2 = H2O, n = 3) and the dihalo complexes (L1, L2 = X, n = 2).109 A new approach by chemometrics in order to build a model to predict the chemical shift of a Ptcomplex on the basis of its molecular features was presented using an artificial neural network algorithm, and was successfully applied such a model to 185 different 195Pt chemical shift values.110 The reactions of [Pt(NH3)2(NHCOtBu)2] and TlX3 (X = NO3, Cl, CF3CO2) yielded dinuclear [{Pt(ONO2)(NH3)2(NHCOtBu)}Tl(ONO2)2(MeOH)] (2) and trinuclear [{PtX(RNH2)2(NHCOtBu)2}2Tl]+ [X = NO3 (3), Cl (5), CF3CO2 (6)], which were spectroscopically and structurally characterised, and strong Pt–Tl interaction in the complexes in solutions was indicated by both 195Pt and 205Tl NMR spectra.111 Some basic theoretical aspects of 195Pt NMR spectroscopy and also the empirical approach used by the researchers in the field were briefly reviewed.112 Density functional theory using the zero-order regular approximately two-component relativistic Hamiltonian was applied to calculate the 195Pt chemical shifts for [PtCl6]2, [PtCl4]2 and [Pt2(NH3)2Cl2(Me3Nucl. Magn. Reson., 2007, 36, 72–112 | 83 This journal is

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CCONH)2(CH2COCH3)]Cl.113 Pd and Pt chloride complexes with pyridine (py), 2, 2 0 -bipyridine (bpy) and 1, 10-phenanthroline (phen), trans-/cis-[M(py)2Cl2], [M(py)4]Cl2, trans-/cis-[M(py)2Cl4], [M(bpy)Cl2], [M(bpy)Cl4], [M(phen)Cl2], [M(phen)Cl4], where M = Pd, Pt, was studied by 1H, 195Pt and 15N NMR.114 The computed chemical shifts of transition-metal complexes with dimetridazole (=1,2dimethyl-5-nitro-1H-imidazole; 1), a prototypical nitro-imidazole-based radiosensitiser, were reported at the GIAO-BP86 and -B3LYP levels for BP86/ECP1-optimised geometries, and the 195Pt chemical shifts of cis- and trans-[PtCl2(1)2] are wellreproduced using the zero-order regular approximation including SO coupling (ZORA-SO), and predictions are also reported for 99Ru and 103Rh chem. shifts, which suggest that these metal centers could be used as additional, sensitive NMR probes in their complexes with nitro-imidazoles.115 Cis-Pt(amine)2I2 were transformed into the iodo-bridged dimers, which were characterised mainly by multinuclear (195Pt, 1H and 13C) magnetic resonance spectroscopy.116 The ZORA spinorbit Hamiltonian, in conjunction with the gauge including orbital (GIAO) method based on DFT theory was used to calculate 195Pt chemical shift of 195PtClxBr6x2 complexes.117 In the solid state, heavier NMR-active nuclei such as 195Pt, 199Hg and 207 Pb commonly exhibit chemical shifts that range well over 1000 ppm, depending upon the orientation of the mol. within the applied magnetic field. Thus, acquiring NMR spectra of polycrystalline samples is often an experimental challenge because of these very broad powder patterns. In acquiring chemical shift powder patterns of these nuclei, the authors provide several examples that demonstrate that a considerable saving in time is realised by using the CPMG experiment as opposed to the standard 1-pulse or spin-echo experiment.118 2.11 Group 11 (63Cu,

107,109

Ag)

63

2.11.1 Copper ( Cu) (I = 3/2). Polycrystalline tetra-nuclear Cu4[S2P(O-iC3H7)2]4, hexa-nuclear Cu6[S2P(OC2H5)2]6 and octa-nuclear Cu8[S2P(O-iC4H9)2]6(S) complexes were synthesised and analysed by means of solid-state 31P CP/MAS and 65Cu static NMR spectroscopy, and the symmetries of the electronic environments around each P-site were estimated from the 31P chemical shift anisotropy (CSA) parameters.119 Polycrystalline tetra-nuclear Cu4[S2P(O-iC3H7)2]4, hexa-nuclear Cu6[S2P(OC2H5)2]6 and octa-nuclear Cu8[S2P(O-iC4H9)2]6(S) complexes were synthesised and analysed by means of solid-state 31P CP/MAS and 65Cu static NMR spectroscopy. 2.11.2 Silver (107,109Ag) (I = 1/2, 1/2). Formation of silver eta 2-alkyne and sigma-alkynyl complexes was detected in situ in reaction of silver triflate with 1hexyne in the presence of a tertiary amine by 1H, 13C and 109Ag NMR spectra.120 109 Ag solid state magic angle spinning (MAS) NMR spectra for different silver oxides, binary as well as ternary were presented and the chemical shift of Ag nuclei is strongly dependent on the Ag oxidation state in these compounds and can thus serve as means to identify the Ag oxidation state in new materials.121 The quadrupolar Carr-Purcell Meiboom-Gill (QCPMG) pulse sequence has received much attention in the recent literature for use in the rapid acquisition of solid-state NMR spectra of half-integer quadrupolar nuclei. Herein the authors investigate the application of the CPMG pulse sequence to enhance the signal-to-noise ratio in the static NMR spectra of spin-1/2 nuclei. The CPMG and CP/CPMG pulse sequences are applied to a series of different NMR nuclides, including 113Cd, 199Hg, 207Pb, 15N and 109Ag.122 2.12 Group 12 (67Zn,

111,113

Cd,

199

Hg)

2.12.1 Zinc ( Zn) (I = 5/2). Quantum chemical methods to predict 67Zn NMR chemical shifts as well as quadrupole coupling constants in a series of biomimetic and inorganic zinc complexes were used, and the 67Zn NMR shifts in a series of 67


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complexes containing N,O ligands are, in general, highly correlated with the number of oxygen ligands.123 2.12.2 Cadmium (111,113Cd) (I = 1/2, 1/2). The synthesis and characterisation by solid-state 111Cd NMR of Cd(2,3-), Cd(2,4-), Cd(2,5-) and Cd(2,6-pyridinedicarboxylato) xH2O was reported.124 Cadmium(II) complexes of imidazolidine-2-selenone (ImSe) and its derivatives, Cd(1-RImSe)2Cl2 (R = Me, Et, Pr, i-Pr) and Cd(Diaz)Cl2 (Diaz = 1,3-diazinane selenone) were prepared and characterised by elemental analysis, IR and NMR (1H, 13C, 77Se and 113Cd) spectroscopy.125 2.12.3 Mercury (199Hg) (I = 1/2). Complexation behaviour of thiacrown ligands and related macrocycles towards the heavy metal ion mercury(II) was discussed using multinuclear NMR data on the complexes, with a particular attention to 199Hg NMR, and correlations between the ligand environment around the Hg(II) ion and 199 Hg NMR chemical shifts were seen.126 Investigation of the solution-state coordination chemistry of mercury was carried out using 199Hg NMR.127 Mercury(II) complexes with L-cysteine (H2Cys) in alkaline aqueous solutions were structurally characterised by means of extended X-ray absorption fine structure (EXAFS) spectroscopy, Raman, 199Hg NMR.128 Measurements of 199Hg NMR chemical shift data for a series of homoleptic Hg(II) complexes with thiacrown ligands and related aza and mixed thia/aza macrocycles were firstly reported, and in mercury(II) complexes containing trithiacrown through hexathiacrown ligands, 199Hg NMR chemical shifts in the range of 298 to 1400 ppm were observed.129 The solvation of the mercury(II) ion in solvents with different solvation properties, water, dimethylsulfoxide, N,N-dimethylthioformamide and liquid ammonia, was studied by means of 199Hg NMR, and the 199Hg chemical shift shows a pronounced dependence on the coordination number of the mercury(II) ion in the solvates resulting in a difference of over 1200 ppm between basically tetrahedral and octahedral complexes.130 The CPMG and CP/CPMG pulse sequences are applied to a series of different NMR nuclides, including 113Cd, 199Hg, 207Pb, 15N and 109 Ag.131 In the solid state, heavier NMR-active nuclei such as 195Pt, 199Hg and 207Pb commonly exhibit chemical shifts that range well over 1000 ppm, depending upon the orientation of the molar within the applied magnetic field. Thus, acquiring NMR spectra of polycrystalline samples is often an experimental challenge because of these very broad powder patterns. In acquiring chemical shift powder patterns of these nuclei, the authors provide several examples that demonstrate that a considerable saving in time is realised by using the CPMG experiment as opposed to the standard 1-pulse or spin-echo experiment.132 2.13 Group 13 (11B,

27

Al,

71

Ga,

203, 205

Tl)

11

2.13.1 Boron ( B) (I = 3/2). Structural features in Pyrex was identified by high resolution 29Si, 27Al and 11B magic-angle spinning MAS NMR spectroscopic measurements at 9.4 and 19.5 T, combined with 27Al and 11B multiple-quantum MAS (MQMAS), and 11B Rotor Assisted Population Transfer (RAPT).133 11B NMR of boron interaction with mineral surfaces(boehmite, silica gel and illite) was presented.134 11B solid-state NMR was used to investigate the rhamnogalacturonan II-borate complex in plant cell walls.135 Boric acid, ‘‘carbonic’’ acid and N-containing oxyacids in aqueous solution were investigated by ab initio studies of structure, pKa, NMR shifts and isotopic fractionations.136 Structural speciation of glasses in the systems PbO–B2O3–SiO2, PbO–B2O3–Al2O3–SiO2 and PbO–Al2O3–SiO2 were studied using solid state 29Si, 27Al, 11B and 207Pb NMR and Raman spectroscopy.137 2.13.2 Aluminium (27Al) (I = 5/2). The chemical knowledge about Macrodefectfree materials was shown critically for both procedure design and exploitation, and Nucl. Magn. Reson., 2007, 36, 72–112 | 85 This journal is

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chemical shifts in both 27Al and 31P MAS NMR spectra confirm Al(6)–O–P(4) crosslinking in virgin probes and indicate secondary hydrolysis during moisture uptake in domains free of cross-links.138 The structures of one synthetic and two natural chlorites of the chlinochlore type were explored using X-ray diffraction, Moessbauer, 29Si magic-angle spinning NMR (NMR) and 27Al 3QMAS NMR.139 The effect of Na/Si on the structure of sodium silicate and aluminosilicate glasses quenched from melts at high pressure were investigated by a multi-nuclear (27Al, 23 Na, 17O) 1D and 2D solid-state NMR.140 27Al-NMR and Raman spectroscopic studies of alkaline aluminate solutions with extremely high caustic content were carried out.141 Perrhenate sodalite were synthesised and the structure was investigated by Raman spectroscopy and 29Si and 27Al MAS NMR.142 A combination of 27 Al magic-angle spinning (MAS)/multiple quantum (MQ)-MAS, 13C-1H CPMAS and 13C–{27Al} transfer of population in double-resonance (TRAPDOR) NMR were used for the structural elucidation of the aluminum alkoxides aluminum ethoxide, aluminum isopropoxide and aluminum tertiarybutoxide.143 Various 2:1 type clay minerals were activated by H2SO4 treatment and the generation of solid acidity was found to be related to the evolution of new tetrahedral Al sites showing a slightly different 27Al MAS NMR chemical shift from the original tetrahedral Al NMR resonance.144 A new aluminophosphate (AlPO) material, EMM-3, was recently synthesised at ExxonMobil, and characterised by multinuclear (13C, 31P, 27 Al), multifield solid-state NMR, SEM and powder XRD measurements.145 Spectroscopic elucidation of a 2-isopropylmalic acid (2-iPMA)-Al(III) complex was carried out using 1H, 13C and 27Al NMR spectroscopy, diffusion-ordered NMR spectroscopy (DOSY) and electrospray ionisation mass spectrometry (ESI-MS).146 Anionic framework aluminophosphates, with different Al/P ratios, were studied by various solid-state NMR techniques, including 27Al, 31P magic angle spinning (MAS), 27Al–31P cross polarisation (CP), 27Al{31P} rotational echo double resonance (REDOR), and 31P{27Al} transfer of population double resonance (TRAPDOR).147 beta-CaAlF5 was synthesised by solid-state reaction, and characterised by X-ray powder diffraction, EPR and 19F and 27Al solid state MAS SATRAS NMR.148 A new aluminum-hydrate species in hydrated Portland cements were characterised by 27Al and 29Si MAS NMR spectroscopy.149 In order to investigate the structural evolution around Al, pulse NMR experiments were carried out on 27Al in the Zr60Ni25Al15 metallic glass and the related crystalline compound, Zr6NiAl2.150 Complex formation between S-histidine (HHis) and aluminum(III) ion in aqueous solution was studied by potentiometric measurements, ESI-MS, 27Al and 13C NMR spectroscopy.151 The dependence of the 27Al NMR shielding on the framework Al position and on the charge compensating cation coordination and hydration was studied for MCM-58 zeolite.152 Hydrothermally stable Al-containing periodic mesoporous organosilicas with various Si/Al ratios 5.6 were easily prepared at room temperature by NH4OH-catalysed, CTAB-templated hydrolysis and condensation of 1,2-bis(triethoxysilyl)ethane and Al isopropoxide, and characterisation data with XRD, TEM, SEM, N adsorption, 29Si and 27Al MAS NMR, pyridine-TPD and hydrothermal test showed that the mesoporous materials possess wormlike channels with high textural porosity, tetrahedrally and octahedrally coordinated Al atoms in their textural structures, and weak acid sites whose contents are proportional to the amount of Al incorporated.153 The synthesis and characterisation of monomeric, oligomeric and polymeric aluminum 8-hydroxyquinolines were carried out using 27 Al NMR.154 Melt and glass structure in the Al2O3–CaO–LaPO4 system were studied by 27Al and 31P NMR, and by Raman scattering.155 Boria–Alumina Mixed Oxides prepared by a sol-gel method was characterised by 27Al and 11B MAS NMR.156 The Effects of T–O–T Bond Angles on NMR Chemical Shifts in Aluminosilicates were explained by a natural bonding orbital (NBO) and natural chemical shielding (NCS) analysis.157 The experimental NMR chemical shift of the central carbon atom in the octahedral [(Ph3PAu)6C]2+ cluster was studied from relativistic density functional calculations.158 The thermal transformation of Ba 86 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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exchanged zeolite X to celsian is studied by scopy.159

27

Al and

29

Si MAS NMR spectro-

2.13.3 Gallium (71Ga) (I = 3/2). GaN crystals doped with Mn ions were synthesised by the alkali metal flux method. Mixtures of metals were premelted to form an alloy and the alloy was mixed with Na/K and heated to 800 1C under 1400 psi N2 in an Al2O3 crucible. Up to 2 mol% Mn could be incorporated into the hGaN lattice, and the products were characterised by solid state 71Ga, 69Ga, 14N NMR, magnetometry, Raman spectroscopy and powder X-ray diffraction.160 A strategy was demonstrated for identifying unambiguously and characterizing quantity of the effects of distributions of conduction electron concentrations arising from intentional or unintentional dopants in semiconductors by 71Ga MAS NMR.161 2.13.4 Thallium (203, 205Tl) (I = 1/2, 1/2). The reactions of [Pt(NH3)2(NHCOtBu)2] and TlX3 (X = NO3, Cl, CF3CO2) yielded dinuclear [{Pt(ONO2)(NH3)2(NHCOtBu)}Tl(ONO2)2(MeOH)] and trinuclear [{PtX(RNH2)2 (NHCOtBu)2}2Tl]+ [X = NO3, Cl, CF3CO2], which were spectroscopically and structurally characterised, and strong Pt–Tl interaction in the complexes in solutions was indicated by both 195Pt and 205Tl NMR spectra.162 2.14 Group 14 (13C,

29

Si,

73

Ge,

117, 119

Sn,

207

Pb)

13

2.14.1 Carbon ( C ) (I = 1/2). Antimicrobial peptides are key components of innate immunity of all life forms. Understanding the structure activity relationship of these peptides is essential for developing them into novel therapeutics that substitutes traditional antibiotics. NMR spectroscopy can provide insights into membrane-targeting antimicrobial peptides from a variety of angles.163 XPA, a 273 amino acid protein, is involved in the early stage of the nucleotide excision repair, by which a variety of DNA lesions are removed from the genome. NMR is used to analyse the structure of the central domain of XPA, which encompasses residues 98 to 219, and contains a zinc coordinating motif. Following chemical shift assignments of the backbone and side-chain 1H, 15N and 13C nuclei, the tertiary structure was determined by multi-dimensional and multi-resonance NMR methods.164 This contribution reviews applications of NMR spectroscopy in the study of the structure and the intra- and intermolecular interactions of purine derivatives.165 Different symmetrical substituted and cyclic dialkydithiocarbamate (R = CH3, C2H5, C3H7, i-C3H7, C4H9, i-C4H9 and R2 = (CH2)5, (CH2)6, (CH2)4O) compounds, such as tetraalkylthiuram disulfides, mononuclear nickel(II), binuclear zinc(II) and heteropolynuclear complexes and their adducts (both non-solvated and solvated forms) with planar and non-planar N-donor organic bases, are prepared and studied by means of natural abundance 13C and 15N CP/MAS NMR spectroscopy. 166 Much progress in terms of sensitivity, leading to much smaller requirements of sample quantities was made by the introduction of Fouriertransform NMR, allowing for more rapid acquisition of spectra and by the construction of cryomagnets with higher fields. These techniques are essentially provided the technology to routinely record 13C-NMR spectra, and 13C chemical shifts prove to be of much use for structure identification.167 2.14.2. Silicon (29Si) (I = 1/2). The thermal transformation of Ba exchanged zeolite X to celsian is studied by 27Al and Si MAS NMR spectroscopy.168 The structures of one synthetic and two natural chlorites of the chlinochlore type were explored using X-ray diffraction, magic-angle spinning NMR and Moessbauer spectroscopy. The authors report unit-cell parameters, Moessbauer isomeric shifts, 29 Si NMR chemical shifts as well as 27Al isotropic shifts and quadrupolar coupling parameters.169 A multinuclear solid-state NMR investigation of the structure of the Nucl. Magn. Reson., 2007, 36, 72–112 | 87 This journal is

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amorphous alteration products (so-called gels) that form during the aqueous alteration of silicate glasses such as are used for radioactive waste containment is reported. Two series of gels were obtained, in acidic and in basic solutions, and were analysed using 1H, 29Si and 27Al MAS NMR spectroscopy.170 A series of synthetic sodium-rich saponites and trioctahedral Na, K and Ba mica solid solutions are investigated by 29Si MAS-NMR spectroscopy.171 Na8(AlSiO4)6(ReO4)2 sodalite was synthesised using a hydrothermal method and its crystal structure was determined from Rietveld refinement of experimental X-ray powder diffraction data. MAS NMR of 29Si and 27Al nuclei showed single intense peaks at diso = 92.4 ppm and diso = 57.5 ppm, respectively, confirming the alternating Si, Al tetrahedral ordering in sodalite deduced from the structural data. Chemical shifts for 29Si and 27Al calculated using correlative structural parameters (56.6 0.8 ppm and 92.3 0.9 ppm) showed good agreement with measured data indicating the validity of data derived from the Rietveld structural refinement.172 MnAPSO-34 molecule sieve was synthesised with triethylamine as the template, characterised with XRD, XRF, 31P, 27 Al and 29Si NMR and FT-IR techniques and compared with SAPO-34.173 A geopolymer material based on dehydrolyed aluminosilicate and phosphoric acid is synthesised from metakaolinite condensed with low-polymeric [PO4]3n–n tetrahedral units in phosphoric acid aqueous solution at room temperature. The material structure and geopolymerisation mechanism of the products are investigated using X-ray diffraction, Fourier transform IR spectroscopy and 29Si, 27Al MAS NMR.174 The authors prepared a hybrid inorganic/organic, anhydride proton-conducting polymer electrolyte (MePEG3SiO3)n. Structural characterisation of this MePEG3 polymer through 29Si NMR spectroscopy and gel-permeation chromatography indicates that the MePEG3 polymer is composed of several different structures giving a distribution of molecular weights and silicon resonances.175 Starting from diorganodichlorosilanes and the tetradentate salen-type ligand 1 o-HO-pMeOC6H3C(Ph):N(CH2)2N:C(Ph)C6H3OMe-p-OH-o, eight hexacoordinate diorganosilanes RR 0 Si[o-O-p-MeOC6H3C(Ph):N(CH2)2N:C(Ph)C6H3OMe-p-O-o] [R, R 0 = Ph, Me (2a); Ph, Et (2b); Ph, Cy (2c); vinyl, Me (2d); Ph, vinyl (2e); Ph, Ph (2f); Me, Me (2g); –(CH2)3– (3)] are synthesised. As proven by 29Si CP/MAS spectra as well as Si chemical shift tensor calculations, in compounds 2a, 2f and 2g the Si atom is most shielded in the direction of the axially arranged Si–C bonds.176 The syntheses of the first two disilynes were reported recently: the first by Wiberg and co-workers, who synthesized RSiRSiR (1; R = SiMe(Si-t-Bu3)2), and the second by Sekiguchi and co-workers, who synthesised RSiRSiR (2; R = Si-i-Pr[CH(SiMe3)2]2), which was also characterised by X-ray crystallography and NMR spectroscopy. The authors report the first detailed quantum-mechanical study of the 29Si NMR chemical shifts of disilynes, RSiRSiR, in particular those with R = H, CH3, SiH3, SiMe(SiH3)2, SiMe(SiMe3)2, SiMe(Si-t-Bu3)2 (1), Si-i-Pr[CH(SiMe3)2]2 (2).177 The 29Si chemical shifts in substituted disilynes are analysed by quantum-chemistry studies using a detailed breakdown of paramagnetic contributions into couplings of occupied and virtual canonical MOs. The results give indications of substituent effects on shielding and confirm the importance of energy denominators in the equation for sp in sym. substituted disilynes (H3SiSiSiSiH3 and H3CSiSiCH3) on their chemical shifts.178 The structures and isomerisation of magnesium chlorosilylenoid H2SiClMgCl are investigated by ab initio MO theory for the first time. Based on the B3LYP/6-31G(d) optimised geometries, 29Si chemical shifts and harmonic frequencies of various structures are obtained.179 Synthesis of the 1st neutral Z6-silabenzene complexes [M(Z6-C5H5SiTbt)(CO)3] [M = Cr (2), Mo (3); Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl] was achieved by the ligand exchange reactions of [M(MeCN)3(CO)3] (M = Cr, Mo) with the kinetically stabilised silabenzene C6H5SiTbt (1). The structures of Z6-silabenzene complexes 2 and 3 were fully characterised by 1H, 13C and 29Si NMR, UV/visible and IR spectroscopic analysis.180 The dependence of the 27Al NMR shielding on the framework Al position and on the charge compensating cation coordination and hydration was 88 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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studied for MCM-58 zeolite. NMR shielding constants are calculated with the large cluster models (E20 framework tetrahedral) at the geometries optimised at the periodic DFT level, employing the PW91 exchange-correlation functional. A simple linear correlation between 29Si NMR chemical shifts and av. T–O–T angles was confirmed for all-SiO2 ITQ-4.181 Intermediates formed in halogen addition (X = Br, Cl, F) to alkynes (ethyne, propyne, 2-butyne, trifluoromethylethyne, trimethylsilylethyne and 1-trimethylsilylpropyne) were studied computationally by MP2 at the MP2/6-311++G(3df,3pd) level and/or by DFT at the B3LYP/6-31+G(d) level. GIAO-MP2 and GIAO-DFT calculations are employed to compute NMR chemical shifts (13C, 19F and 29Si as appropriate).182 The hydration characteristics and the engineering properties of three types of eco-cement pastes, including their compressive strength, speciation, degree of hydration and microstructure, are studied and compared with those of ASTM type I ordinary Portland cement. The resultant degree of hydration and the increase in the length of the CSH gels with the curing age, are confirmed by 29Si NMR techniques.183 In 13C NMR spectroscopy, there are many empirical methods for fast and exact computation of 13C chemical shifts; comparable procedures for 29Si NMR chemical shifts are not existing or are older than 20 years. On basis of the largest database of 29Si chemical shifts available, along this paper a relatively simple procedure for the similarly exact calculation of the 29Si chemical shifts of disilanes (average margin of error ca. 3.7 ppm) is given.184 Treatment of Si(TPP)Cl2 (TPP = tetraphenylporphyrinato) with 2 equiv. of Na/ Hg in THF yields the reduced porphyrin complex, Si(TPP)(THF)2, in which the porphyrin ring system has an oxidation state of 4- and the complex is antiarom. Experimental 1H and 29Si NMR chemical shifts and NICS (nucleus-independent chemical shift) calculations on a model compd. indicate a strong paratropic ring current in Si(TPP).185 The authors present the application of the magic-angle turning technique to 29Si solid-state NMR of natural abundance crystalline and amorphous solids. Correlations between the isotropic and anisotropic chemical shifts are obtained by rotation of the sample around a single axis at the magic angle.186 The reaction between transPcSiCl2 (1) and the K salts of six fatty acids (2a–2f) led to the transPcSi[OOC(CH2)nCH3]2 compounds (3a–3f), which were characterised by elemental analysis IR, UV/visible and 1H, 13C and 29Si NMR spectroscopy.187 The synthesis and isolation of 12 a-aryl, b, b 0 -disilyl-substituted vinyl cations 1b-l, 7 and 8 with the tetrakis(pentafluorophenyl)borate counter anion is reported. The vinyl cations are characterised by NMR spectroscopy and are identified by their specific NMR chemical shifts (d 13C(C+) = 178.1–194.5; d 13C(Cb) = 83.3–89.9; d 13C(Cipso) = 113.6–115.2; d 29Si = 25.0–12.0), supported by density functional calculations at the B3LYP/6-311G(2d,p)//B3LYP/6-31G(d) level.188 Hartree-Fock SCF (HF-SCF) theory and the Gauge-including AO (GIAO) methods were used in the calculation of 29 Si NMR chemical shifts for ABOUT 90 units of 19 compounds of various silicate species of precursors for zeolites.189 Density functional theory at the B3LYP/6311++G(d,p) level is applied to calc. the 29Si NMR chemical shifts of a variety of organosiloxane moieties including monomers or precursors for polymerisation and representative segments of organosiloxane polymers or thin films.190 Inorganicorganic hybrid materials produced by the sol-gel method from Si(OR)4 and R 0 xySi(OR)y (R,R 0 -CnHm groups) compounds are very interesting materials for new optical techniques. Copolymerisation of tetraethoxysilane (TEOS) and of the organic modifiers was studied by means of both the 29Si MAS NMR and the FTIR spectroscopy.191 Hexacoordinate trifluoroacetohydrazonic acid silicon O,N-dicarboxylates having bulky cyclohexyl ligand at silicon undergo dissociation one of the chelating hydrazide nitrogens rather than the dissociation of the chloride acidoligand; however, corresponding triflate and iodide undergo ionisation of the acidoligands. Hypercoordinate [[CF3C(O):NNMe2-kO,kN]2Si(C6H11)Cl] (3, C6H11 = cyclohexyl) undergo reversible dissociation of one of the nitrogen arm of the trifluoroacetohydrazonate at room temperature in solution, which results in about Nucl. Magn. Reson., 2007, 36, 72–112 | 89 This journal is

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60 ppm increase of the 29Si NMR chemical shift.192 Rice (Oryza sativa L.) is a typical silicon (Si)-accumulating plant, but the mechanism responsible for the translocation from the root to the shoot is poorly understood. In this study, the form of Si in xylem sap is identified by 29Si-NMR spectroscopy.193 It has long been recognised that the 29 Si and 27Al NMR chemical shifts for aluminosilicate crystals and glasses correlate to some extent with the T–O–T bond angle (T is the tetrahedral atom Si or Al). With increasing T–O–T bond angle, the 29Si and 27Al NMR shieldings increase and the shifts thus become more negative This result was demonstrated both experiment and through quantum computations. However, no simple qualitative explanation has ever been given for what appears to be a simple qualitative trend. The authors provide such an explanation based upon quantum calculations.194 N-Methyl-2[(trialkylsilyl)methyl]pyridinium cations [R3 = Me3 (6a), iso-Pr3 (6b), Me2(Me3C) (6c)] and 4-[(trialkylsilyl)methyl]pyridinium cations (same R3, 5a–c, respectively) were prepared and studied by using 29Si and 13C NMR and single-crystal X-ray crystallography (for 5b and 6b).195 Samples in the system Lu2xYxSi2O7 (0 r x r 2) were synthesised following the sol-gel method and calcined to 1300 1C, a temperature at which the b-polymorph is known to be the stable phase for the end-members Lu2Si2O7 and Y2Si2O7. 29Si MAS NMR spectra of the different members of the system agree with the XRD results, showing a linear decrease of the 29Si chemical shift with increasing Y content.196 2.14.3 Germanium (73Ge) (I = 9/2). The cation capture/transport ability of diazacrowns, one with side chains containing germanium (5a), another with side chains not containing germanium (7), and 4,13-diaza-18-crown-6 (8), was found to decrease in the order 5a 4 7 4 8. Titrimetric experiment and 73Ge NMR failed to give an unequivocal rationalisation of the results.197 The authors report on the pressure-induced novel phases of ferromagnetism (FM) and superconductive (SC) in the itinerant ferromagnet UGe2 through 73Ge-NQR measurements under pressure (P). Recent advances in 73Ge NMR spectroscopy are reviewed.198 High-resolution solid-state magic angle spinning 73Ge NMR spectra of hexavalent germanium compounds, i.e. diiodogermylene and bis(1-pyrrolyl)(meso-tetraphenylporphyrinato)germanium , were determined.199 High-resolution solid-state magic angle spinning 73Ge NMR spectra of some organogermanium compounds were measured.200 2.14.4 Tin (117, 119Sn) (I = 1/2, 1/2). Novel polymeric derivatives of various average molecular weights bearing tributyltin carboxylate moieties as terminal groups were prepared by esterification with bis(tributyltin) oxide of the corresponding poly(ethylene glycol)s functionalised with dimethylenecarboxylic end groups. Low-molecular-weight compounds were also synthesised, with the aim of investigating the influence of the polymeric chain on tin properties. As investigated by Sn NMR and Fourier transform IR, the metal center appears to be completely tetracoordinated in chloroform solution at room temperature, whereas at low temperature, the tin atom undergoes a fast exchange between intramolecular pentacoordination with the ethereal oxygen atoms and the unassociated form.201 Novel polymeric derivatives bearing tributyltin carboxylate moieties in the side chain were synthesised. The coordination at tin in solution and in the solid state was investigated by both Sn-NMR and FT-IR.202 New organotins containing the (ortho-MeEC6H4-CH2-), L, group, E = O, S, Se and CH2, will be reported. The rationale for studying such systems was to evaluate their structures with respect to the intramolecular E Sn interaction and to evaluate the role of the E group in modifying their biocidal properties. Solid state Sn NMR data and biocidal activity against a suite of bacteria will also be presented.203 1,3-dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates of the types SCH2CH2SSn[S2CNR2]Cl (I) and SCH2CH2SSn[S2CNR2]2 (II) (where R = CH3, C2H5 and –CH2–CH2–) were 90 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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synthesised by the reaction of 2,2-dichloro-1,3-dithia-2-stannacyclopentane and sodium/ammonium salts of dialkyldithiocarbamates in 1:1 and 1:2 molar ratios, respectively, in anhydrous benzene. These newly synthesised derivatives were characterised by elemental analyses, thermal as well as spectral [UV, IR and multinuclear NMR (1H, 13C and 119Sn)] studies.204 The first isolation of diarylstannanethione (tin–sulfur double-bond compound) and diarylstannaneselone (tinselenium double-bond compound), Tbt(Ditp)SnQX (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl; Ditp = 2,2 0 -diisopropyl-m-terphenyl-2 0 -yl; X = S and Se) was accomplished by dechalcogenation of the corresponding highly hindered tetrachalcogenastannolanes, Tbt(Ditp)SnX(4). The 119Sn NMR of stannanethione (Tbt(Ditp)SnQS) and stannaneselone (Tbt(Ditp)SnQSe), showed only one lowfield broad signal at 531 and 440 ppm, respectively, characteristic of a tricoordinated tin, and hence, the stannanethione and stannaneselone display an intrinsic nature of tin-chalcogen double-bond compounds.205 Six new derivatised deltahedral Zintl ions were synthesised by reactions between the known Zintl ions Ge(9) (n-) with the halides R(3)EX and/or the corresponding anions R(3)E(-) for EQGe or Sn. The tincontaining anions were characterised also in solutions by 119Sn NMR spectroscopy.206 A series of (salen)tin(II) and (salen)tin(IV) complexes was synthesised. All complexes were fully characterised by 1H NMR spectroscopy, mass spectrometry and elemental analysis, while some were characterised by 13C, 19F and 119Sn NMR spectroscopy.207 A series of diorganotin(IV) and dichlorotin(IV) derivatives of 4-Xbenzohydroxamic acids, [HL(1) (X = Cl) or HL(2) (X = OCH(3))] formulated as [R(2)SnL(2)] (R = Me, Et, nBu, Ph or Cl; L = L(1) or L(2)), along with their corresponding mixed-ligand complexes [R(2)Sn(L(1))(L(2))] were prepared and characterised by FT-IR, 1H, 13C and 119Sn NMR spectroscopy, mass spectrometry, elemental analysis and melting points.208 Dialkyltin(IV) and trialkyltin(IV) complexes of the deacetoxycephalo-sporin-antibiotic cephalexin [7-(d-2-amino-2-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid] (Hceph) were synthesised and investigated both in solid and solution phase. Analytical and thermogravimetric data supported, while structural information was gained by FT-IR, 119Sn Mossbauer and 1 H, 13C, 119Sn NMR data.209 2.14.5 Lead (207Pb) (I = 1/2). Metal has the power to induce biological activity by interaction with DNA by thread binding mechanism. Achieving optimal chemopreventive potency with lowest toxicity continues to be our primary goal in designing and developing lead(II) complexes of phenenthrolines and dicarboxylic acids. These complexes were characterised by chemical analysis, IR, 1H, 13C and 207Pb NMR spectral studies, X-ray powder diffraction, molecular weight determinations.210 Crystals of the layered metal organic framework solid Pb[B(Im)4](NO3)(nH2O) can undergo exchange of the nitrate for perrhenate, a model for pertechnetate, forming Pb[B(Im)4](ReO4). The authors can monitor this reaction by 207Pb solidstate NMR and can isolate single crystals of the resultant material through growth in the presence of an excess of perrhenate.211 Lead(II) complexes with 2,4,6-tris(2pyridyl)-1,3,5-triazine (trz) were synthesised using a direct synthetic method and characterised by IR and 207Pb NMR spectroscopy and CHN elemental analysis.212 1:1 and 1:2 lead(II) complexes with 2,9-dimetyl-1,10-phenanthroline (Dmphen), {[Pb(Dmphen)(NO3)n] and [Pb(Dmphen)2(ClO4)2]} were synthesised and characterised by CHN elemental analysis, IR, 1H NMR, 13C NMR and 207Pb NMR spectroscopy.213 Structural speciation of glasses in the systems PbO–B2O3–SiO2, PbO–B2O3–Al2O3–SiO2 and PbO–Al2O3–SiO2 were studied using solid state 29Si, 27 Al, 11B and 207Pb NMR and Raman spectroscopy.214 Lead(II) complexes with ethane-1,2-diamine (en) containing two different anions, [Pb(en)(CH3COO)X] (X = NCS, ClO4 or NO3), were synthesised and characterised by CHN elemental analysis, IR, 1H NMR, 13C NMR and 207Pb NMR spectroscopy.215 A novel 3dimensional polymeric heteropolynuclear Na(I) Pb(II) complex containing different Nucl. Magn. Reson., 2007, 36, 72–112 | 91 This journal is

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ligands, [NaPb(ClO4)(en)(NO2)2] was synthesised and characterised by elemental analysis, IR and 1H, 13C, 207Pb NMR spectroscopy.216 Lead(II) complexes with 2,2 0 :6 0 ,200 -terpyridine (tpy) and 2,4,6-tris(2-pyridyl)-1,3,5-triazine (trz) ligands, [Pb(tpy)(CH3COO)2] and [Pb(trz)(CH3COO)2], were synthesised and characterised by IR, CHN elemental analysis and 207Pb NMR.217 The structure of (25–x/2) Li2O (25–x/2)Na2O xPbO 50P2O5 phosphate glasses (0 r x r 50 mol%) was investigated by Raman spectroscopy and 31P-MAS and 207Pb-VOCS NMR.218 The phase transitions of a ferroelastic CsPbCl3 single crystal grown by using the Bridgman method were studied using 133Cs and 207Pb NMR.219 A new Pb(II) complex of 2.2 0 -bipyridine (bpy), acetate and thiocyanate was synthesised and characterised by CHN elemental analysis, IR, 1H NMR, 13C NMR and 207Pb NMR spectroscopy.220 {Pb(m-Br)ArPri2}2 (1), {Pb(m-Br)ArPri2But}2 (2), Pri2Ar (Me)PbPb(Me)ArPri2 (3). {Pb(C6H4-4-But)ArPri2}2 (4), Pb(But)ArPri2 (5), [Pb(CH2C6H4-4-Pri)ArPri3](6) and [Pb(Si(SiMe3)3)ArPri3](7) were characterised with use of X-ray crystallography, 1H, 13C and 207Pb NMR and UV-Vis spectroscopy.221 Pb(II) complexes with the 4,4 0 -bipyridine (4,4 0 -bipy) ligand were synthesised and characterised by CHN elemental analysis, IR, 1H NMR, 13C NMR and 207 Pb NMR spectroscopy.222 A 207Pb spin echo signal and a 17O–207Pb spin echo double resonance signal were measured in the metallic phase of BaPb1xBixO3 oxides (x o 0.15).223 The inhomogeneous magnetic broadening of the 17O and 207Pb NMR spectra resulting from a distribution of the Knight shifts was studied in the metallic phase of BaPb1xBixO3 oxides (0 r x r 0.33).224 An attempt to prepare Ce- and La-doped SiO2–PbO glasses for applications as scintillators was realised via aerogel route. Both 207Pb and 29Si magic angle spinning (MAS) NMR were used to investigate local order and connectivity.225 Reactions of triethylmetal(IV) chlorides (for example, Et3GeCl) with sodium salts of internally functionalised oximes (for example, 2-acetylpyridyl oxime) in a 1:1 molar ratio in refluxing anhydrous benzene yielded [Et3M{ON:C(R)Ar}] [where R = H, Me; M = Ge, Sn or Pb; Ar = 2C5H4N, 2-C4H3O or 2-C4H3S]. The derivatives were characterised by elemental analysis and IR and NMR [1H, 13C{1H}, 119Sn{1H} and 207Pb{1H}] spectroscopic studies.226 The quadrupolar Carr-Purcell Meiboom-Gill (QCPMG) pulse sequence has received much attention in the recent literature for use in the rapid acquisition of solid-state NMR spectra of half-integer quadrupolar nuclei. Herein we investigate the application of the CPMG pulse sequence to enhance the signal-to-noise ratio in the static NMR spectra of spin-1/2 nuclei. The CPMG and CP/CPMG pulse sequences are applied to a series of different NMR nuclides, including 113Cd, 199 Hg, 207Pb, 15N and 109Ag.227 New Pb(II) complexes, Pb(dmphen)X2 (X = NO3, ClO4 and CH3COO; dmphen = 2,9-dimethyl-1,10-phenanthroline), were synthesised and characterised by CHN elemental analysis, IR, 1H, 13C and 207Pb NMR spectroscopy.228 A new class of Pb(II) and Sn(II) complexes of a macrocyclic Schiff base ligand containing a thiosemicarbazone moiety was prepared, [M(H2MacL2)X2], where M = Pb(II) or Sn(II); H2MacL2 = 3,4,9,10-tetraphenyl1,2,5,6,8,11-hexaazacyclododecane-7,12-dithione-2,4,8,10-tetraene; X = Cl or NO3. Thus, when the triaza-macrocycle I (H2MacL1) in EtOH reacts with CrCl3, the macrocyclic ligand H2MacL2 (II) is formed. The complexes were characterised from elemental analysis, molar conductance, magnetic susceptibility, IR, 1H NMR, 119 Sn NMR, 207Pb NMR and XRD.229 Lead fluoride, a superionic conductor was prepared in its nanostructured form by Inert Gas Condensation Technique (IGCT) using an Ultra High Vacuum (UHV) chamber. Solid state 207Pb MAS NMR was carried to average out the dipolar interaction and the resultant isotropic peaks were assigned to the corresponding phases.230 The results of the extensive investigations of the variation of the EPR and 207Pb NMR spectra of active centers due to the existence of the native defects generated by disorder in the IV–VI semiconductor matrixes are presented.231 The 207Pb static, magic-angle spinning (MAS) and two-dimensional phase-adjusted spinning sidebands (2-dimensional-PASS) NMR experiments were performed on (1–x)PMN/ 92 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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xPSN [where PMN stands for Pb(Mg1/3Nb2/3)O3 and PSN stands for Pb(Sc1/2Nb1/2)O3] relaxor ferroelecs.232 Novel nonstoichiometric mixed lead and Sn niobates with the pyrochlore structure were synthesised via a solid-state route. The materials were characterised by bulk chemical analysis, single-crystal and powder X-ray diffraction, 207Pb, 119Sn and 93Nb (single and triple quantum) solid-state NMR spectroscopy.233 207Pb, 45Sc and 93Nb nuclear-magnetic-resonance (NMR) spectra of partially ordered relaxor ferroelectric PbSc1/2Nb1/2O3 (PSN) were studied at 77– 420 K234 [PBun4]2[PbPh2Cl4] and [PPh4][PbPh3Cl2] were characterised by NMR (1H, 13 C, 31P and 207Pb), IR, MS and X-ray crystallography.235 In the solid state, heavier NMR-active nuclei such as 195Pt, 199Hg and 207Pb commonly exhibit chemical shifts that range well over 1000 ppm, depending upon the orientation of the mol. within the applied magnetic field. Thus, acquiring NMR spectra of polycrystalline samples is often an experimental challenge because of these very broad powder patterns. In acquiring chemical shift powder patterns of these nuclei, the authors provide several examples that demonstrate that a considerable saving in time is realised by using the CPMG experiment as opposed to the standard 1-pulse or spin-echo experiment.236 A Pb(II) complex with three ligands, 4,4 0 -bipyridine (4,4 0 -bpy), nitrate and thiocyanate, was synthesised and characterised by CHN elemental analysis, IR-, 1H-, 13C- and 207 Pb NMR spectroscopy.237 A 2.8 kV/cm electric field was applied parallel to the external magnetic field along the [111] direction of a PMN single crystal and the 207 Pb NMR spectra were measured at 9.1 T.238 The coordination polymer Pb[B(Im)4](NO3)(xH2O), constructed by using Na tetrakis(imidazolyl)borate and Pb(NO3)2 solutions, is a layered material with the metal centers facing the interlayer spacing. As in naturally occurring layered minerals, this compound can readily undergo anion exchange and reversible intercalation of solvent H2O in the solid state with retention of crystallinity. The authors observed changes in solvent intercalation by 207Pb solid state NMR (SSNMR) and TGA.239 2.15 Group15 (14,15 N,

31

P)

2.15.1 Nitrogen (14,15 N) (I = 1, 1/2). The measurement of amide nitrogen 14N quadrupolar coupling by two-dimensional 14N/13C correlation experiment is presented with a natural abundant polypeptide. Directly bonded 14N/13C pairs are correlated through J and residual dipolar coupling under magic-angle spinning using a HMQC-type pulse sequence. The 14N quadrupolar coupling is measured from the isotropic second-order quadrupolar shift obtained by comparing the 14N peak positions with the 15N chemical shifts.240 The high resolution offered by magicangle spinning (MAS), when compared to the static condition in solid-state NMR of powders, was used to full advantage in a 14N MAS NMR study of some ammonium salts: CH3NH3Cl, (NH4)2(COO)2 H2O, Me3(C6H5CH2)NCl, Me3PhNI, [Bu4N]2Mo2O7, (NH4)2HPO4 and NH4H2PO4.241 Derivatives of 3-imidazoline 3-oxide were studied by 14N and 17O NMR methods. Regularities of the influence of substituents and of a hydrogen bond on chemical shifts were made apparent.242 13C, 14N, 15N, 17 O and 35Cl NMR parameters, including chemical shift tensors and quadrupolar tensors for 14N, 17O and 35Cl, are calculated for the crystalline forms of various amino acids under periodic boundary conditions and complemented by experiment where necessary.243 The electronic structures and mol. properties of S2N2 as well as the currently unknown chalcogen nitrides Se2N2 and SeSN2 were studied using various ab initio and density functional methods. Predictions for the vibrational frequencies, IR intensities, Raman activities and 14N, 15N, 77Se chemical shifts, as well as singlet excitation energies of Se2N2 and SeSN2, were made.244 GaN crystals doped with Mn ions were synthesised by the alkali metal flux method. Mixtures of metals were premelted to form an alloy and the alloy was mixed with Na/K and heated to E8001 under E1400 psi N2 in an Al2O3 crucible. Up to 2 mol% Mn could be incorporated into the h-GaN lattice, and the products were characterised by solid state 71Ga, 69Ga, 14N NMR, magnetometry, Raman spectroscopy and powder X-ray Nucl. Magn. Reson., 2007, 36, 72–112 | 93 This journal is

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diffraction.245 Exploiting naturally abundant 14N and 31P nuclei by high-resolution MAS NMR (magic angle spinning NMR) provides a molecules view of the electrostatic potential present at the surface of biol. model membranes, the electrostatic charge distribution across the membrane interface and changes that occur upon peptide association. The spectral resolution in 31P and 14N MAS NMR spectra is sufficient to probe directly the negative charged phosphate and positive charged choline segment of the electrostatic PQO–CH2–CH2–N+(CH3)3 headgroup dipole of zwitterionic DMPC (dimyristoylphosphatidylcholine) in mixed-lipid systems.246 14 N magic-angle spinning NMR spectra were obtained and analysed for the nitrate ions of the two isomorphous room-temperature phases RbNO3(IV) and CsNO3(II).247 This review covers current trends in studies of membrane amphiphiles and membrane proteins using both fast tumbling bicelles and magnetically aligned bicelle media for both solution state and solid state NMR.248 The author’s results obtained from studies of the chemical micro-mechanisms of nitramines initiation from the point of view of organic chemistry were summarised. The relationships were presented and discussed between the characteristics of impact and electric spark sensitivities, detonation and thermal decomposition, on the one hand, and 15N NMR chemical shifts of N atoms of nitroamino groups, on the other.249 A review describes the recent progress in studies of RNA-metal systems. The metal ligands provides the chemical basis for mechanistic studies of metal complexes. Topics discussed include the hammerhead ribozyme and its metal ion-binding motif; analysis of titration experiments by 15N NMR spectroscopy; perturbations in 1H and 13C chemical shifts; interactions with other metal cations; comparisons with crystal structures; possible functions of a shared-type G–A pair in biological systems; sequence requirements for the binding of metal ions; and roles of the metal cation at the binding motif.250 Antimicrobial peptides are key components of innate immunity of all life forms. Understanding the structure activity relationship of these peptides is essential for developing them into novel therapeutics that substitutes traditional antibiotics. NMR spectroscopy can provide insights into membranetargeting antimicrobial peptides from a variety of angles.251 A review on the synthesis and structure of side-on-bound dinitrogen complexes of lanthanides, actinides and transition elements over the past 40 years is given. Hydrogenation and alkyne addition to side-on transition metal dinitrogen complexes yielded in sideon-coordinated (alkenyl)hydrazido species, cleavage of the N–N-bond gave nitridoand amido-bridged complexes. A compilation of N–N-bond lengths and 15N NMR chemical shifts, IR and Raman data for side-on metal dinitrogen complexes is presented.252 XPA, a 273 amino acid protein, is involved in the early stage of the nucleotide excision repair, by which a variety of DNA lesions are removed from the genome. NMR was used to analyze the structure of the central domain of XPA, which encompasses residues 98 to 219, and contains a zinc coordinating motif. Following chemical shift assignments of the backbone and side-chain 1H, 15N and 13 C nuclei, the tertiary structure was determined by multi-dimensional and multiresonance NMR methods.253 NMR spectroscopy is rapidly becoming an important technique for the study of membrane protein structure and dynamics. NMR experiments on large perdeuterated proteins typically exploit the favorable relaxation properties of backbone amide 15N–1H groups to obtain sequence-specific chemical shift assignments, structural restraints and a wide range of dynamics information.254 This contribution reviews applications of NMR spectroscopy in the study of the structure and the intra- and intermolecular interactions of purine derivatives. Purines represent a highly important class of heterocyclic compounds that are widely distributed in all living organisms, not only as constituents of nucleic acids, but also as signal molecules. In the following text, NMR methods suitable for studying the purine structure and their application to exploring samples at natural levels of the 13C and 15N isotopes are briefly reviewed. As are shown, isotropic 13C and 15N chemical shifts, 1H–13C one- and three-bond J-coupling constants and 1 H–15N one- and two-bond couplings are the commonly used characteristic 94 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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parameters for NMR in the solution state.255 Different symmetrical substituted and cyclic dialkydithiocarbamate (R = CH3, C2H5, C3H7, i-C3H7, C4H9, i-C4H9 and R2 = (CH2)5, (CH2)6, (CH2)4O) compounds, such as tetraalkylthiuram disulfides, mononuclear nickel(II), binuclear zinc(II) and heteropolynuclear complexes and their adducts (both non-solvated and solvated forms) with planar and non-planar Ndonor org. bases, were prepared and studied by means of natural abundance 13C and 15 N CP/MAS NMR spectroscopy.256 2.15.2 Phosphorus (31P) (I = 1/2). Different K salts and Zn(II) and Ni(II) O,O 0 dialkyldithiophosphate complexes were studied by solid-state 31P CP/MAS and static NMR and ab initio quantum mechanical calculations.257 Polycrystalline tetranuclear Cu4[S2P(O-i-C3H7)2]4, hexa-nuclear Cu6[S2P(OC2H5)2]6 and octa-nuclear Cu8[S2P(O-i-C4H9)2]6(S) complexes were synthesised and analysed by means of solid-state 31P CP/MAS and 65Cu static NMR spectroscopy.258 Glasses and melts in the system (NaPO3)(1x)(Al(PO3)3)x were studied with the aim of obtaining information about the structure on the next larger scale beyond the PO4 group. Magic angle spinning NMR was applied to the pure NaPO3 glass and Raman scattering to systems with x = 0.00, 0.03, 0.06, 0.15 and 0.60 in the temperature range T = 300–1100 K. Comparison of the 31P chemical shift between glass and crystalline forms revealed that polymerisation of the metaphosphate into tricyclophosphatelike (PO3)3(3-) rings is the dominant structure, ca. 80%, formed by the twofold vertex-joined PO4 groups in the glass.259 Coronary angiography is still the gold standard for the diagnosis of cardiac allograft vasculopathy (CAV) for which alternative non-invasive diagnostic approaches are currently investigated. In this study, the authors assessed whether 31P magnetic resonance chemical shift imaging can diagnose CAV by studying variations in cardiac high-energy phosphates in a population of adult heart transplant recipients.260 In the present study the authors applied proton-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) to noninvasively assess liver metabolism in patients who had undergone a partial hepatectomy (PH). Proton-decoupled 31P chemical shift imaging was performed in 47 patients 2–28 days following major hepatectomy, and the results were compared with those from eight control subjects.261 The interactions of synthetic chalcocite surfaces with diethyldithiophosphate, potassium salt, K[S2P(OC2H5)2], are studied by means of 31P cross-polarisation/magic angle spinning (CP/MAS) NMR spectroscopy and scanning electron microscopy (SEM).262 Three new amine-templated zinc phosphates, [C4N2H14][Zn(HPO4)2] H2O, AU-I, [C4N2H14][Zn2(H(0.5)PO4)2 (H2PO4)], AU-II and [C4N2H14][Zn5(H2O)(PO4)4], AU-III, are prepared by hydrothermal synthesis using an organic amine, N,N 0 -dimethylethylendiamine CH3NHCH2CH2NHCH3, as structure-directing agent. The phase stability investigated by systematic hydrothermal synthesis is presented, and the materials are further characterised by 31P solid-state MAS NMR, for example, by determination of 31P chemical shift anisotropies for AU-III, while the thermal behaviour is investigated by thermogravimetry (TG).263 2.16 Group 16 (17O,

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S,

77

Se,125Te)

2.16.1 Oxygen (17O) (I = 5/2). Sodium germanate glasses are well-studied materials in which, unlike silicates but analogous to borates, the major structural consequence of alkali addition is generally thought to involve a coordination no. increase of the network-forming Ge cations. However, the nature of this change, in particular quantifying fractions of nonbridging oxygens and of five- and/or sixcoordinated Ge, has remained unresolved. The authors present here high-resolution 17 O results, including triple-quantum MAS NMR (3QMAS), on a series of crystal model compounds that allow the definition of ranges of chemical shifts corresponding to oxygens bonded to various coordinations of Ge.264 Effects of temperature and some aqueous solutions of electrolytes consisting of ions in natural water on the Nucl. Magn. Reson., 2007, 36, 72–112 | 95 This journal is

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chemical shifts of NMR of water (17O NMR) are measured.265 The natural abundance 17O NMR chemical shift data for 3,5-diarylisoxazoles (1a–k) and 3,5diarylisoxazolines (2a–j) in acetonitrile at 75 1C are reported.266 A phosphane sulfate relativistic DFT method (ZORA) was used to calculate the 183W and 17O NMR chemical shifts for large polyoxotungstates, including W6O192, CH3OTiW5O183, W5O18WIINO3, W10O324, a-d-g-XW12O40n, b-PW9O28Br63, P2W18O626, PW2O143 and W7O246, based on their optimised molecular structures.267 A relativistic DFT method (ZORA) is used to calculate the 183W and 17O NMR chemical shifts for the reduced polyoxotungstates W5O18WIINO3, g-SiW12O406, P2W18O628 and W10O326 with different degrees of (de)localisation of the electrons introduced.268 17O NMR spectroscopy of oxo ligand of oxo metalloporphyrin can be considered as an excellent means to derive information about structure, electronic state and reactivity of the metal bound oxo ligand. To show the utility of 17O NMR spectroscopy of oxo ligand of oxo metalloporphyrin, 17O NMR spectra of oxo ligands of dioxo ruthenium(VI), oxo chromium(IV) and oxo titanium(IV) porphyrins are measured.269 The authors investigate the performance for nuclear magnetic constants calculations for a selective set of density functional methods (B3LYP, PBE0, BLYP, PBEPBE, OLYP and OPBE). The testing set includes the 13C, 15N, 17 O and 19F magnetic shieldings and chemical shifts of 23 molecules with 64 comparisons altogether.270 The 17O chemical shifts of substituted benzyl ethers and a set of organotin(IV) derivatives containing O,C,O-chelating ligands are studied.271 17O NMR spectra of a-diesters are measured at natural abundance in acetonitrile solutions.272 Derivatives of 3-imidazoline 3-oxide were studied by 14N and 17O NMR methods.273 A systematic solid-state 17O NMR study of a series of carboxylic compound, maleic acid, chloromaleic acid, KH maleate, KH chloromaleate, K2 chloromaleate and LiH phthalate MeOH, is reported.274 The solvent exchange between bulky TMU (1,1,3,3-tetramethylurea) molecules and the TMU molecules bound to metal cations (Mn(II), Fe(II), Ni(II), Cu(II) and Fe(III)) in neat TMU was studied by the oxygen-17 NMR line-broadening and chemical shift method.275 Two novel derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), TTDA-BOM and TTDA-N 0 -BOM, each having a benzyloxymethyl group, are synthesised. 17O NMR longitudinal and transverse relaxation rates and chemical shifts of aqueous solutions of their Gd(III) complexes were measured at variable temperature with a magnetic field strength of 9.4 T.276 Water clusters of Na+, K+ and NH4+ ions with Cl and I counterions were studied using 17 O NMR spectroscopy.277 Among the synthesis of a series of five well-known 2trifluoroacetyl-1-methoxycycloalkenes derived from cyclopentanone and substituted cyclohexanones, this paper describes the synthesis of three new 2-trifluoroacetyl-1methoxycycloalkenes derived from cycloheptanone, cyclooctanone and cyclododecanone in 60–68% yield. Subsequently, the 17O NMR chemical shift analysis of the carbonyl and the methoxy groups for these cyclic molecules clearly showed the electron push-pull phenomenon and revealed large and irregular variations of 17O NMR chemical shifts with the ring size.278 The complex formation of uranium(VI) with four nucleotides, adenosine- (AMP), guanosine- (GMP), uridine- (UMP) and cytidine-monophosphate (CMP), was studied in the alkali pH range (8.5–12) by 1H, 31 P, 13C and 17O NMR spectroscopy, providing spectral integral, chemical shift, homo—and heteronuclear coupling and diffusion coefficient data.279 1H, 19F, 13C, 15 N and 17O NMR chemical shifts and 1H–1H, 1H–19F, 1H–13C, 19F–13C and 19 F–15N coupling constants are reported for 2-(trifluoromethyl)-2-oxazoline.280 Solution 17O NMR spectroscopy was used for structure elucidation of siloxane copolymers with the natural abundance of 17O, i.e. without any enrichment prior to spectroscopy.281 Recently available ultrahigh magnetic fields offer new opportunities for studies of quadrupole nuclei in biological solids because of the dramatic enhancement in sensitivity and resolution associated with the reduction of secondorder quadrupole interactions. Here, the authors present a new approach for understanding the function and energetics of ion solvation in channels using solid96 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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state 17O NMR spectroscopy of single-site 17O-labeled gramicidin A.282 13C, 14N, 15 N, 17O and 35Cl NMR parameters, including chemical shift tensors and quadrupolar tensors for 14N,17O and 35Cl, are calculated for the crystal forms of various amino acids under periodic boundary conditions and complemented by experiment where necessary.283 A variety of computational tools were used to study the chemical properties of point defects in the crystalline phase of ZrSiO4, and their effect in its lattice parameters. Our calculations also show that vol. swelling in crystal ZrSiO4 would produce a considerable displacement of the 17O and 91Zr chemical shifts towards higher values, whereas the 29Si spectra would be largely independent of the defect-induced swelling.284 The temperature dependence of 17O and 25Mg NMR chemical shifts in solid MgO were calculated using a 1st-principles approach.285 The structure of poly di-Et siloxane (PDES) was characterised using solid-state NMR of 17 O.286 The salvation shell structure of Y3+ and the dynamics of the hydrated ion in an aqueous solution of 0.8 M YCl3 are studied in two conditions with and without an excess proton by using first principles molecular dynamics method. A detailed analysis relying upon localised orbitals reveals that the complexation of water molecules with yttrium cation leads to a substantial amt. of charge redistribution particularly on the oxygen atoms, giving rise to the chemical shifts of E20 ppm in 17 O NMR relative to the computed nuclear shieldings of the bulk water.287 The 17O NMR spectrum of CaAl2Si2O8 glass shows two types of O sites that are not present in the crystal material. One of these, with 17O NMR parameters CQ = 2.3 MHz and d = +20 ppm, was assigned to a ‘‘tricluster’’ O, a local geometry in which the O is coordinated to three tetrahedrally coordinated atoms, either Al or Si.288 The N 0 -monoamide derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10triazadodecanedioic acid), N 0 -methylamide (TTDA-MA), N 0 -benzylamide (TTDABA) and N 0 -2-methoxybenzylamide (TTDA-MOBA), were synthesised. The 17O NMR chemical shift of H2O induced by [Dy(TTDA-MA)(H2O)] at pH 6.80 showed 0.9 inner-sphere H2O molecules.289 2.16.2 review.

Sulfur (33S) (I = 3/3). No reference was founded during the period of this

2.16.3 Selenium (77Se) (I = 1/2). 1,3-Bis(ferrocenylchalcogeno)propanes (FcE (CH2)3E 0 Fc, E and E 0 = Se and Te) and 1,2-bis(ferrocenylseleno)ethane (FcSe(CH2)2SeFc) were prepared, characterised and included in a spectroscopic and electrochemical study of a series of compounds containing two ferrocenes linked by a chalcogen-containing bridge. 77Se and 125Te NMR spectroscopic measurements reveal that the 77Se chemical shift of Fc2Se2 is anomalously high, which correlates with the long wavelength of its lowest energy electronic absorption.290 The orientational effect of p-YC6H4 (Ar) on d(Se) is elucidated for ArSeR, based on experimental and theoretical investigations.291 The oxidation products of selenomethionine (SeMet) are studied via experimental 77Se NMR and theoretical 77 Se chemical shifts.292 The theoretical chemical shifts of a large series of selenium compounds are calculated using GIAO-MP2 and -DFT methods in several basis sets.293 The electronic structures and molecular properties of S2N2 as well as the currently unknown chalcogen nitrides Se2N2 and SeSN2 are studied using various ab initio and density functional methods. Predictions for the vibrational frequencies, IR intensities, Raman activities and 14N, 15N, 77Se chemical shifts, as well as singlet excitation energies of Se2N2 and SeSN2, were made.294 Weak nonbonded interaction between a divalent selenium and an oxygen atom (i.e., Se O interaction) frequently plays important roles in chemical and biological functions of selenium compounds. To establish that 77Se NMR is an easy experimental probe to diagnose the strength of an Se O interaction, 3 series of 2-substituted benzeneselenenyl derivatives, which have an intramolecular Se O interaction in solution, were employed. By comparing the 77Se NMR chemical shifts (dSe) with those observed for other series of Nucl. Magn. Reson., 2007, 36, 72–112 | 97 This journal is

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selenium compounds, which have an intramolecular Se Y (Y = N, O, F, Cl, or Br) interaction, approximately linear correlation was found between the dSe values and the strengths of the nonbonded Se Y interactions evaluated by natural bond orbital analysis at the B3LYP level.295 Three mixed ligand complexes of Au(I) with phosphines and selenones, [Et3PAu(Se:Co)]Br [Se:C o = imidazolidine-2-selenone (ImSe), N-methylimidazolidine-2-selenone (MeIMSe), 1,3-diazinane-2-selenone (DiazSe)] as analogs of auranofin (Et3PAuSR) were prepared and characterised by elemental anal., IR and NMR methods. Large 77Se NMR chemical shifts (55 ppm) upon complexation in the solid state for [Et3PAuDiazSe]Br compared to [Et3PAuImSe]Br (10 ppm) indicates the former to be more stable and the Au–Se bond to be stronger than in the latter complex.296 The ability of MP2, B3PW91 and PBE0 methods to produce reliable predictions in structural and spectroscopic properties of small Se-halogen molecules and cations was demonstrated by using 6-311G(d) and cc-pVTZ basis sets. The calculated isotropic shielding tensors can be used in the spectroscopic assignment of the 77Se chemical shifts of novel Se-halogen molecules and cations.297 Phosphinoselenoic chlorides bearing two different organic substituents at phosphorus were prepared by partial alkylation or arylation of phenyldichlorophosphine in the presence of elemental selenium; phosphinoselenoic esters, thio- and selenoesters were also prepared. Linear correlations were observed between the experimental 77Se NMR chemical shifts or the coupling constants of P–Se bonds in the esters and the calculated P–Se bond lengths of the model compounds.298 2.16.4 Tellurium (125Te) (I = 1/2). 1,3-Bis(ferrocenylchalcogeno)propanes (FcE(CH2)3E 0 Fc, E and E 0 = Se and Te) and 1,2-bis(ferrocenylseleno)ethane (FcSe(CH2)2SeFc) were prepared, characterised and included in a spectroscopic and electrochemical study of a series of compounds containing two ferrocenes linked by a chalcogen-containing bridge. Cyclic and differential pulse voltammetry show that there is electronic communication between the two ferrocene units when the bridge is short (as in Fc2E), but that the interaction rapidly becomes weaker with increasing Fe Fe distance, and is undetectable for the ethane and propane derivatives. 77Se and 125Te NMR spectroscopic measurements reveal that the 77Se chemical shift of Fc2Se2 is anomalously high, which correlates with the long wavelength of its lowest energy electronic absorption.299 The quasirelativistic (QR) generalised UHF method for the magnetic shielding constant [R. Fukuda, M. Hada and H. Nakatsuji, J. Chem. Phys., 2003, 118, 1015; R. Fukuda, M. Hada and H. Nakatsuji, J. Chem. Phys., 2003, 118, 1027] was extended to include the electron correlation effect in the level of the 2nd-order Moller-Plesset perturbation theory (MP2). The authors implemented the energy gradient and finite-perturbation methods to calculate the magnetic shielding constant at the QR MP2 level and applied to the magnetic shielding constants and the NMR chemical shifts of 125Te nucleus in various tellurium compounds.300 A series of N-arylimines of 2-telluro-2cyclohexene-1-carboxaldehydes were prepared; their crystal structures indicate dative hypervalent-type bonding interactions between tellurium and imine nitrogen. 2-Chloro-1-cyclohexenecarboxaldehyde was coupled with MeTeLi; after bromination of the tellurium atom and reaction with ArNH2, [2-(XTe)-1-cyclohexenylmethylene]arylamines (X = OAc, Br, F; aryl = 2,6-Me2C6H3, 4-MeC6H4) were prepared. Aryltelluro compound (X = 4-EtOC6H4, Ar = 4-MeC6H4) was also prepared. Crystal structures of these compounds were determined, and Te–N distances indicate strong dative interactions for compounds bearing electronegative substituents at tellurium (Br, F, OAc). The 125Te NMR chemical shifts of these compounds span the wide range of 734.3–1622.4 ppm.301 2.17 Group 17 (19F,

35,37

Cl)

2.17.1 Fluorine ( F) (I = 1/2). 19F NMR spectra of two neutral, organic-soluble helical peptide octamers, each labeled at its N terminus with either 19


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4-fluorobenzamide or 4-trifluoromethylbenzamide, in solvents with widely varying dielectric constants were observed.302 1H-decoupled 19F NMR was used to monitor the highly regioselective oxidation of a fluorine-tagged thia-fatty acid derivatives by castor stearoyl-ACP D9 desaturase.303 Human manganese superoxide dismutase (MnSOD) is a homotetramer of 22 kDa subunits, a dimer of dimers containing dimeric and tetrameric interfaces. The authors investigated conformational mobility at these interfaces by measuring amide hydrogen/deuterium (H/D) exchange kinetics and 19F NMR spectra, both being excellent methods for analyzing local environments.304 19F NMR chemical shifts are calculated in order to study the F-environment in double four ring (D4R) containing Si/Ge-zeolites.305 A series of 19 psubstituted aromatic trifluorovinyl ether compounds were prepared from versatile intermediatep-Br-C6H4-O-CF:CF2 and underwent thermal radical mediated cyclodimerisation to new difunctional compounds containing the 1,2-disubstituted perfluorocyclobutyl (PFCB) linkage. 19F NMR spectra confirmed that p-substitution affects the trifluorovinyl ether group chemical shifts.306 The authors investigate the performance for nuclear magnetic constant calculations for a selective set of density functional methods (B3LYP, PBE0, BLYP, PBEPBE, OLYP and OPBE). The testing set includes the 13C, 15N, 17O and 19F magnetic shieldings and chemical shifts of 23 molecules with 64 comparisons altogether.307 The authors report the effective 19F NMR chemical shift of 3-fluorobenzoic acid as in situ probe of the acidity of extensively frozen electrolyte solutions.308 The conformational free energy (A value) of the trifluoromethyl group was determined by variable temperature 19F NMR studies of trifluoromethylcyclohexanes bearing a substituent at the 4 position.309 For the first time, a small amount of sevoflurane ((CF3)2CHOCH2F) in carbon dioxide and xenon as the gaseous solvents was studied using 19F and 1H NMR spectra.310 For the first time, theoretical evidence that confirms the importance of the Berry pseudorotation process in the interpretation of the 19F NMR spectrum of phosphorus pentafluoride (PF5) is presented.311 Gene therapy has emerged as a promising strategy for treatment of various diseases. The authors previously demonstrated the ability to detect b-galactosidase (b-gal) activity on the basis of 19F NMR chemical shift associated with release of fluorophenyl aglycons from galactopyranoside conjugates. Use of fluoropyridoxol as the aglycon provides a potential less toxic alternative and the authors now report the design, synthesis and structural analysis of a series of novel polyglycosylated fluorinated vitamin B6 derivatives as 19F NMR-sensitive aglycons for detection of lacZ gene expression.312 19 F NMR chemical shifts and transverse relaxation times T2 were measured as a function of time after quick stopped-flow dilution of aqueous solutions of sodium perfluorooctanoate (NaPFO) with water.313 THF solutions of the cationic chiral 1,3diphenylallyl bidentate phosphine complexes lsqb;Pd(Z3-PhCHCHCHPh)(Duphos)](CF3SO3), Duphos = 1,2-Bis-[(2R,5R)-2,5-dimethylphospholanoenzene], 2 and [Pd(Z3-PhCHCHCHPh)(P,S)]BF4, 4, P,S = lsqb;8-(o-(diphenylphosphino)benzyl)thiomethyl]-(7,7 0 -dimethyl)-exo-norborneol, were studied via pulsed gradient spin-echo (PGSE) diffusion, 1H, 19F HOESY and a variety of other multi-dimensional NMR methods.314 b-CaAlF5 was synthesised by solid-state reaction. The precise structure was refined from X-ray powder diffraction data in the monoclinic space group P21/c with a 5.3361, b 9.8298, c 7.3271 A˚ and b 109.911(Z = 4). Crystallographic data and atomic coordinates are given. 19F and 27Al solid state NMR spectra were recorded using MAS and SATRAS techniques.315 The authors report the design, synthesis and evaluation of novel enhanced reporter molecules, which reveal lacZ gene expression: trifluoromethylated aryl b-D-galactopyranosides. P-Trifluoromethyl-o-nitrophenyl b-D-galactopyranoside (PCF3ONPG) was found to exhibit valuable properties including a single 19F NMR signal, stability in aqueous solution and with wild type cells, but a chemical shift response to enzyme cleavage (Dd = 1.14 ppm) in breast cancer cells transfected to stably express lacZ.316 Intermediates formed in halogen addition (X = Br, Cl, F) to alkynes (ethyne, propyne, 2-butyne, trifluoromethylethyne, trimethylsilylethyne and Nucl. Magn. Reson., 2007, 36, 72–112 | 99 This journal is

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1-trimethylsilylpropyne) were studied computationally by MP2 at the MP2/ 6-311++G(3df,3pd) level and/or by DFT at the B3LYP/6-31+G(d) level. Structure optimisation and frequency calculations were performed to identify the min. and to obtain their relative energies. PCM calculations (with H2O, CH2Cl2 and CCl4 as model solvents) were employed to examine solvation effects on the relative stabilities in the resulting bridged halonium, b-halovinyl, or a-halovinyl cations. GIAO-MP2 and GIAO-DFT calculations were employed to compute NMR chemical shifts (13C, 19F and 29Si as appropriate).317 1H, 19F, 13C, 15N and 17O NMR chemical shifts and 1H–1H, 1H–19F, 1H–13C, 19F–13C and 19F–15N coupling constants are reported for 2-(trifluoromethyl)-2-oxazoline.318 The long-range coupling constants (JFH) of 1-methylpyrazoles and the chemical shifts of trifluoromethyl groups in the 19F NMR spectra can be used for the determination of regio-isomeric structures of mono(trifluoromethyl)-substituted pyrazoles.319 The authors present a facile 19F NMR spectroscopic approach for the characterisation of bistable RNA.320 Monofluorinated polycyclic aromatic hydrocarbons (F-PAHs) have attracted much attention in analytical, environmental, toxicological and mechanistic studies because of their physico-chemical properties, which are closely similar to those of the parent PAHs. Because of this, full NMR characterisation has become of interest. Complete 1 H, 13C, 19F NMR chemical shifts, and also 1J(H,C), nJ(C,F), nJ(H,F) and nJ(H,H) coupling constants, were assigned for the F-PAHs 1-fluoronaphthalene, 2-fluorofluorene, 5-fluoroacenaphthylene, 2-fluorophenanthrene, 3-fluorophenanthrene, 3-fluorofluoranthene, 1-fluoropyrene, 1-fluorochrysene, 2-fluorochrysene, 3-fluorochrysene and 9-fluorobenzo[k]fluoranthene.321 The authors present a simple model for predicting the principal site for nucleophilic substitution in aromatic perfluorocarbons. Model is based on the relative stabilities of the Meisenheimer complexes as calculated using density functional theory with a modest basis set. (Hartree-Fock theory will do just as well.) Predictions from model agree with experimental observations for 16 aromatic perfluorocarbons, and together with additional NMR calculations, lead us to conclude that the earlier prediction that perfluoroanthracene undergoes nucleophilic substitution in the 2-position is incorrect, and is based on a misinterpretation of the experimental 19F NMR spectrum.322 The insulin hexamer is an allosteric protein widely used in formulations for the treatment of diabetes. The hexamer exhibits positive and negative cooperativity and apparent half-site binding activity, reflecting the interconversion of three allosteric states, designated as T6, T3R3 and R6. The authors exploit the high sensitivity of 19F NMR chemical shifts and fluorinated carboxylates to reveal subtle differences in the anion-binding sites of T3R3 and R6.323 A computational study shows that Ge is pentacoordinated in the double four rings (D4R) of Si/Ge AST zeolites; the calculated chemical shifts of F-D4R containing 8Si, 7Si1Ge and 8Ge reproduce the trends of 19F NMR experiments.324 Seventeen N-(mono-, di-, tri-, tetra- and penta-fluorophenyl)-N 0 -(3-nitrophenyl)ureas were prepared and characterised. Complete assignment of their 1H, 13C and 19F NMR data was undertaken and the correlation of the chemical shifts of the ureido protons with field-inductive and mesomeric electronic substituent parameters was studied using the Swain-Luptonmodel.325 A series of sterically hindered o-hydroxy Schiff bases derived from o-hydroxyaceto- and benzophenones with very short intramolecular hydrogen bonds were described. Structures, 1H, 19F, 13C chemical shifts and deuterium isotope effects on 13C chemical shifts were calculated by ab initio methods.326 The stability constants for the diaza-18-crown-6 ethers (2–6) and alkali metal cations (Na+, K+, Rb+ and Cs+) were determined using potentiometry in 95% methanol. For each metal ion the stability constants of the partially-fluorinated ligands 3–6 were larger than that of the non-fluorinated ligand 2, which might reflect an interaction between fluorine atoms and alkali metal cations. The stability constant of the ligand 4 was larger than that of the ligand 5 for each metal cation tested. This finding was also supported by the results of cation-induced chemical shifts in 1 H-, 19F-NMR.327 19F NMR isotropic chemical shift calculations were performed in 100 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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crystalloid compounds using the GIAO method with the B3LYP hybrid functional at DFT level.328 The influence of water on the NMR and IR spectra of bis((perfluoroalkyl)sulfonyl)imides was investigated.329 The higher order high-resolution 31 P and 19F NMR spectra of hexafluorocyclotriphosphazene (F2PN)3 were measured at 183 K and interpreted using subspectral analysis and iterative fitting computation.330 The 19F NMR nuclear shieldings of fluoride ligands in uranium complexes UFnCl6n (n = 1–6) were studied quantum chemistry, using different exchangecorrelation functionals and a relativistic small-core pseudopotential on uranium.331 Relativistic density functional theory (DFT) was applied to the calculation of the 19F and 235U NMR chemical shifts of uranium(VI) chloride fluorides UF6nCln.332 Ten crosslinked polystyrene-supported, protected chiral amines featuring both a spacer, comprising from 5 to 15 atoms, and a fluorinated linker were successfully prepared. The development of the monitoring technique by gel-phase 19F NMR spectrometry on cross-linked polystyrene derivatives proved to be of high value in four steps of the process, as shown by the comparison of data gathered from both a classic NMR spectrometer and elemental analysis.333 A series of thioanilides and corresponding anilides, some of which contain fluorinated Ph rings, were synthesised as model compounds. They all contain rather strong intramolecular hydrogen bonds, the strength of which varies. Deuterium isotope effects on 19F and 13C chemical shifts due to deuteration at the NH proton show interesting new long-range isotope effects on chemical shifts that may be related to the existence of an intramolecular hydrogen bond and to transmission of the isotope effect due to an electrical field effect.334 2.17.2 Chlorine (35,37Cl) (I = 3/2,3/2). 1H, 23Na, 35Cl, 79Br and 81Br NMR chemical shifts and signal half widths were measured in aqueous electrolyte mixtures [tetrahydrofuran/H2O/NaCl and 3-methylpyridine (3MP)/H2O/NaBr] at different mass fractions of salt (X) in the one-phase region, close to their lower critical soluble points (TCL).335 13C, 14N, 15N, 17O and 35Cl NMR parameters, including chemical shift tensors and quadrupolar tensors for 14N, 17O and 35Cl, are calculated for the crystal forms of various amino acids under periodic boundary conditions and complemented by experiment where necessary.336 The 35Cl NMR chemical shift and line width and the 1H chemical shifts of cetylpyridinium chloride, CPyCl, change abruptly at the critical micelle concentration, indicating conversion of monomeric surfactant into micelles within a very small range of concentration.337 The results of a detailed systematic chlorine solid-state NMR study of several hydrochloride salts of amino acids implicated in chloride ion transport channel selectivity are reported. 35 Cl and 37Cl NMR spectra were obtained for stationary and/or magic-angle spinning powder samples of the following compounds on 500 and/or 900 MHz spectrometers: DL-arginine HCl monohydrate, L-lysine HCl, L-serine HCl, L-glutamic acid HCl, L-proline HCl, L-isoleucine HCl, L-valine HCl, L-phenylalanine HCl and glycine HCl.338 2.18 Group 18 (3He,

83

Kr,

129

Xe)

2.18.1 Helium ( He) (I = 1/2). NMR spectra of 3He introduced in Linde-type A zeolites were traced, which show that chemical shifts depend on the cations incorporated in the micropore. The chemical shift reflects the interaction with cations, the magnitude of which depends on the effective channel dimensions. 3He NMR can probe the smaller pores with much shorter periods than the conventional 129 Xe NMR.339 The chemical shift of tetramethylsilane (TMS) is usually taken to be zero. However, it does vary slightly with temperature, having obvious implications for studies of temperature effects on chemical shifts. The authors measure the variation in the chemical shift of TMS with temperature in three solvents, CDCl3, CD3OD and DMSO-d6, relative to the resonant frequency of 3He gas, which can be reasonably assumed to be t temperature independent. Data are included for 3He 3


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resonance frequencies at 110 to +1801, along with new measurements of volume magnetic susceptibilities of the three solvents and estimates of their temperature dependence.340

2.18.2 Krypton (83Kr) (I = 9/2). A wealth of information about porous materials and their void spaces was obtained from the chemical shift data in 129Xe NMR spectroscopy during the past decades. In this contribution, the only NMR active, stable krypton isotope 83Kr (spin I = 9/2) is explored as a novel probe for porous materials.341

2.18.3 Xenon (129Xe) (I = 1/2). The dependence of the 129Xe NMR chemical shift value of XeF2 on temperature and concentration was determined in a variety of prototypic media: in acidic (anhydride HF, aHF), nonprotic but polar (dichloromethane) and basic (CD3CN-EtCN, 1:3 vol./vol.) solvents.342 The 129Xe NMR line shapes of xenon adsorbed in the nanochannels of the ()-[Co(en)3]Cl3 ionic crystal were calculated by grand canonical Monte Carlo (GCMC) simulations.343 The 129Xe chemical shift of xenon dissolved in isotropic liquids is very sensitive to solvent density, which in turn is dependent on the sample temperature. Therefore, the 129Xe chemical shift can be used as the basis of a thermometer for measuring actual sample temperatures in NMR experiments.344 The pressure dependence of a 129Xe chemical shift (d) and the local density of xenon adsorbed in activated carbon fiber (ACF) with slit-pore widths of 0.7–1.1 nm was studied using in situ high-pressure 129Xe NMR.345 129Xe NMR spectroscopy is applied for direct observation of Xe confined in the porous Vycor glass.346 Polymer gel dosimeters consist of monomers, with or without crosslinking agents, dispersed in a gel. Upon exposure to ionizing radiation, polymerisation proceeds within the gel matrix, thereby changing several measurable phys. properties that can then be related quant. to absorbed dose. Several previous studies have examined how various NMR (NMR) properties, such as the relaxation rates of water protons, change with dose, and magnetic resonance imaging (MRI) was used successfully to measure three-dimensional dose distributions in irradiated polymer gels. Here we report our first observations of the manner in which the chemical shift of xenon gas (129Xe) dissolved in a gel changes with absorbed dose and we introduce the potential use of high resolution xenon NMR spectra for understanding better the dose response of gels.347 The application of continuous-flow hyperpolarised 129Xe NMR spectroscopy to investigate the pores of three shapepersistent organic macrocycles. Peaks with xenon chemical shifts between 160 and 200 ppm are assigned to xenon atoms trapped in highly confined pores while NMR peaks with chemical shifts of 100 to 140 ppm are assigned to xenon present in channels that exist through the center of the stacked macrocycles.348 The formation of two aluminophosphate frameworks, AlPO4-5 and AlPO4-18, was monitored using hyperpolarised 129Xe NMR as a probe.349 An extensive study was made on a series of multifunctional mesoporous silica materials, prepared by introducing two different organoalkoxysilanes, namely 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane (AEPTMS) and 3-cyanopropyltriethoxysilane (CPTES) during the base-catalysed condensation of tetraethoxysilane (TEOS), using the variable-temp. (VT) hyperpolarised (HP) 129Xe NMR technique.350 The chemical shift of the 129Xe NMR signal was shown to be extremely sensitive to the local environment around the atom and was used to follow processes such as ligand binding by bacterial periplasmic binding proteins. The authors show that the 129Xe shift can sense more subtle changes: magnesium binding, BeF3 activation and peptide binding by the Escherichia coli chemotaxis Y protein.351 This paper is a commentary on the paper Distinguishing multiple chemotaxis Y protein conformations with laser-polarised 129 Xe NMR by Lowery et al. in this issue.352 102 | Nucl. Magn. Reson., 2007, 36, 72–112 This journal is

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322 M. Muir and J. Baker, Journal of Fluorine Chemistry, 2005, 126, 727–738. 323 M. Bonaccio, N. Ghaderi, D. Borchardt and M. F. Dunn, Biochemistry, 2005, 44, 7656– 7668. 324 G. Sastre, A. Pulido and A. Corma, Chemical Communications (Cambridge, United Kingdom), 2005, 2357–2359. 325 A. Abad, C. Agullo, A. C. Cunat and C. Vilanova, Magnetic Resonance in Chemistry, 2005, 43, 389–397. 326 A. Filarowski, A. Koll, M. Rospenk, I. Krol-Starzomska and P. E. Hansen, Journal of Physical Chemistry A, 2005, 109, 4464–4473. 327 K. W. Chi, K. T. Shim, H. Huh, U. Lee and Y. J. Park, Bulletin of the Korean Chemical Society, 2005, 26, 393–398. 328 M. Body, G. Silly, C. Legein and J.-Y. Buzare, Journal of Physical Chemistry B, 2005, 109, 10270–10278. 329 M.-H. Tu and D. D. DesMarteau, Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 2005, 61A, 1701–1705. 330 L. Kapicka, D. Dastych, V. Richterova, M. Alberti and P. Kubacek, Magnetic Resonance in Chemistry, 2005, 43, 294–301. 331 M. Straka and M. Kaupp, Chemical Physics, 2005, 311, 45–56. 332 G. Schreckenbach, International Journal of Quantum Chemistry, 2005, 101, 372–380. 333 M. Hourdin, G. Gouhier, A. Gautier, E. Condamine and S. R. Piettre, Journal of Combinatorial Chemistry, 2005, 7, 285–297. 334 J. G. Sosnicki and P. E. Hansen, Tetrahedron Letters, 2005, 46, 839–842. 335 V. Balevicius, Z. Gdaniec and H. Fuess, Journal of Chemical Physics, 2005, 123, 224503/ 1–224503/5. 336 C. Gervais, R. Dupree, K. J. Pike, C. Bonhomme, M. Profeta, C. J. Pickard and F. Mauri, Journal of Physical Chemistry A, 2005, 109, 6960–6969. 337 S. J. Yunes, N. D. Gillitt and C. A. Bunton, Journal of Colloid and Interface Science, 2005, 281, 482–487. 338 D. L. Bryce, G. D. Sward and S. Adiga, Journal of the American Chemical Society, 2006, 128, 2121–2134. 339 S. Hayashi, Chemistry Letters, 2006, 35, 92–93. 340 R. E. Hoffman and E. D. Becker, Journal of Magnetic Resonance, 2005, 176, 87–98. 341 C. F. Horton-Garcia, G. E. Pavlovskaya and T. Meersmann, Journal of the American Chemical Society, 2005, 127, 1958–1962. 342 V. V. Bardin and H.-J. Frohn, Magnetic Resonance in Chemistry, 2006, 44, 648–650. 343 D. N. Sears, R. E. Wasylishen and T. Ueda, Journal of Physical Chemistry B, 2006, 110, 11120–11127. 344 J. Saunavaara and J. Jokisaari, Journal of Magnetic Resonance, 2006, 180, 58–62. 345 T. Ueda, H. Omi, T. Yukioka and T. Eguchi, Bulletin of the Chemical Society of Japan, 2006, 79, 237–246. 346 Y. Hiejima, M. Kanakubo, Y. Takebayashi, T. Aizawa, Y. Kurata and Y. Ikushima, Journal of the Physical Society of Japan, 2006, 75, 024603/1–024603/4. 347 J. M. Joers, P. M. Fong and J. C. Gore, Physics in Medicine & Biology, 2006, 51, N23–N30. 348 K. J. Ooms, K. Campbell, R. R. Tykwinski and R. E. Wasylishen, Journal of Materials Chemistry, 2005, 15, 4318–4327. 349 D. N. Sears, B. A. Demko, K. J. Ooms, R. E. Wasylishen and Y. Huang, Chemistry of Materials, 2005, 17, 5481–5488. 350 S.-J. Huang, S. Huh, P.-S. Lo, S.-H. Liu, V. S.-Y. Lin and S.-B. Liu, Physical Chemistry Chemical Physics, 2005, 7, 3080–3087. 351 T. J. Lowery, M. Doucleff, R. E. Ruiz, S. M. Rubin, A. Pines and D. E. Wemmer, Protein Science, 2005, 14, 848–855. 352 E. Brunner, Protein Science, 2005, 14, 847.


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Theoretical aspects of spin–spin couplings Hiroyuki Fukui DOI: 10.1039/b601640p

1. Introduction During the last decade, an important breakthrough in the theoretical calculation of indirect nuclear spin–spin coupling constants (SSCCs) have taken place, since within the density functional theory (DFT) using the coupled-perturbed (CP) approach, i.e., CPDFT, it becomes possible to calculate SSCCs with reasonable accuracy for polyatomic compounds. The aim of this review is to provide readers with information about important works made in theoretical aspect of spin–spin couplings which appeared from June 2005 to May 2006.

2. NMR spectroscopy and chirality Nuclear magnetic resonance (NMR) is a hugely important technique in chemistry and biochemistry. However, it is a blind to chirality. That is, the parameters that determine an NMR spectrum, namely the chemical shifts and nuclear spin– spin coupling constants, are identical for D and L enantiomers. Chiral discrimination has been achieved in NMR only through addition of a chiral reagent or solvent,1–4 producing a change in the environment around the active nuclei.5 An odd-parity property is necessary for chiral discrimination in NMR. For example, a property linking an induced electric dipole moment to the magnetic dipole moment of a nucleus can bring about an ability for discriminating chirality in NMR. Time-reversal symmetry requires that a slowly rotating nuclear magnetic moment cannot induce an electric dipole moment in a molecule in the absence of a magnetic field. However, the magnetic field of the NMR spectrometer lifts this restriction and permits the production of molecular properties that are odd under the simultaneous sign changes of all space coordinates, called a parity transformation. Buckingham6 showed that in chiral but not achiral liquid samples in a magnetic field B0z, a nuclear magnetic dipole moment mMx induces a molecular electric dipole moment mey that is opposite in sign for D and L enantiomers. The coherent precession of nuclear spins following application of a p/2 pulse to a chiral liquid sample will produce a rotating macroscopic electric polarization leading to discrimination of chirality. Buckingham showed that the chirality should be detectable in favourable cases, foreshadowing a new dimension for NMR spectro~ produces the scopy. Harris and Jameson7 showed that an external electric field E chiral dependent part of the spin–spin coupling for each enantiomer. The proof of existence of the chiral portion however does not suggest how large the chiral dependent quantity is. It is known that the parity nonconservation (PNC) terms of the molecular Hamiltonian may offer a difference in the NMR parameters of enantiomers.8,9 Since the first paper which proposed the possible existence of PNC terms in weak interactions,10 and the first experimental evidence,11 several theoretical and experimental studies have been devoted to PNC problems, with a special emphasis on the problem of molecular chirality and of the origin of bio-chirality.12–16 Barra and Robert8 derived the formulae giving the PNC contribution to the nuclear magnetic shielding tensor s^, to the indirect nuclear spin–spin coupling tensor Jˆ, and to the spin-rotation coupling tensor Cˆ. They applied the perturbation theory to the parity Kitami Institute of Technology, 165 Koencho, Kitami 090-8507, Japan. E-mail: [email protected]; Fax: +81-157-24-7719; Tel: +81-157-26-9402


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violating electron–nucleon interaction HeN PNC. In the nonrelativistic approximation, HeN PNC may be written as GF eN s ½~ p; dð~ rÞþ ðZð1 4 sin2 yÞ NÞ 4lN ð~ HPNC ¼ pffiffiffiffiffiffiffiffiffiffi f~ s~ IN Þ~ s 2 2me c 2 ½~ p; dð~ rÞþ ð1 4 sin yÞg;

ð4:1Þ

where GF = 2.22254 1014 a.u. is the Fermi coupling constant, c light speed, me electron mass, and y is the Weinberg-Salam angle (sin2y = 0.2236). Z is the atomic number, N the neutron number, ~ p the electron momentum, ~ s the electron spin vector operator, I~N the nuclear spin vector operator of nucleus N, and [ ]+ denotes the anticommutator. lN is a nuclear factor of nucleus N which fluctuates around unity. Besides the PNC Hamiltonian HeN PNC, one must consider the so-called anapole term, an additional contribution to the electron–nucleon interaction, which was first introduced by Zel’dovich.17 The parity non-conserving nucleon–nucleon interactions lead to the existence of a first rank magnetic moment, the nuclear anapole moment ~ a. The nuclear anapole moment ~ a arises from the electromagnetic current density ~ j(~ r) existing inside the nucleus. Barra and Robert showed that the PNC contribution to the tensor JˆNN 0 comes from one first-order perturbation term and two second-order perturbation contributions. The first-order PNC correction to the tensor JˆNN 0 is NN 0 NN 0 antisymmetric, i.e., Jtu ¼ Jut (t, u A x, y, z). So such a contribution cannot be detected by high resolution NMR spectra in isotropic phases where only Tr(JˆNN 0 ) is observed. A quantitative estimation for the PNC contribution to JˆNN 0 was not performed while the preliminary calculations for the PNC shifts on molecules containing Pt or Pb, using a relativistically parametrized extended Hu¨ckel method, gave a difference in the chemical shifts of enantiomers of the order of a few m Hz. Weijo et al.18 evaluated the PCN contributions to nuclear spin–spin couplings for the first time at the first-principles level. Calculations were carried out for two chiral halomethanes, bromochlorofluoromethane and bromofluoroiodomethane. It was shown that leading-order parity-violation effects on the isotropic spin–spin coupling constants in CHFClBr and CHFBrI are at most in the order of 109 Hz.

3. Relativistic calculation of spin–spin coupling constants During the last decade there have been great advances in theory and modeling of high resolution NMR spectroscopy.19–23 NMR has traditionally relied on interpreting spin–spin coupling constants (SSCCs) to get an information about the arrangement of coupled nuclei in the molecules. Empirical relations connecting SSCC with molecular structure are well established for organic compounds and have frequently been employed in studying molecular structure and chemical bonding of organic compounds. However, the status of the NMR technique is quite different when one enters the domain of heavy element compounds.24 For such compounds, only hypothetical relationships between SSCCs and molecular structures are known and the interpretation of NMR spectra for such compounds has still not been established. In future, NMR for heavy element compounds will become important in biochemistry studying the functional centers of enzymes which often contain a metal atom. One of the difficulties for calculating SSCCs in molecules containing heavy elements is the relativistic effects on SSCC. Oprea et al.25 presented a scheme for evaluating the relativistic spin-orbit corrections to SSCC using quadratic response density functional theory (QRDFT). The formalism is applied to the homologous systems H2X (X = O, S, Se, Te) and XH4 (X = C, Si, Ge, Sn, Pb) to calculate the SSCCs between the protons. Accurate calculations of SSCC pose significant challenge for quantum chemistry methods due to the need for accurately describing static and dynamic electron correlations, and in particular the capability for correctly treating the effects of spin dependent perturbation operators, as well as an accurate description of the electron density near the nucleus. Application of 114 | Nucl. Magn. Reson., 2007, 36, 113–130 This journal is

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ab initio methods capable of fulfilling these requirements, such as the multi configurational self-consistent field (MCSCF) method, is restricted to molecules consisting only of a few atoms due to its large computational cost. Spin-restricted DFT, on the other hand, does not formally fulfill all these requirements, but provides a practical recipe that gives reliable SSCCs for most species. The spinrestrict DFT above all does not suffer from the triplet instability problem. In the nonrelativistic limit, the indirect spin–spin coupling tensor consists of five contribution as first shown by Ramsey,26 NR DSO PSO FC SD FC=SD K^ MN ¼ K^ MN þ K^ MN þ K^ MN þ K^ MN þ K^ MN ;

ð4:2Þ

where KˆNR MN is the nonrelativistic reduced coupling tensor between nuclei M and N. Here DSO, PSO, FC, and SD represent diamagnetic spin-orbital, paramagnetic spin-orbital, Fermi contact, and spin dipolar mechanisms, respectively. The picture of the nonrelativistic SSCC is consistent up to order O(a4) in the fine structure constant a D 1/137. Therefore, leading relativistic corrections to the SSCC are of order O(a6) and they can be obtained through the perturbation theory by combining various terms of the Breit-Pauli Hamiltonian. Oprea et al.25 limited themselves to the spin-orbit (SO) corrections, which dominate heavy element induced relativistic effects on SSCCs of light atoms. Following Kirpekar et al.27 and Vaara et al.,28 the SO corrections to the indirect reduced nuclear spin–spin coupling tensor are evaluated using the nuclear magnetic moments ~ mM and ~ mN as DD EE @2 FC=SO FC PSO PSO HM ; Hð1e K^ MN ð1e or 2eÞ ¼ or 2eÞ ; HN 0;0 @~ mM @ ~ mN ð4:3Þ DD EE FC SO PSO ; þ HN ; Hð1e or 2eÞ ; HM 0;0

SD=SO K^ MN ð1e or 2eÞ ¼

DD EE @2 SD SO PSO HM ; Hð1e or 2eÞ ; HN 0;0 @~ mM @ ~ mN DD EE SD SO PSO ; þ HN ; Hð1e or 2eÞ ; HM

ð4:4Þ

0;0

where the one- and two-electron SO operators are given in atomic units (i = 1, e = 1, me = 1, 4pe0 = 1, c = 137.0359895) by ge X SO ¼ 2 ZK r3 l iK ; ð4:5Þ si ~ Hð1eÞ iK ~ 4c iK SO ¼ Hð2eÞ

ge X 3 r ð~ si þ2~ sj Þ ~ l ij : 4c2 i6¼j ij

ð4:6Þ

In eqns (4.5) and (4.6) the following notations are used: ZK is the atomic number of ^ ) (i2 = 1) is the angular momentum of electron i nucleus K, ~ l iK = ~ rik (ir i around the position of nucleus K, ~ rik = ~ ri ~ rK is the position vector of electron i with respect to nucleus K, ~ si is the spin vector of electron i, ge = 2.002319315 denotes ^ ) is the angular momentum of electron i the free electron g factor, ~ l ij = ~ rij (ir i around the position of electron j, ~ rij = ~ ri ~ rj is the position vector of electron i with respect to electron j, and finally a quadratic response function at zero frequencies of three arbitrary operators, H1, H2, and H3, is defined as X h0jH jki½hkjH jmi d h0jH j0ihmjH j0i 1 2 2 3 km hhH1 ; H2 ; H3 ii0;0 ¼ ðE0 Ek ÞðE0 Em Þ k;m40 ð4:7Þ þ pertutations for H1 ; H2 ; H3 : Nucl. Magn. Reson., 2007, 36, 113–130 | 115 This journal is

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Oprea et al. employed three different exchange-correlation functionals: SVWN (local exchange-correlation functional),29,30 BLYP (generalized-gradient approximation exchange-correlation functional),31,32 and B3LYP (hybrid exchange-correlation functional).29–33 The performance of DFT calculation was carefully assessed by comparing the DFT results with high-level ab initio methods, MCSCF and SOPPA (second-order polarization propagator approximation). Overall, the DFT approach provided a reliable description of nonrelativistic SSCC and their SO corrections, whereas the performance of various exchange-correlation functionals for the Fermi contact contribution to 2JNR(H,H) varied from one molecular system to another. The B3LYP exchange-correlation functional, which is widely used in evaluating SSCC, provided in some particular molecular systems, such as SiH4, rather inaccurate Fermi contact contributions compared to other exchange-correlation functionals. The undesirable varistions in the accuracy obtained with the DFT using the different exchange-correlation functionals were found in the XH4 series, and a uniform performance for the whole series of compounds could not be achieved for any used exchange-correlation functionals. It was found that the accuracy of JSO decreases in the order of SVWN, BLYP, and B3LYP. This indicates that the triplet instability increases in the above order of functionals. The conventional perception that the triplet instability problems are insignificant in the DFT evaluations of SSCC is questionable. Despite these difficulties, the DFT approach provided at least a qualitatively correct description of SSCC and in some particular cases, such as GeH4, surpassed ab initio methods. It was found that the two-electron SO contributions is negligible, and the SD/SO contribution involving the SD operator is small. The consideration of only one-electron FC/SO term was sufficient. The SO correction to 2J(H,H) was largest for H2Te in which it was 14.1%–19.2% of the 2 NR J (H,H). The SO corrections to 2J(H,H) in the XH4 series were small and only for PbH4 they were noticeable but they were less than 5.6% of 2JNR(H,H). Melo et al.34 employed the Douglas-Kroll-Hess (DKH) approximation to derive the perturbative Hamiltonian for the calculation of SSCC in molecules containing heavy elements. They applied their method to the calculation of one-bond spin–spin coupling constant 1J(H,X) in the series of tetrahydrides XH4 (X = C, Si, Ge, Sn) using finite perturbation theory (FPT) with Hartree-Fock (HF) approximation and DFT. They tested different levels of the DKH approximation and three representative functionals: PBE,35 PBEh,36,37 and B3LYP.33 It was shown that the secondorder DKH approximation (DKH2) reproduces accurate four-component DiracHartree-Fock (DHF) calculation results.38 The results obtained for the 1J(X,H) in XH4 series suggested that DKH2 is a worthy alternative for the quasirelativistic calculation of SSCC.39 The DFT calculation showed that the three functionals employed by them tend to correct the overestimation of the magnitude of the coupling given by the HF approximation, and therefore the agreement with experiment is better in DFT than in HF. Bagno et al.40 performed relativistic calculation of SSCCs of 119Sn in stannane, tetramethylstannane, methyltin halides Me4-nSnXn (X = Cl, Br, I; n = 1–3), tin halides, and some stannyl cations by means of the zeroth-order regular approximation (ZORA) method. Calculated coupling constants between 119Sn and halogen nuclei reproduced well experimental results when we take into account the large uncertainties in the experimental values. Relativistic SO effects were considerable. Calculated coupling constants were strongly affected by the inclusion of the SO term in the Hamiltonian. Although calculated couplings of 119Sn to 13C and 1H fell, on the average, on the same correlation line, the slope of the linear fit (0.3) is far from unity. Hence, there are still important issues to be addressed before such calculations enter into widespread usage.

4. Relationships between spin–spin coupling constants and structures Some transition-metal complexes include hydrogen atoms in the coordination sphere of the metal, and stretched or elongated dihydrogen complexes (H2 ligands) are 116 | Nucl. Magn. Reson., 2007, 36, 113–130 This journal is

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formed. Sometimes stretched dihydrogen complexes show surprising and unique NMR properties. Contrary to what has been reported for ‘‘classical’’ dihydride complexes (RH–H 4 1.5 A˚) and ‘‘nonclassical’’ dihydrogen complexes (RH–H o 1.0 A˚), stretched dehydrogen complexes show a clear temperature dependence of the 1 J(H,D) coupling constant in NMR experiments in which the H2 ligand is substituted by HD. Moreover, for a family of complexes, different opposing temperature dependences of 1J(H,D) have been observed. By virtue of a well-established inverse relationship between 1J(H,D) and RH–H,41 this temperature dependence of 1 J(H,D) yields the information for shortening or lengthening of RH–H with temperature. Gelabert et al.42 showed that it is possible to distinguish elongated dihydrogen transition-metal complexes from compressed dihydride transition-metal complexes with measuring the temperature dependence of the 1J(H,D) coupling constant in 1H NMR spectroscopy. It was predicted that elongated dihydrogen complexes will show decreasing 1J(H,D) with temperature but compressed dihydride complexes, on the other hand, will show increasing 1J(H,D) with temperature. Kareev et al.43 investigated variable temperature 19F NMR spectra of fullerene C60Fn (CF3) compounds. An analysis of 19F NMR spectra showed that nJ(F,F) (n Z 4) coupling constants in the slow-exchange-limit spectra of 1,9-C60F(CF3) and the two isomers of C60F17(CF3) are due to the through-space coupling mechanism (i.e., direct overlap mechanism between fluorine atom lone-pair orbitals) rather than through-bond coupling mechanism. Aromaticity of organic compounds has been an interesting problem. Mitchell et al.44–48 have suggested an experimental method to estimate relative antiaromaticities. Mitchell et al.49 used an analysis of ring current and coupling constant changes of dihydropyrene probe on annelation to estimate the relative antiaromaticity of cyclopentadienone. Their analysis indicated that cyclopentadienone behaves as an antiaromatic 4n–p system and that cyclopentadienone shows about 80% of benzene in the bond delocalization energy (resonance energy). There is considerable interest in 77Se NMR parameters50,51 as a result of numerous applications of selenium compounds in synthesis and their biochemical relevance. Although a large data set exists for SSCCs nJ(77Se, X),51 these coupling data are less well understood when compared with chemical shift data. Wrackmeyer52 calculated some coupling constants nJ(77Se, 77Se) (n = 1,2,3) at the DFT/B3LYP/6311+G(d,p) level, and compared the computed values with experimental data if available. It was shown that there is no obvious relationship between calculated Se–Se bond lengths and the values of computed 1J(77Se, 77Se). Furthermore, it was found that non-contact contribution by the PSO and SD terms can become much larger than that of the FC term and that these PSO and SD terms are mainly responsible for both the sign and magnitude of 1J(77Se, 77Se). Spectroscopic features of azo-compounds have been studied for many decades.53–59 NMR parameters of azo-compounds have also been a target of investigation.60 However, coupling constants for azo-compounds are not well understood. Wrackmeyer and Ko¨hler61 presented calculation of SSCCs J(N, N), J(N,13C), and J(29Si, N) of noncyclic azo-compounds and cyclic azo-compounds by DFT method at the B3LYP/6-311+G(d,p) level. The 29Si NMR spectrum indicated that 1J(29Si, 15N) in bis(trimethylsilyl)diazene is negative. This negative sign is remarkable, since for the majority of other compounds including Si–N bond the sign of 1J(29Si, 15N) is positive. Theoretical calculation showed that this change in sign can be qualitatively attributed to the influence of the lone pair of electrons at the azo-nitrogen atom.62 The calculated value of 1J(N, N) for Me2C–(CH2)3–CMe2N+QN was very close to the experimental one,63 and this suggests that the calculated negative sign is correct. The dominating term for 1J(N, N) arose from the negative contribution by the PSO for all azo-compounds. The one-bond coupling constants 1J(15N, X) (X = 1H, 13C) for the diazene were remarkably small and positive (X = 1H) or negative (X = 13C). In the latter case, there is agreement with experimental data.64,65 The negative sign of 1 15 J( N, 13C) was mainly the result of the influence of the lone pair of electrons at the Nucl. Magn. Reson., 2007, 36, 113–130 | 117 This journal is

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azo-nitrogen atom.62 The calculations showed that in the nitrenes the coupling constants 1J(14N, X) are large and positive for X = 1H and small and of either sign for X = 13C. The geminal coupling constants 2J(N, N, X) in the azo-compounds and nitrenes were small and of either sign. The vicinal coupling constants 3J(X, NN, X) were all positive. In the case of the cyclic azo-compounds, the calculated values for 3 J(X, NN, X) showed the effect of multiple coupling pathways, and each contribution to the coupling may have different sign. Wrackmeyer et al.66 computed the coupling constants 1J(13C, 13C) for silacyclopentadienes by using DFT method. The magnitude of 1J(13CQ13C) becomes markedly smaller with increasing number of organometallic substituents at the CQC bond.67–72 The agreement between experimental and calculated coupling constants was acceptable. The calculations also predicted that the magnitude of 2J(29Si, 13C) should be much smaller than that of 3J(29Si, 13C), in agreement with the experimental data. The important concept of hyperconjugation helps to explain structure, stabilisation, and reactivity in various fields of organic and organometallic chemistry.73–79 Wrackmeyer and Tok80 investigated hyperconjugation in trialkylboranes by using coupling constants 1J(13C, 11B) and 1J(13C, 13C). Results of DFT calculations at the B3LYP/6-311+G(d,p) level showed satisfactory agreement with the experimental data. Hyperconjugation arising from C–C s bonds adjacent to the tricoordinate boron atom was indicated by comparing the experimental and calculated data of 1 13 J( C, 13C). It was shown that hyperconjugation in boranes is reflected by the smaller magnitude of coupling constants 1J(13C, 13C) for C–C s bonds adjacent to the electron deficient boron atom. The agreement between calculated and experimental data of 1J(13C, 11B) and 1J(13C, 13C) for the trialkylboranes, and also for the carbocation [Me3C]+, is certainly promising for similar compounds which is less accessible to experimental studies. Bakardjiev et al.81 calculated coupling constants, 1 31 J( P, 13C), 2J(31P, C, 1H), and 1J(31P, 31P), of phosphacarborane using the DFT method at the level of B3LYP/6-311+G(d,p). The molecular geometries of all compounds were optimized by ab initio calculation at a correlated level of theory using the 6-31G* basis set. A reasonable agreement between calculated and experimental data was obtained. It appeared that the correct signs of the coupling constants may be predicted. It was shown that the negative sign of 1J(31P, 13C) is expected to result from the effects of the lone electron pair on the phosphorus atom.62 Many chemical transformations and rearrangements of oximes, hydrazones, and other imines utilized in the synthesis of azoles and other larger nitrogen-containing heterocycles occur stereoselectively and make the problem of the configurational assignment at the CQN bond to be of crucial importance. Krivdin et al.82–85 have proposed to use the one-bond carbon–carbon coupling constants, 1J(C, C), in the NMR spectra for the configurational structure determination of these nitrogen compounds. It is known that the 1J(13C, 13C) coupling constant is very sensitive to the orientation of the lone electron pairs (LEPs) owing to the so-called LEP effect.82,84 It was shown theoretically86–88 that the LEP effect on the 1J(13C, 13C) coupling constants results from a through-space interaction of the LEP of a heteroatom with bonding and antibonding orbitals of the neighboring carbon– carbon bond, which results in an increase or a decrease in the s-character of the bond, i.e., in a positive or a negative contribution to the corresponding 1J(C, C) coupling constants. Krivdin et al.89 provided the configurational assignment of aminosulfonylamidines. It is well known that in oximes the one-bond 1J(C, C) coupling constants involving the a-imino carbon demonstrate a profound stereochemical dependence on the orientation of the nitrogen lone pair.86–88,90,91 Indeed, the difference between 1Jcis and 1Jtrans (see Scheme 1 for notations) amounts up to 20% of their total values and provides an unambiguous guide to the configurational assignment at the CQN bond in oximes and their derivatives. Krivdin et al.89 performed a detailed SOPPA study of 1J(C, C) in 1E and 1Z isomers of the model compound, aminosulfonylamidine 1. The calculation showed that 1Jcis(13C, 13C) is 118 | Nucl. Magn. Reson., 2007, 36, 113–130 This journal is

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Scheme 1

greater than 1Jtrans(13C, 13C) by ca. 20%. The marked difference between the calculated 1Jcis and 1Jtrans constants originating in the LEP effect of the imino nitrogen was solely due to the changes in the FC contributions. Comparison of the measured 1J(13C, 13C) in eight aminosulfonylamidines under study (about 45 Hz) with the calculated 1Jtrans (43 B 45 Hz) in 1E isomer and 1Jcis (53 B 55 Hz) in 1Z isomer of the model aminosulfonylamidine 1 allowed one to perform the unambiguous assignment of the measured 1J(C, C) to E-configuration. The double bond CQN is one of the most important functional groups in organic chemistry.92,93 Krivdin et al.94 performed the configurational assignment at the CQN bond of the seven azomethine derivatives by means of 1J(C, C) and 1J(C, H) coupling constants involving the a-amino carbon. Calculations of 1J(C, C) and 1J(C, H) in the model compounds of azomethine derivatives were carried out with the SOPPA method which is approved for the evaluation of SSCCs of different type of compounds in a number of publications by Sauer et al.95–107 Results of the SOPPA calculations of the 1J(C, C) and 1J(C, H) coupling constants in the model compounds were compared with the experimental values in the original compounds. Both the 1J(C, C) and 1J(C, H) results enabled one to perform the unambiguous assignment of all of the parent azomethines to the E-configuration. Shcherbina et al.108 carried out the SOPPA calculation of 1J(13C, 13C) coupling constants for a series of ketone oximes. They further performed the calculations of Møller-Plesset second-order perturbation theory (MP2), DFT with the use of B3LYP correlation functional, and coupled cluster theory with single and double amplitudes (CCSD). The methods of MP2, B3LYP, and CCSD ensured that the best agreement between the calculated and experimental values of 1J(13C, 13C) coupling constants is obtained when they were estimated by SOPPA procedure. It was shown that coupling constants calculation without taking into consideration the internal correlation functions underestimates energy values of the excited states and therefore overestimates the magnitude of the FC contribution. However, the incorporation of polarization p-functions for hydrogen atoms and of diffuse functions (s-functions for hydrogen and s, p-functions for atoms of the second period) was not of fundamental importance for the coupling calculation. Rusakov et al.109 determined the conformation of pyrrolylpyridines using 1J(13C, 1H) and 1J(15N, 1H) coupling constants. Pyrroles, an important class of the nitrogen-containing heterocycles, are widespread in nature and are extensively applied in medicine and high technologies.110 Pyrrolylpyridines provides an interesting example of three linked heterocycles with free internal rotation around two interheterocyclic bonds. Taking into account the stabilizing effect of the aromatic p,p-conjugation between pyridine and pyrrole moieties, one should expect the existence of three planar rotational conformations with different spatial arrangements of the heterocyclic nitrogens, i.e., cis–cis, cis–trans, and trans–trans. Calculations of spin–spin couplings were performed at the SOPPA level. All 1J(13C, 13C) Nucl. Magn. Reson., 2007, 36, 113–130 | 119 This journal is

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coupling constants showed no conformational dependence. The difference of the 1 15 J( N, 1H) coupling constant in s–cis and s–trans conformers was found to be ca. 3.5 Hz. The calculated value of 1J(15N, 1H) in s–cis conformer matched its experimental value within ca. 0.5 Hz. Comparison of calculated and experimental values of 1J(13C, 1H) and 1J(15N, 1H) showed without doubt that pyrrolylpyridines adopt predominantly s–cis conformations. Contreras et al.111,112 investigated hyperconjugative interactions using the natural bond orbital (NBO) approach113 and calculation of SSCCs. Coupling constants are affected differently by hyperconjugative interactions, depending on the number of bonds separating the coupled nuclei. Contreras et al.111 calculated nJ(C, F) (n = 4, 5) at the DFT/B3LYP/6-311G** level for the series 1-F,4-X-cubanes, where the a atom of the X group is a carbon atom. The unusual 4J(C4, F1) coupling constants known in 1-F, 4-X-cubanes were rationalized as originating from mainly two factors, namely, (i) the strong s-hyperconjugative interactions involving as donors the cage C–C bonds; (ii) the particular arrangement of cage bonds. Contreras et al.112 studied hyperconjugative and electrostatic interaction effects on 1J(C, H) SSCCs in the series of 1-X-bicyclo[1.1.1]pentane and 1-X-3-methylbicyclo[1.1.1]pentane from both theoretical and experimental point of view. It was shown that (a) hyperconjugative interactions from the sCH bond or into the s*CH antibond containing the coupling nuclei yield a decrease of the corresponding 1J(C, H) SSCC and (b) hyperconjugative interactions from other bonds involving the coupling C nucleus yield an increase of that 1J(C, H) SSCC. Dodziuk et al.114 calculated the SSCCs for trans- and cis-decalins using the DFT approach. Trans- and cis-decalins constitute important fragments of many natural products, such as steroids and terpenoids, often displaying pharmacological activity.115–118 NMR spectra of substituted trans- and cis-decalins were recently used to prove the structure of natural compounds.119 However, no data on the coupling constants for decalins have been published. Of all the SSCCs, only most of 1J(C, C) and 1J(C, H) values could be extracted from the observed spectra, and the corresponding computed values were in good agreement with experiment. It appeared that the applied DFT approach overestimates slightly the J(C, C) coupling and underestimates the differences between one-bond 1J(C, H) coupling constants. For all J(C, C), J(C, H), and J(H, H) coupling constants through one to three bonds, which could not be obtained experimentally, the predicted values were in good agreement with the general rules relating SSCCs to the number and spatial arrangement of the intervening bonds. Katritzky et al.120 measured and calculated the magnitude of one bond and long-range coupling constants in 3-nitropyridine and its derivatives. Pyridine and its derivatives have been the subject of extensive research from both experimental121,122 and theoretical123,124 points of view. It is therefore valuable to stock NMR data of pyridine and its derivatives. The calculated data by DFT were compared with the experimental NMR data. A good linear correlation was obtained between the calculated and experimentally measured values of the vicinal and long-range coupling constants. Notario et al.125 performed a theoretical study on the conformational interconversions in 1,3-dithianesulfone and investigated the correlation between C–H bond orientation and the magnitude of the corresponding 1J(C, H) one-bond coupling constant. A useful correlation between C–H bond orientation and the corresponding 1J(C, H) constant was found by Perlin and Casu.126 Wolfe et al.127 proposed that stereoelectronic effects upon one-bond C–H coupling constants be termed ‘‘Perlin effects’’. In particular, the magnitude of the one-bond C–H coupling constant for an axial C–H bond adjacent to oxygen or nitrogen in a six-membered ring is smaller by 8–18 Hz than 1J(C, H) in the corresponding equatorial bond, i.e., 1J(C, Heq) 4 1J(C, Hax). This situation represents a ‘‘normal’’ Perlin effect (NPE) and is usually interpreted in terms of an interaction between a pair of nonbonded electrons on oxygen or nitrogen and the axial adjacent C–Hax bond,128,129 which weakens such a C–Hax bond and results in smaller coupling constants. In contrast, in sulfur-containing 1,3-dithiane analogues 120 | Nucl. Magn. Reson., 2007, 36, 113–130 This journal is

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Scheme 2

it have been shown130 that they exhibit an opposite behavior: 1J(C, Heq) o 1 J(C, Hax), which is now termed a ‘‘reverse’’ Perlin effect (RPE). This reversal of the relative magnitude of the coupling constants in 1,3-dithianes was explained by Wolfe et al.127,130 as a result of an interaction between sC–S bond and the equatorial C–Heq bond. Notario et al.125 carried out calculations of the 1J(C, H) one-bond coupling constants in 1,3-dithianesulfone and explained their magnitude in terms of stereoelectronic interactions, i.e., NPE and RPE. Krcsmar et al.131 investigated the through-space 19F, 19F spin–spin coupling of 1,1 0 -difluoro-9,9 0 -bifluorenylidene (Scheme 2). They observed J(F, F) of 11.0 Hz in the 2Z isomer, but not in the 2E isomer of above compound 2. A DFT/B3LYP/631+G(d) calculation of 2Z as an isolated molecule gave a non-bonded F F distance d(F, F) of 2.711 A˚ and an angle between the two C–F bond vectors of 34.11. The through-space J(F, F) coupling equation derived by them,132,133 J(F, F)/Hz = 275 000 exp[3.211d(F, F)/A˚],

(4.8)

predicted ca. 46 Hz. The predicted value of ca. 46 Hz is much larger than the experimental value of 11.0 Hz. They concluded that a simple eqn (4.8) is not sufficient to describe through-space couplings and that an angular factor should also be taken into account. Zhu et al.134 calculated theoretically SSCCs in model N-acetylated aldopyranosides using DFT to predict the substitution effect in OH or NHCOCH3 substitution at C2 on J(C, H) and J(C, C) values in aldopyranosyl rings. The predicted coupling constants were in agreement with experimental findings. Sanz et al.135 carried out DFT calculations of coupling constants of 5-hydroxy-5-trifluoromethyl-D2 isoxazolines at the B3LYP/6-311++G* level to solve the problem of the assignments of the diastereotopic protons. They could assign successfully the couplings in spectra. It was found that in absolute value, the geminal coupling constants 2J(H, H) are larger in pyrazolines than in isoxazolines. Oliveira et al.136 performed theoretical calculations of H, H couplintg constants of a cycloheptenone derivative, a key intermediate for the synthesis of perhydroazulene terpenoids, at the B3LYP/cc-p VDZ level of DFT to support assignments. A very good correlation between experimental and theoretical J(H, H) data was obtained.

5. Assessment of density functional theory Yanai et al.137 recently introduced a new hybrid exchange-correlation energy functional for Kohn-Sham DFT, based on Coulomb-attenuating method Nucl. Magn. Reson., 2007, 36, 113–130 | 121 This journal is

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(CAM).138–141 Preliminary investigations by Yanai et al.137,142 demonstrated that CAM-B3LYP functional provides significantly improved Rydberg and charge transfer (CT) electronic excitation energies, due to an improved description of the long-range exchange interaction. The key step in the Coulomb-attenuating method of ref. 137 is the partitioning of the r121 operator, in the exchange interaction, into two parts 1 ½a þ berf ðmr12 Þ 1 ½a þ berf ðmr12 Þ ¼ þ ; r12 r12 r12

ð4:9Þ

where m is a parameter of dimension L1 and a and b are dimensionless parameters satisfying 0 r a + b r 1, 0 r a r 1, and 0 r b r 1. Ikura et al.138 proposed that 143 a = 0.19, b = 0.46, and m = 0.33 a1 calculated SSCCs as one of the 0 . Peach et al. second-order response properties with CAM-B3LYP and B3LYP functionals to assess the quality of a new functional CAM-B3LYP. It was shown that CAMB3LYP and B3LYP provide comparable quality for NMR shielding constants and indirect nuclear spin–spin coupling constants. Maximoff et al.144 investigated the performance of 20 approximate density functionals for the calculation of 1J(C, H) SSCCs. They attempted to answer the important practical question of how well approximate functionals predict experimental SSCCs. Little was known about the accuracy of approximate functionals in predicting SSCCs except for SSCCs over a small set of molecules.68,145–147 The simplest functional, the local spin-density approximation (LSDA), depends solely on the electron spin-density. Addition of the first derivatives of density to LSDA leads to generalized gradient approximations (GGAs). Hybrid functionals introduce a mixture of exact (Hartree-Fock type) exchange, yielding very successful functionals for thermochemistry.148 To ensure the validity of assessment, they tested the 20 chosen functionals over 72 chemically diverse molecules that correspond to 96 experimentally measured 1J(C, H) couplings involving 22 aromatic, 28 sp3, 34 sp2, and 12 sp C atoms. It was found that all GGA functionals improve over the simplest LSDA functional. However, hybrid functionals did not necessarily improve over GGA functionals. Their findings did not support the common belief that hybrid functionals (particularly B3LYP) surpass GGAs for calculation of SSCCs.

6. Hydrogen bonding effects on nuclear spin–spin coupling constants Sychrovsky´ et al.149 performed the CPDFT68,145,150 calculation of indirect NMR SSCCs 3hJ(P, C) and 2hJ(P, H) of the P–O H–C link between the nucleic acid (NA) backbone phosphate and the H–C group (s) of the NA base in order to correlate the above coupling constants with the local structure of the linkage. It was shown that a short distance between the NA base and phosphate group and the smaller angle between P H–C and P–O H than 501 are prerequisites for obtaining a measurable spin–spin interaction of either coupling (|J| 4 1 Hz). The angular arrangement of atoms in the P–O H–C linkage dominated the values of the calculated couplings. Therefore, measurements of 3hJ(P, C) and 2hJ(P, H) couplings can provide critical constraints on the NA base and phosphate geometry and help to determine the structure of NAs. Conformational stability of G-quartets (G4s) found in telemeric DNA quadruplex structures requires the coordination of monovalent ions (Li+, Na+, K+). Mourik and Dingley151 calculated SSCCs and isotropic chemical shifts in G4s with DFT/ B3LYP/6-311G(d). The results showed that the sizes of the trans-hydrogen-bond couplings are influenced primarily by the hydrogen bond geometry and only slightly by the presence of the ion. The calculations showed that the RN2N7 distance of the N2–H2 N7 hydrogen bond has a strong correlation with the 2hJ(N2, N7) constant. They found the following relationship: JN2N7 /Hz = 2316 exp(1.96RN2N7/A˚).

2h


c


(4.10)

Scheme 3

The computed trans-hydrogen-bond couplings were shown to correlate with the experimentally determined coupling constants. Rudner et al.152,153 investigated the importance of intramolecular hydrogen bonding between the carboxylate oxygen and amide proton of succinamate monoanion (Scheme 3) as a function of solvents using NMR spectroscopy. The roughly planar symmetry of the amide and carboxylate substituents of succinamate anion and the possibility of intramolecular hydrogen-bond formation together suggest that the orientational degrees of freedom of the substituents could play an important role in the equilibrium of the CH2–CH2 torsion and consequently the observed vicinal proton–proton couplings. Theoretical coupling constants calculated from the Boltzmann populations and the quantum mechanical two-dimensional potential energy surfaces (PESs) were compared with experimental values of coupling constants for three kinds of solvents, dioxane, acetone, and water. For water solvent with the largest basis set, aug-cc-pVTZ(-f), the good agreement was obtained. Using the 1H, 13C, and 15N NMR spectroscopies and DFT calculations, Afonin et al.154 investigated the N–H O, N–H N, and C–H N intramolecular hydrogen bonds in 2-substituted pyrroles and 1-vinyl pyrroles. They observed that the strong N–H O intramolecular hydrogen bond in the Z-isomers of 2-(2-acylethenyl)pyrroles causes the decrease in the absolute size of the 1J(N, H) coupling constant by 2 Hz in CDCl3 and by 4.5 Hz in DMSO-d6. The N–H N intramolecular hydrogen bond in the 2-(2 0 -pyridyl)pyrrole led to the increase of the 1J(N, H) coupling constant by 3 Hz, and the C–H N intramolecular hydrogen bond in the 1-vinyl-2-(2 0 -pyridyl)pyrrole resulted in the increase of the 1 J(C, H) coupling constant by 5 Hz. The CPDFT69,150,155 calculation showed that the FC mechanism only is responsible for the increase of the coupling constant in the case of the predominantly electrostatic hydrogen bonding, whereas both the FC and PSO mechanisms bring about the decrease of coupling constant in the case of the predominantly covalent hydrogen bonding. Maiti et al.156 studied the correlation between 1J(C, H) and alcohol hydrogen bond strength. The strength of the H-bond donation by alcohols is reflected in the carbon–hydrogen bond of the H–C–O–H functional group. Maiti et al. found that the 1J(C, H) SSCC of hexafluoroisopropanol (HFIP) correlates with the strength of the H-bond in various HFIP–amine complexes with a slope of ca. 0.2 Hz in 1J(C, H) per ca. 1 kJ mol1 increase in the H-bond enthalpy. DFT calculations of 1J(C, H) using the B3LYP functional33 confirmed the potential of using 1J(C, H) coupling as a reporter for H-bonding. It was shown that the decrease in 1J(C, H) is attributed to an increased overlap of the H-bonding s orbital with the antibonding s* orbitals of the vicinal C–H bonds.

7. Conformational analysis The sensitivity of indirect nuclear SSCCs to structual changes makes NMR a powerful tool for determining molecular structures and conformations. As an example we can mention the dependence of SSCC on dihedral angles.157–161 Provasi and Sauer162 investigated the angular dependence of the vicinal fluorine–fluorine coupling constant, 3J(F, F), for 1,2-difluoroethane with several methods including Nucl. Magn. Reson., 2007, 36, 113–130 | 123 This journal is

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polarization propagator approximation (PPA) methods. It is known that the DFT method has problems for reproducing coupling constants that involve at least one fluorine atom.106,145,146,155,163,164 Provasi and Sauer calculated the 3J(F, F) of 1,2-difluoroethane with RPA (random phase approximation), RAS (restricted active space), MCRPA (multiconfigurational random phase approximation), SOPPA, and SOPPA(CCSD) using the geometries optimized for each dihedral angle at the levels of DFT/B3LYP and MP4 (fourth-order Møller-Plesset perturbation).165 Polarization propagator166,167 or linear response function methods168 can yield evaluation of SSCCs without explicit calculation of the excited states.169 Provasi and Sauer showed that for dihedral angles in the range from the cis to the gauche conformation the total 3J(F, F) coupling constant is dominated by the FC contribution, whereas around the trans conformation it is dominated by the PSO term. All calculated values by them around the gauche conformations gave negative values for 3J(F, F) while the Dirac vector model170 predicts a positive 3J(F, F) coupling. It was shown that the SOPPA(CCSD) results are in general in better agreement with experimental couplings than SOPPA results. They observed that the calculated coupling constant curves change continuously from RPA through increasingly larger MCRPA calculations to SOPPA(CCSD), i.e., with a better and better description of dynamic correlation. The calculated coupling constant curves were fitted to a truncated Fourier cosine series in the dihedral angle with 8 coefficients, whereas the original Karplus equation for 3J(H, H) uses only the three coefficients for the truncated Fourier cosine series. The capricious form of the 3J(F, F) Karplus curve in 1,2-difluoroethane was attributed to electron correlation effects on the FC contribution. Habeck et al.171 applied the Bayesian data analysis theory172 to analyze three bond scalar coupling constants, 3J, data measured on ubiquitin.173,174 Since the Karplus coefficients are sensitive to the chemical environment of the macromolecule,175,176 use of empirically parametrized Karplus curves may introduce systematic errors. Therefore, the Karplus coefficients should, in principle, be calibrated for each molecular structure separately. But then a previous structure determination must have been carried out. Furthermore, the chemical environment may differ for solution and crystal structure. However, the Bayesian probality theory makes it possible to simultaneously determine protein torsion angles and the unknown Karplus parameters directly from experimental 3J data without assuming prior knowledge of a pre-determined structure. It was however concluded that it is difficult yet to determine macromolecular structures from NMR 3J data alone. Kleinpeter et al.177 applied the conformational dependence of 1J(C, H) to conformational analysis for a number of methyl substituted 1,3-dioxanes, 1,3-oxathianes, and 1,3-dithianes. The Perlin effect that 1J(C, Heq) 4 1J(C, Hax)126 has been used for a long time as a reliable indicator of the stereochemistry at the anomeric center of carbohydrates. This situation was correctly reproduced in the calculations by Kleinpeter et al. in which the Amsterdum Density Functional (ADF)178 computer program was used. In the 1,3-dioxanes the Perlin effect was observed while in the 1,3-dithianes the reversed Perlin effect was obtained. In the corresponding 1,3-oxathianes the two 1J(C, H) coupling constants approached each other. The experimental tendency in 1J(C, H) was well corroborated. Even if the energy difference between the chair and the energetically nearest twist conformer is not very large, the calculated 3J(C, Hax and Heq) constants proved to be an unequivocal indicator of the preferred conformation. When considering the correlation coefficients for 1J(C, H)exp vs. 1J(C, H)calcd., the agreement between the experimental and calculated 1J(C, H) values appeared to be excellent. It was shown that theoretically calculated 1J(C, H) coupling constants (dominated by the FD term) are very useful in conformational analysis of small organic compounds. Bourˇ et al.179 calculated SSCCs for the L-alanyl-L-alanine (LALA) zwitterion in water as a function of two main chain torsion angles. They used for the calculation of SSCCs the DFT/B3LYP scheme33 and a polarizable continuum solvent model (PCM).180 Traditionally, the relation between the SSCCs and molecular structures is described 124 | Nucl. Magn. Reson., 2007, 36, 113–130 This journal is

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Scheme 4

by empirical Karplus-type relations.181–186 It is, however, problematic to apply these equations to compounds chemically different from those ones used for their calibration.187,188 In such a situation, it is more suitable to use ab initio analysis which provides more reliable estimates of SSCCs for various types of compounds in various molecular conformations. In LALA, as in most peptides, conformational dynamics is governed mostly by the main chain torsions. Changes of the LALA molecular shape can be described using a two-dimensional torsional Schro¨dinger equation. All chemical shifts and detectable direct, geminal, and vicinal coupling constants were measured for isotopically labeled isomers of LALA. With the aid of ab initio DFT calculation of the NMR parameters, the chemical shift and spin–spin coupling surfaces were determined. The results of NMR data analysis were consistent with the theoretical molecular potential energy surface (PES). The effect of the anharmonic averaging on the NMR parameters appeared to be overshadowed by other inaccuracies. It was shown that chemical shifts and coupling constants are most useful for a peptide structural determination. Stoyanova et al.189 investigated synthesis of compounds containing a tetrahydroisoquinoline fragment (Scheme 4). The same fragment is present in various natural alkaloids190,191 and displays important biological properties including antitumor, antibacterial, anti-allergic, and psychotropic activities.192–197 Some of the synthesized compounds showed unexpected 1H NMR properties, i.e., unexpected values for 3J(H3, H4). The 3J(H3, H4) value of 4-[(pyrrolidine-1-yl)-carbonyl]-3-furyl2-phenethyl-1,2,3,4-tetrahydroisoquinolin-1-one (4a) in CDCl3 was 6.7 Hz, but in DMSO-d6 it was 2.0 Hz. Stoyanova et al. gave an explanation for these unexpected values of 3J(H3, H4) that in solution 4a is a mixture of two conformers with dipseudoequatorial (ee) and dipseudoaxial (aa) substituents at C-3 and C-4. A DFT/B3LYP calculation of SSCCs showed that theoretical 3J(H3, H4) constants for ee and aa conformers were 11.4 and 1.9 Hz, respectively. The experimental value of 3J(H3, H4) = 6.7 Hz in CDCl3 corresponds to a practically equal population of both conformers (ee:aa = 50.4:49.6), but this result did not correlate with their energy difference.

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Applications of spin–spin couplings Krystyna Kamien´ska-Trelaa and Jacek Wo´jcikb DOI: 10.1039/b618337a

1. Introduction The material in this chapter covers the period from 1 June 2005 to 31 May 2006. It has been arranged as was done previously,1 i.e. according to (i) the increasing atomic number of the nuclei involved, and (ii) the number of the bonds separating them. We follow the IUPAC2 recommendations with one notable exception, namely, the nucleus with the smaller mass is given first. For the sake of simplicity the following symbols are used throughout the paper: H for 1H, D–2H, T–3H, Li–6Li, Be–9Be, B–11B, C–13C, N–15N, O–17O, F–19F, Al–27Al, Si–29Si, P–31P, S–33S, V–51V, Mn–55Mn, Fe–57Fe, Co–59Co, Cu–65Cu, As–75As, Se–77Se, Br–79Br, Y–89Y, Nb–93Nb, Mo–95Mo, Ru–99Ru, Tc–99Tc, Rh–103Rh, Ag–109Ag, Cd–113Cd, In– 113/115 In, Sn–119Sn, Sb–121Sb, Te–125Te, I–127I, Cs–133Cs, W–183W, Os–187Os, Pt–195Pt, Hg–199Hg, Tl–205Tl, Pb–207Pb. All the other isotopes are described explicitly. A systematic development of relativistic molecular Hamiltonians and various nonrelativistic approximations has been presented by Perera and Bartlett.3 They concentrated their attention mostly on the operators which were used to calculate the NMR chemical shifts and spin–spin couplings. Applications of 19F multidimensional spectroscopy NMR have been reviewed by Battiste and Newmark.4 Advances in theoretical and physical aspects of spin–spin couplings have been presented by Contreras et al.5 An extensive review of synthesis and NMR of the intramolecularly Sn–N coordinated organotin hydrides has been written by Komsta et al.;6 it also includes a wealth of X–Sn (X = H, C, N) spin–spin couplings. An overview of 195Pt NMR spectroscopy which also included Pt–X coupling data has been published by Priqueler et al.7 Strategies and tools for structure determination of natural products using modern methods of NMR spectroscopy have been reviewed by Bross-Walch et al.8 The article that reviews the use of the generalized Karplus type equation for 3JHH couplings to quantify the conformational behaviour of ribofuranose in solution has been given by Gautier.9 A short review of residual dipolar couplings as a valuable parameter for structure determination of small organic molecules has been given by Gschwind.10 This parameter appears to be especially useful in assigning diastereotopic protons, determining the relative orientation of protons far away from each other, and elucidating the absolute configuration of diastereomers. A review that addresses recent advances in techniques for the measurement of RDCs for studying biomolecular structure and dynamics has been written by Bax and Grishaev.11 The authors have concluded that RDCs restraints have a ‘global’ character and their use results in a considerable improvement in Ramachandran map quality and in better agreement with crystallographically derived structures. An overlook of the use of RDCs to study protein–protein, protein–RNA and protein–DNA interactions has been given by Kaptein and co-workers.12 The RDCs in combination with other experimental data allow to determine accurately the structures of complexes up to 50 kDa. Flinders and Dieckmann13 have published a a

Polish Academy of Sciences, Institute of Organic Chemistry, ul Kasprzaka 44, 01-224, Warszawa, Poland b Polish Academy of Sciences, Institute of Biochemistry and Biophysics, ul. Pawin´skiego 5a, 02-106, Warszawa, Poland


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short review on NMR parameters used in NMR spectroscopy of RNA. These include scalar and residual dipolar couplings as well as couplings across the hydrogen bond. Two reviews have been devoted to methods for studying the structure and dynamics of RNA. NMR techniques used for probing RNA dynamics at the atomic-level have been reviewed by Al-Hashimi.14 These include studies of dihedral fluctuations faster than milliseconds on timescales characterised by measuring multiple scalar coupling interactions and collective motions occurring over submillisecond timescales probed by measuring residual dipolar couplings in partially oriented RNAs. Also Pardi and co-workers15 have reviewed the applications of RDCs for determining the global structure of larger RNAs and for studies of their dynamics. In addition, the authors have reviewed couplings through hydrogen bonds as tools for identifying hydrogen-bond donors and acceptors. The sizes of such couplings are correlated with hydrogen-bond lengths and therefore may be incorporated directly into RNA structure refinements. A review of NMR spectroscopy in structural studies of nucleic acids has been published by Gdaniec.16 Progress in Multiple-Quantum MAS NMR spectroscopy has been presented by Rocha et al.17

2. New methods A new signal processing method, harmonic inversion noise reduction (HINR), has been presented by Kunikeev et al.18–20 which significantly improved weak NMR signal detection and allowed the observation of scalar couplings. The method was earlier successfully employed for the detection of CC couplings19 and the observation of 13C satellites in 31P NMR spectra.20 A new NMR experiment, 1H-detected double-J-modulated (DJM)-INEPT-INADEQUATE, for simultaneous determination of one-bond and long-range carbon– carbon connectivities and the measurement of all carbon–carbon couplings has been devised by Uhrin and co-workers.21 They have shown that, using a 600-MHz cryoprobe and 20 mg of a monosaccharide, couplings as small as 2 Hz can be obtained within a reasonable time. As an example a spectrum of b-Me-xylopyranoside has been registered and the corresponding JCC couplings across one and two bonds presented. Levitt and co-workers22 have developed a double-quantum-filtered spin-echo (DQF-SE) method to measure 1JCC couplings in MAS 13C2-labelled large biomolecules. Using this method they showed that the protein environment does not perturb the electronic structure of the conjugated system of the 11-Z-retinylidene chromophore. A rotor-synchronized 2D triple-quantum MAS correlation experiment based on the INADEQUATE experiment has been applied by Schmedt auf der Gu¨nne et al.23 to resolve possibly overlapping peaks in the spectrum of poly (carbonsuboxide). New spin-edited 2D HSQC-TOCSY experiments have been designed by Nolis and Parella24 for the measurement of the sign and magnitude of homonuclear and heteronuclear couplings. In the case of peptides at 13C and 15N natural abundance a set of couplings, 2JHaN, 3JHbN, 2JNHCa, 2JHbCa, 3JHgCa, 3JNHHa and 3JHaHb, can be measured with good precision. The proposed techniques are particularly suited for molecules presenting a great number of CH and NH spin systems including carbohydrates. Parella and co-workers25 have introduced an efficient IPAP strategy to achieve S3 editing simultaneously for all multiplicities in the acquisition dimension of the HSQC experiment. The authors have provided an application of the method for measuring the sign and magnitude of geminal, 2JHH and 1JHC or 1JHN couplings, and for measurement of long range 2,3JHC couplings. New 2D (HNCO)-(J-CA)NH and 3D (HN)CO-(J-CA)NH experiments for the measurement of 1DHaCa in 13C and 15N labelled proteins have been developed by 132 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Uhrı´ n and co-workers.26 Selective manipulation of HaCa spins yields higher precision of HaCa splitting determination than is achievable with existing frequency based methods. Griesinger and co-workers27 have applied the 1H homonuclear dipolar coupling during acquisition into the HSQC experiment for the measurement of 1DHC. Incorporation of Flip-Flop decoupling improves resolution by a factor of 1.5–4.2 and signal intensity by an average factor of 1.6–1.7. Vijayan and Zweckstetter28 have modified the 3D TROSY-HNCO and the 3D CBCA(CO)NH experiments for efficient measurement of one bond 1DHN, 1DC 0 N, 1 DHaCa, 1DHbCb, and 1DCaC 0 couplings in small to medium sized 13C-, 15N-labelled proteins. A single reference experiment is used in this strategy, thereby reducing the required measurement time. The IPAP-SOFAST-HMQC pulse scheme has been presented by Brutscher and co-workers.29 These 2D heteronuclear correlation experiments allow the measurement of 1JHC and 1JHN scalar and dipolar couplings in proteins with adjusting the acquisition time down to the minimal time of a few seconds. A new set of HCACO based 3D experiments for measuring 1DHaCa, 1DCaC 0 and 2DHaC 0 couplings of 13C-, 15N-labelled proteins has been presented by Permi and co-workers.30 The experiments are especially suitable for small or medium sized proline-rich proteins, or proteins that require high pH solvent conditions. The HNCO-based E.COSY pulse sequences have been proposed by the same group31 for simultaneous measurement of 1DCaC 0 , 1DCaN and 2DCaN couplings in proteins. Two new NMR experiments for accurate measurements of heteronuclear dipolar couplings in the static solids have been proposed by Dvinskikh and co-workers.32,33 The first32 is based on the windowless isotropic mixing approach. In the second experiment33 homonuclear dipolar coupling and chemical shifts are simultaneously suppressed using BLEW, a spin-lock based on a multiple pulse sequence. Riek and co-workers34 have implemented experimental relation between the 1DHN coupling and 15N chemical shift in 3D HNCA experiments with simultaneous detection of 1H and 15N chemical shifts. This concept, called SITAR, reduces the dimensionality of the 3D experiment to 2D and enables the recording of 3D experiment in several minutes. The FS-J-RES method for measuring scalar heteronuclear coupling between spin 1/2 and quadrupolar nuclei in the solid phase has been provided by Pruski and coworkers.35 The method has been applied to AlPO4–VPI5 yielding two values of the 2 JAlP of 18 5 and 35 7 Hz, corresponding to two different Al–O–P distances and angles present in the sample. Pines and co-workes36 have shown that it is possible to use hyperpolarized 129 Xe as a dipolar sensor for measuring the proton spectra of concentrated solutions with the resolution sufficient to observe homonuclear proton–proton couplings. The feasibility of liquid-state proton, carbon and fluorine ultrahigh-resolution NMR spectroscopy in the Earth’s magnetic field has been presented by Appelt et al.37 They emphasize that the accuracy of the JHSi and JHF couplings measured by this technique is between a few up to 20 millihertz. The physical limitations of the J-coupling NMR spectroscopy of liquids in nT fields have been discussed by Bernarding and co-workers.38 The authors have shown that the increase of J/dn in the spectrum of 2,2,2-trifluoroethanol led to merged lines due to their natural lifetime broadening 1/pT2, whereas in the spectrum of trimethyl phosphate the 31P multiplet was below noise level. The ACCA method (Automatic Coupling Constant Analyzer) which allows a high degree of automation in the extraction of coupling patterns even in the case of complex multiplets, has been published by Cobas et al.39 Its usefulness has been demonstrated by the application to strychnine, for which couplings not detected previously have been extracted. Nucl. Magn. Reson., 2007, 36, 131–169 | 133 This journal is

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3. One-bond couplings to hydrogen 1

JHH couplings across the electron bridging dihydrogen bond in the imidazolecontained anion derivatives have been calculated by Yan et al.40 The couplings are dominated by the paramagnetic and diamagnetic spin-orbit contributions instead of the Fermi contact contribution, and their values increase upon the increase of the electronegativity of the heavy atoms involved. Density functional approach has been applied by Le Guennic et al.41 to study H–D couplings in heavy metal dihydrogen and dihydride complexes, and by Gelabert et al.42 in order to provide experimental tests which would allow one to distinguish between elongated dihydrogen and compressed dihydride complexes. 1 JHD couplings of 6.5 and 7.7 Hz have been measured by Jagirdar and co-workers43 for H2D and HD2 isotopomers of the cis-dihydrogen/hydride complex of iridium, cis-[Ir(H)(Z2-H2)(Z2-S2CH)(PCy3)2][BF4], and used by the authors to elucidate the H–H distances in the complex. It has been shown by Maiti et al.44 that the one-bond H–C coupling in hexafluoroisopropanol (HFIP) correlates with the strength of the H bond in HFIP-amine complexes. Thus, the determination of 1JHC should provide insight into the strength of the H-bonds by the alcohol. Assessment of density functionals for predicting 1JHC couplings has been performed by Scuseria and co-workers,45 who used for this purpose 72 diverse molecules that represent multiple types of hybridization of the carbon atoms involved in the coupling. Experimental and theoretical hyperconjugative effects on 1 JHC couplings have been studied by Tormena and co-workers.46 It has been established by Makulski47 that 1JHC and 1JDC couplings measured in the gas phase for dimethyl ether and its isotopomers are almost independent of pressure. 1JHC coupling and carbon magnetic shielding of gaseous benzene have been studied by Jackowski et al.48 in CO2 and Xe. The authors have shown that the proton–carbon coupling is more affected by CO2 molecules than Xe atoms. 1 JHC couplings have been used by Kleinpeter et al.49 in the conformational analysis of a series of methyl substituted 1,3-dioxanes, 1,3-oxathianes and 1,3thianes. The extensive DFT calculations of 1JHC couplings have been performed by Fischer and Reinscheid50 for cytidine in order to get information on its conformation. They have shown that the 1JHC couplings show a clear dependence on the glycosidic torsion that enables one to identify the w angle. This result is in contrast to a recent suggestion by Serianni51 that the 1JH 0 C 0 couplings are unaffected by Nglycosidic torsion. 1JHC couplings have been measured by Crich et al.52 for the a- and b-rhamnopyranosides. The presence of C–H O hydrogen bonds in a complex of 2-(acrylamido)-6(methylamido) pyridine and 1-octyl thymine in solution has been demonstrated by Li et al.53 The authors have observed the increase of the corresponding 1JHC coupling by 8.3 Hz. Deelchand et al.54 have proposed to measure localized 13C NMR spectra in vivo without proton decoupling. These measurements are performed for monitoring incorporation of the 13C label from 13C-labelled glucose into human brain amino acids. The authors have shown that the presence of 13JHC couplings in the spectrum increases the uncertainty of analysis but opens the prospect of safely measuring spectra in humans at high magnetic fields. The calculations of 1JHC couplings by the use of the DFT (B3PW91) approach have been performed by Solans-Monfort and Eisenstein55 for the a-alkylidene C–H bond in several high oxidation state d0 transition metal-alkylidene complexes (M = Re, Mo, Ta). The authors have shown that the calculations well reproduce the trends in the 1JHC values over a range of 75–150 Hz. It has been shown by Messerle and co-workers56 that dinuclear coordination of a novel four-electron reduced m-Z1, Z3-allene ligand occurs upon direct addition of allene to (C5Me5)2Ta2(m-Cl)4 yielding the (C5Me5)2Ta2(m-Z1, Z3-C3H4)(m-Cl)Cl3 134 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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complex; the disparate 1JHC coupling values have been observed for the associated carbon atom confirming the probable existence of a b-agostic C–H Ta interaction. The relation of basis set completeness and performance in the calculation of magnetizability, nuclear magnetic shielding, and spin-coupling has been tested by Manninen and Vaara.57 The calculations of 1JHX couplings have been performed for H2O, NH3 and CH4 molecules. Relativistic calculations of 1JHX couplings (X = C, Si, Ge, Sn) in a series of tetrahydrides, CH4, SiH4, GeH4 and SnH4, have been performed by Melo et al.58 who used the Douglas-Kroll-Hess approximation. The position of the equilibrium in a Schiff base, N-(3,5-dibromosalicylidene)methylamine, a model for the hydrogen bonded structure of the cofactor pyridoxal5 0 -phosphate, has been determined by Sharif et al.59 by the use of one-bond 1JHN and vicinal 3JHaNH couplings. The tautomerism of sterically hindered Schiff bases has been studied by Filarowski et al.60 who have shown that intrinsic deuterium isotope effects are exerted on chemical shifts of these compounds as well as on 1JHN couplings. This suggests that a zwitterionic resonance form is dominant for the proton transferred form. Different types of hydrogen bonds have been observed and investigated by Afonin et al.61 in 2substituted pyrroles and 1-vinylpyrroles by the use of 1JHN and 1JHC couplings. Among others, they found that the strong N–H O intramolecular hydrogen bond in the Z-isomers of 2-(2-acylethenyl)pyrroles causes the decrease in the absolute value of the 1JHN couplings by 2 Hz in CDCl3 and by 4.5 Hz in DMSO-d6. 1 JHN couplings have been reported by Carlton et al.62 for 1-alkyl-4-imino-1,4dihydro-3-quinolinecarboxylic acids and related compounds, by Laihia et al.63 for some methyl and alkylamino derivatives of 4-halopyridine N-oxides, by Wood et al.64 for a variety of dipyrromethanes and dipyrromethenes for which consistently 1 JHN couplings of 96 Hz have been found, and by Srivastava and co-workers65 for a series of benzamidoximes where couplings of ca. 87 Hz have been found. A detailed discussion of the 15N chemical shifts and 13JHN couplings measured for N-nitroso- and N-nitraminotetrazoles and for their precursors, aminotetrazoles, has been presented by Karaghiosoff et al.66 The first complex with simultaneous Si–H and RuCl SiCl inter-ligand interactions, Cp(Me)5(i-Pr3P)Ru(Cl)(Z2-HSiClMe2), has been synthesized by Osipov et al.67 The 1JHSi coupling of 33.5 Hz measured at 40 1C for this compound suggests the presence of a Si–H s-interaction in it. Experimental and calculated 1JHSi couplings for several model compounds have been also included in this work. 1 JHW of 38.2 Hz has been measured for the dihydrogen complex of tungsten W(CO)5(H2) and 1JHD of 35.3 Hz for its HD isotopomer providing unequivocal evidence structure thereof;68 in the HD isotopomer of the analogous chromium complex, Cr(CO)5(H2), 1JHD = 35.8 Hz has been found. 1 JHOs of ca. 44 Hz and 1JPOs couplings have been reported by Deeming and coworkers69 for [Os3(m-H)2(CO)10] and for a series of hydride bridged triosmium clusters with chiral diphosphine ligands, [Os3(m-H)2(CO)8(m-L)], L = tolBINAP, dppm, dppe; for [Os3(m-H)2(CO)8(m3-BINAP-H)] two 1JHOs couplings, 30.7 and 33.7 Hz, have been reported. The structure of [Os3(m-H)2(CO)8(m-dppm)] has been established by X-Ray and therefore the similarity of the 1JHOs values in this compound and in the [Os3(m-H)2(CO)8(m-tolBINAP)] complex in the solution spectra has been used by the authors as corroboration of the hydride location in the latter.

4. One-bond couplings not involving hydrogen LiN couplings have been extensively used by Reich and co-workers70 to establish solution structure and chelation properties of 2-thienyllithium reagents, and by Collum and co-workers71 to study solvent-dependent aggregate structures of lithiated imines. Nucl. Magn. Reson., 2007, 36, 131–169 | 135 This journal is

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The presence of a strong Li–Si coupling, of ca. 50–60 Hz, observed by Strohmann et al.72 in the NMR spectra of two chiral lithiosilanes, [(Lis)-PhMe2SiLi THF (–)sparteine] and [Ph2(NEt2)SiLi (–)-sparteine], indicates a distinct Si–Li contact on the NMR timescale in both compounds. The 1JBP, 1JCP and 1JHP couplings have been measured by Dornhaus et al.73 for a series of phosphanylborohydrides and their derivatives. The 1JBP coupling values obtained for BH3(H)PPh2, BH3(CH3)PPh2 and K[(BH3)2PPh2], 42, 55 and 64 Hz, respectively suggest that BH3PPh2 forms the strongest [BH3] adduct of all three compounds studied. An interesting interpretation of the spin–spin coupling mechanism in saturated carbocycles via plots of current density induced by 13C nuclear magnetic dipoles and related maps of coupling density has been proposed by Soncini and Lazzeretti.74 Within the picture proposed by them, the multipath coupling model does not seem to be of great importance. Low-temperature 13C INADEQUATE measurements performed by Bugaj and Kamien´ska-Trela75 for 4-dimethylamino-but-3-en-2-one and 4-methylaminobut-3-en-2-one yielded one-, two- and three-bond carbon–carbon couplings in s-cis and s-trans rotamers of these compounds. A reasonably good agreement has been observed between the experimental and B3LYP calculated values. Dynamically averaged 1JCC couplings in nitrosobenzene, p-substituted (F, Cl, Br, I, Me, NO2, OMe and NMe2) nitrosobenzenes and o-nitrosotoluene have been measured by Biedrzycka et al.76 For the same set of compounds as well as for benzene, the DFT J couplings across one, two and three bonds have been calculated; the simplest possible relationship 13JCC(exptl) = 13JCC(calcd) has been obtained over a broad range of the couplings, starting from 2JCC = 2.5 Hz in benzene up to 1 JCC = 70.5 Hz in p-fluoronitrosobenzene. 1 JCRC coupling of 85.7 Hz has been determined by Harris et al.77 for the (Z2Ph13CR13CPh)Pt(PPh3)2 complex in solution. It is, however, worth noting that much lower 1JCC values have already been reported by Chisholm et al.78,79 for the alkynes bonded to hexaalkoxides of dimolybdenum and ditungsten; see also refs. in Kamien´ska-Trela.80 Spin–spin couplings determined from the NMR spectra of gaseous mixtures have been collected by Jackowski81 for a series of small molecules. This included 1JCC couplings in acetylene and acetonitrile. 1JCC and 1JCH couplings have been measured and computed by Dodziuk et al.82 for trans- and cis-decalins and good agreement has been observed between the experimental and computed data. Nonempirical calculations on NMR indirect spin–spin carbon–carbon couplings have been continued by Krivdin and co-workers. This included azomethines of the a,bunsaturated aldehydes,83 a series of ketone oximes,84 amidine derivatives of aarylglycines from N-(aryl-2,2,2-trichloroethyl)amides of arenesulfonic acids and secondary amines,85 2-(2-pyrrolyl)pyridine and 2,6-di-(2-pyrrolyl)pyridine,86 the configurational assignment at the CQN bond of methyl 2-methoxy-N-methyl-2,3butadienimidothioate, a representative member of an allenylthioimidates series,87 and the configurational assignment of aminosulfonylamidines.88 It follows from an analysis of one-bond carbon–carbon couplings performed by Wrackmeyer and Tok89 for trialkylboranes that hyperconjugation in these compounds arises from C–C s bonds adjacent to the tricoordinate boron. 13 JCC couplings in a series of specifically labelled methyl 2-acetamido-2-deoxy-D[1-C]aldohexopyranosides have been measured by Serianni and co-workers,90 and for some model compounds DFT calculations have been performed. A full set of 1JCC, 1JCN and 1JHN couplings has been calculated for the 5hydroxyindole ring in three conformers of serotonin using the GIAO method at the B3LYP level by Manivet and co-workers.91 A statistical analysis has been performed by Claramunt et al.92 for a set of experimental and computed one-bond and long-range JCC, JHC and JCN couplings 136 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Fig. 1

obtained for eight N-R-pyrazoles where R = H, CH3, C6H5, COCH3, NH2, NO2, SO2CF3 and Si(CH3)3. Labelled acrylamide and N-methylolacrylamide, 15N-acrylamide, 13C-NMA, 15 N-NMA, and 13C, 15N-NMA have been synthesized by Brown and Frazier93 and for all these isotopomers spin–spin couplings measured. A detailed analysis of the NMR spectra of per-15N labelled etioporphyrins performed by Lash and Chen94 yielded 1JCN, 2JCN, 1JNH and 3JHN couplings in these important compounds. NMR spectra of 1,2-dibromo-1,1-difluoroethane and 1-bromo-2-iodo-tetrafluoroethane dissolved in nematic liquid crystalline solvents have been analysed by Emsley et al.95 to yield the magnitudes and signs of the scalar couplings between all the 1H, 13C and 19F nuclei, except those between two 13C nuclei. Among others, 1JCF and 2JCF couplings have been determined. No clear evidence of a significant contribution of the anisotropy in the J couplings of either of the two molecules studied has been found. Mu¨ller and co-workers96 have continued their studies on a-aryl-substituted vinyl cations (Fig. 1). A Hammett-type analysis which relates the 1JCSi coupling with the electron-donating ability of the aryl group of the form 1JCbSi = (4.2 0.5) s+ + (18.6 0.1) has been used by them as an indication that an inverse relation between the extent of Si–C hyperconjugation and p-donation occurs in the compounds studied. The 1JCP, 2JHP and 1JPP couplings have been measured and calculated for diphosphacarbollide analogues of the C5H5 anion, the nido-di- and triphosphacarboranes 7,8,9-P2CB8H10, [7,8,9-P2CB8H9], [7,8,10-P2CB8H9], and 7,8,9,10P3CB7H8.97 A series of mono- and dicationic trimethylsilylmethyl complexes supported by THF and 12-crown-4 ligands has been prepared by Elvidge et al.98 from the corresponding neutral precursors [Ln(CH2SiMe3)3Ln] (Ln = Sc, Y, Lu; L = THF, n = 2 or 3; L = 12-crown-4, n = 1); for the yttrium derivatives 1JCY couplings of ca. 40 Hz have been observed. The rare instance of 1JCNb coupling has been reported by Lo et al.;99 1JCNb = 220 Hz has been observed in the 13C MAS NMR spectrum of half-sandwich niobium metallocene, (PhH2COC)CpNb(CO)4. This is the first 1JCNb coupling measured in the solid state; the value found is very close to that found for labelled CpNb(13CO)4 in solution. 1 JCRh and 1JPRh couplings have been reported by Varshavskii et al.100 for two series of Rh(I) carbonyl carboxylate complexes, [Rh(m-RCOO)(CO)2]2 and transRh(m-RCOO)(PPh3)2(CO) where R = H, CH3 and CF3. Three new penta- and hexacoordinated tin compounds have been obtained by Camacho-Camacho et al.101 One-bond carbon–tin couplings, 1JCSn, measured for 3methyl-2-oxo-cyclopentanen-1-one-chlorodiphenyltin, 935 Hz, and 3-methyl-2-oxocyclopentanen-1-one-triphenyltin (657 Hz) are typical of pentacoordinated tin, whereas 1JCSn of 1230 Hz found for [(O–Sn)ethanol]-(3-methyl-2-oxo-cyclopentanen-1-one-dichlorophenyltin) indicates that this compound is hexacoordinated. Nucl. Magn. Reson., 2007, 36, 131–169 | 137 This journal is

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HR MAS NMR spectroscopy has been applied by Deshayes et al.102 to study dialkyltin chloride grafted to a cross-linked polystyrene, with the formula [P–H](1t)[(P–CH2)nSnBuCl2]t where P = [CH2CH(p-C6H4)], t = the degree of functionalization, and n = 6 or 11. Although the 1H HR MAS spectra of these compounds are complex, the authors have been able to measure accurately the 13 JCSn and nJHSn couplings from the E.COSY pattern of the coupling satellites. These couplings have been found to be extremely valuable parameters for a positive identification of the exact chemical nature of the grafted organotin functionality as well as of the coordination state of the tin atoms. Assuming that the general rule 1J 4 3J 42J 4 4J is valid in the case of C–Sn couplings Schumann et al.103 have assigned the signals in the 13C NMR spectra of some organo-all-tin dendrimers with different peripheral substituents. 1 JCPt and 1JPPt couplings have been measured by Gudat et al.104 for a series of cis and trans arranged organometallic (phosphane)platinum(II) complexes, [Pt(Ar)2 (PtEt3)2], and compared with the calculated J values. This approach allowed the authors to establish the configuration of the compounds studied; in particular, the calculated 1JCPt couplings are in excellent agreement with the experimental ones and clearly support the assignment of cis and trans configurations, whereas the 1JPPt couplings reflect the cis/trans variation only qualitatively. 1 J14N111Cd couplings of 87.8 and 123.5 Hz have been observed by Mendoza-Dı´ az et al.105 in the spectra of solid-state 111Cd NMR of the Cd(II)-2,4- and Cd(II)-2,3pyridinecarboxylate, respectively. 1 J14NPb of 63 Hz and a 14N–207Pb dipolar coupling of 149 Hz have been observed by Buston et al.106 in the 207Pb CP MAS NMR spectrum of a 1:1 crystalline complex of lead(IV) tetraacetate and pyridine confirming its structure. The one-bond N–N coupling in a highly explosive azide, N5SbF6, has been measured by Kunikeev et al.18 The absolute 1JNbNg coupling value of 26.5 Hz is one of the largest 1JNN couplings observed to date. DFT calculations of nitrogen parameters which also included 1JNN, 1JCN and 1 JNSi couplings have been performed by Wrackmeyer and Koehler for a series of noncyclic and cyclic azo compounds.107 An analysis of 15N and 19F NMR spectra has been performed by Fir et al.108 for F5TeNH2, F5TeNF2, [F5TeN(H)Xe][AsF6], [F5TeNH3][AsF6] and their 15N isotopomers yielding, among others,1JNF, 1JNTe and 1JFTe couplings. The solid-state isomerization of nitrito- and nitro-pentamminecobalt(III) chloride has been studied by Ooms and Wasylishen109 by the use of the solid-state NMR spectroscopy, and 1JNCo = 63 2 Hz has been observed for the nitro isomer. It has been shown by Jolibois and co-workers110 that 19F chemical shifts and 1JFP couplings calculated for the five fluorine atoms of phosphorous pentafluoride, PF5, converge towards the NMR equivalence of the five fluorine atoms in this molecule when the Berry pseudorotation process in the interpretation of its 19F NMR spectrum is taken into account. The fluoride congener of Wilkinson’s catalyst, [(Ph3P)3RhF], has been synthesized and fully characterized by Macgregor et al.111 by the use of NMR. This included a full set of one- and two-bond couplings; among others, 1JFRh = 77.6 Hz, 2JFP(trans) = 172.4 Hz and 2JFP(cis) = 28.5 Hz have been reported. Similar data has been obtained for trans-[(Ph3P)2Rh(Ph2PF)(Cl)] and trans-[(Ph3P)2Rh(Ph2PF)(F)] compounds. A two-dimensional 29Si INADEQUATE spectrum measured by Fyfe and Brouwer112 for the ZSM-5-a-naph-d4 complex allowed the assignment of the signals in the 29Si NMR spectrum of this compound. The conformational dependence of one-bond and through-space phosphorous– phosphorous couplings in four tetraphosphane-1,4-diides [M(L)x]2[P4R4], where M = Na or K; R = Mes, Ph, t-Bu; L = THF, x = 2, 2.5, 3, has been studied by Kaupp et al.113 by DFT methods. Good agreement has been observed between 138 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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the computed JPP couplings based on experimental solid-state structures and the solution NMR data. The chemical shifts and phosphorous–phosphorous couplings have been computed by Galasso114 for some selected medium-sized bicyclic diphosphines by DFTbased methods and satisfactory agreement with the experimental data has been observed. The theoretical results indicate that the strong orientational effects of the phosphorus lone pair and coordination are exerted on the sign and magnitude of the couplings studied. 1 JPX couplings of 1166 10, 101 20 and 384 50 Hz for X = F, Cl and Br, respectively have been observed by Rabis et al.115 in the 31P MAS NMR spectra of pyridine stabilized dithiomonometaphosphoryl halides, Py - PS2F, Py - PS2Cl and Py - PS2Br, respectively. Additionally, a residual coupling between phosphorus and halogen atoms has been observed in the two latter compounds. 1 JPCu couplings of ca. 1 kHz have been measured by Hanna et al.116 in the CP MAS spectra for a series of four-coordinate copper(I) complexes [Cu(PPh3)X] and [Cu(PPh3)(CH3CN)]X where X = Cl, Br, I, ClO4, BF4, SiF5 and PF6. The solid state 29 Si CP MAS spectrum of the pentafluorosilicate anion in [Cu(PPh3)(CH3CN)]SiF5 CH3CN afforded also 1JFSi = 146 Hz. 1 JPSe couplings of 716 to 744 Hz have been measured by Dubrovina et al.117 for several new electron-reach chiral 1,3-diphosphines of the BDPP type prepared from 1,3-diphenylpropane-1,3-diol (BDPP = chiral 2,4-bis(diphenylphosphino)pentane), and 1JPSe of 722 and 788 Hz have been found by Otto et al.118 in SeQPTA and [SeQPTA-Me]I complexes, respectively (PTA = 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane). The already published 1JPSe couplings and PQSe bond distances have been compared by the latter group of authors for a large series of phosphines. They came to the conclusion that no linear correlation exists between these two parameters. The existence of such correlation was suggested some time ago by Malito and Aleya.119 The indirect spin–spin coupling between 113/115In and 31P spins, 1JPIn, in Fe-doped InP semiconductor and 1JInSb(As) coupling in InSb(As) semiconductors have been reported by Iijima et al.120,121 Absolute isotropic 1JPIn = 224 5 Hz,120 1JInSb = 478 10121 and 1JInAs = 730 40 Hz121 values have been reported. The coordination chemistry of equimolar amounts of silver(I) with the long chain diphosphine ligands Ph2P(CH2)nPPh2 (n = 6, 8, 10, 12) has been studied by Sekabunga et al.122 In all cases two silver(I)/phosphine complexes have been observed in solution at room temperature with 1JP107Ag = 500 Hz. This indicates that silver(I) is coordinated to two phosphorus atoms in a linear mode. 1 JP107Ag and 1JP109Ag couplings have been used by Effendy et al.123 to characterize some new complexes containing unidendate N-donor azole-type ligands; the complexes have been obtained from the interaction between azole-type ligands and [AgX(PPh3)n] (X = Cl, n = 3; X = MeSO3, n = 2) compounds. Variable-temperature solid–state 2H, 15N and 31P NMR studies performed by Wasylishen and co-workers124 for 1:1 adduct of silver nitrate and triphenylphosphine, AgNO3 PPh3, revealed a solid–solid phase transition at 300 K. The indirect spin–spin coupling between phosphorus and the naturally occurring isotopes of silver, 1JPAg of ca. 830 Hz, has been also measured and found to be independent of temperature. According to the NMR data the cis coordination only takes place when the two novel diphosphine ligands, 1,2-bis(3-(diphenylphosphino)-4-methoxyphenyl)benzene and 1,2-bis(2-diphenylphosphino)benzene, react with PtCl2(cod), which results in large 1JPPt couplings, 3810 and 3712 Hz, respectively.125 NMR parameters including 1JPPt and long-range nJHP and nJCP couplings have been measured by Longato et al.126 to characterize some new azametallacycle complexes obtained via Pt(II)-mediated coupling reactions of acetonitrile with the exocyclic nitrogen of 9-methyladenine and 1-methylcytosine, Nucl. Magn. Reson., 2007, 36, 131–169 | 139 This journal is

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Fig. 2

cis-[L2PtNHQ C(Me){9-MeAd(2H)}]NO3 and cis-[L2PtNHQC(Me){1-MeCy (–2H)}]NO3, L = PMePh2 and PPh3. 1 JPHg couplings have been collected by Bowmaker et al.127 for a series of mercury complexes. A considerable increase in 1JPHg has been observed from [Hg(PBz3)2](BF4)2 to [Hg(PBz3)2](NO3)2 and interpreted in terms of the incorporation of the nitrate group into the coordination sphere of the latter compound. Relativistic DFT calculations of 119Sn chemical shifts and couplings have been performed by Bagno et al.128 for a series of methyl tin halides, Me4nSnXn (X = Cl, Br, I; n = 1–3); the computed 1JClSn, 1JBrSn, 1JISn couplings as well as the remaining ones have been compared with the experimental values if available. A comparison of experimental 2D 59Co COSY and DQF COSY NMR spectra with simulated ones has been performed by Kempgens et al.129 for three tetrahedral mixed-metal clusters, which allowed them to elucidate the 1JCoCo couplings in these compounds. 1JCoCo’s of ca. 140, 165 and 45 Hz have been found for HFeCo3 (CO)11PPh3, HFeCo3(CO)11P(OMe)3 and HFeCo3(CO)11PCy3 (Cy = cyclohexyl), respectively. An analysis of the 1JSeTl and 2JTlTl couplings has been performed by Schrobilgen and co-workers130 for three Tl2Se66–, Tl3Se65– and Tl3Se75– anions in order to establish their structures. 1 JSnSn couplings of 6294 to 8925 Hz have been observed by Stalin´ski and coworkers131 in three new distannanes containing the chiral 2-(4-isopropyl-2-oxazolinyl)-5-phenyl ligand, which provided evidence that penta-coordination at the tin centre in these compounds takes place (Fig. 2). In one of these compounds also a rarely reported coupling between the nitrogen and tin atoms, 1JNSn of 20 Hz, has been observed. A very rough correlation (r2 = 0.87 only) between the tungsten tin solid state bond distance (rSnW) and the solution state one-bond scalar coupling of tungsten to tin, 1JSnW, has been observed by Mobley et al.132 in a series of hydrido- and chlorotungstenocene diorganostannylchlorides with sterically demanding organic substituents, Cp2WXSnClR2, X = H or Cl; R = t-Bu or Ph: rSnW = (2.4 104 A˚/Hz) 1JSnW + 3.02 A˚. It should also be mentioned at this point that the coupling values can be strongly affected by the solvent; for example, 1JSnW of 947 and 882 Hz have been observed for Cp2WClSnCl-t-Bu2 in THF-d8 and CDCl3, respectively. High-resolution solid-state 119Sn and 195Pt NMR spectra of MPtSn semiconductors (M = Ti, Zr, Hf and Th) have been measured by Grykazowska and Nowak,133 and 1JSnPt couplings have been reported for TiPtSn and ZrPtSn. 140 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Very large 1JPtTl couplings have been reported by Chen et al.134 for dinuclear [{Pt(ONO2)(NH3)2(NHCO-t-Bu)}Tl(ONO2)2 (MeOH)] and trinuclear [{Pt(NO3)(NH3)2(NHCO-t-Bu)2}2Tl]PF6 2MeOH complexes, 146.8 and 88.84 kHz, respectively.

5. Two-bond couplings to hydrogen Geminal and vicinal H–H couplings have been reported for a variety of natural products, such as products of hydroxylation of human steroid hormones by a housefly cytochrome P450,135 benzylidenebenzyl butyrolactone lignans,136 for various compounds extracted from lettuce leaves,137 and for two unusual kaurene diterpenes from Erythroxylum barbatum.138 It has been shown by Winkler139 that the compound recently isolated from Dahlbergia sympathetica by Shanmugam et al.140 is not a novel, as suggested by the authors, dihydroxy-N-methyl piperidone but in reality an already well known Nmethyl-trans-4-hydroxy-L-proline, often occurring in plants. The structure elucidation has been done by Winkler on the basis of good agreement between chemical the shifts and H–H couplings reported for the isolated compound and those published in the literature for N-methyl-trans-4-hydroxy-L-proline. It has been concluded by Celebre et al.141 on the basis of proton–proton couplings, 2,3,5 JHH, measured for acrolein in CDCl3 that its conformation in this solution is very similar to that existing in the nematic liquid crystal phase 152. Geminal and vicinal H–H couplings have been reported for (+)-2-bromo-3isopropenyl-6-methyl-cycloheptenone by de Oliveira et al.142 and by Edmonds et al.143 for methylphenylarsinic acid-L-glutathione and phenylarsonic acid-(1-mercapto-2-propanol)2 diastereoisomers. An analysis of the fragment CH2CH2NH in the spectra of two new palladium (II) compounds, PdCl2(1-[2-(ethylamino)ethyl]-3,5-dimethylpyrazole) and PdCl2(1-[2(tbutylamino)ethyl]-3,5-dimethylpyrazole), performed by Pan˜ella et al.144 yielded all two- and three-bond H–H couplings, and the data obtained agree with the conformation of the Namino–CH2–CH2–Npz twist boat configuration, which has been corroborated by the X-ray crystal study. An NMR method for the determination of the equilibrium constant for the liquid H2O–D2O–HOD mixture has been designed by Duplan et al.145 The method also gives access to the value of the scalar coupling between the proton and the deuterium across two-bonds. A large set of two- and three-bond proton–carbon couplings has been measured by Lacerda Jr et al.146 for various cyclopentane derivatives by the use of a 2D heteronuclear correlation experiment G-BIRDR,X-CPMG-HSQMBC. A variabletemperature NMR study of the enol forms of benzoylacetones has been performed by Borisov et al.147 by the use of long-range carbon–hydrogen couplings involving the chelate OH proton. An extensive study has been devoted by Serianni and co-workers148 to geminal 2 JHC couplings as probes of the glycosidic torsion angle in oligosaccarides. The J-based configuration analysis, recently proposed by Murata et al.149 which relies on the extensive use of 2,3JHC and 3JHH couplings in combination with NOE data and molecular modelling, has been applied by Arda´ et al.150 in order to establish the relative configurations of the two leucine-like fragments of a new tetrachloroamino acid derivative dysithiazoloamide, isolated from an unidentified sponge of the genus Dysidea. Further examples of the application of 2,3JHC couplings to elucidation of the absolute configuration include a novel class of C-10 halogenated and C-12 oxygenated prostaglandin-A2 derivatives,151 and tedanolide C, a potent new 18-membered-ring cytotoxic macrolide isolated from the Papua New Guinea marine sponge Ircinia sp.152 Nucl. Magn. Reson., 2007, 36, 131–169 | 141 This journal is

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Fig. 3

The results of the studies on sevoflurane, (CF3)2CHOCH2F, in carbon dioxide and xenon as gaseous solvents have been published by Maci˛ega et al.153 Among others, two- and three-bond H–F couplings have been determined. It has been observed by Sato et al.154 that in the reaction of dibenzoselenophene Se-oxide and 2,2 0 -biphenylenedibromotellurane with methyllithium the corresponding, stable at low temperature, intermediate hypervalent compounds are formed. In particular, strong evidence has been provided by the presence of 2JHSe = 17.5 Hz and 2JHTe = 36 Hz observed in the spectra of 2,2 0 -biphenylenedimethylselenurane and 2,2 0 -biphenylenedimethyltellurane, respectively (Fig. 3). 2 JHSn and 1JCSn couplings have been used by Ta´rkańyi and Dea´k155 to calculate Me–Sn–Me angles for two cyclic tetrameric [Me3SnON(NO)Ph]4 and [Me3Sn(ON (NO)Ph)2]2. The results obtained indicate that in noncoordinating solvents, such as CDCl3 and CD2Cl2, both these compounds are predominantly monomeric. The relevant 1JCSn and 2JHSn couplings have been breported by the same group of authors156 for three new chiral organotin (IV) carboxylates: Me2Sn(nap)2, {[Me2Sn (nap)]2O}2 and Me3Sn(nap) where nap = ((S)-(+)-6-methoxy-a-methyl-2-naphtaleneaceto) anion. Significantly different 2JHPt couplings have been observed by Frøseth et al.157 in the spectrum of the platinum iminoylcarbene complex [3-Me-1-{C(C6H5)N(2,6-iPr2C6H3)}–C3H2N2]PtMe2: 2JHPt = 63.1 Hz for the methyl group cis to the carbene and 2JHPt = 92.0 Hz for the trans methyl group (Fig. 4).

6. Two-bond couplings not involving hydrogen Carbon–carbon couplings including those across one-bond and long-range ones have been measured by Anklin and Alemany158 for fullerene C70 under very highprecision conditions. The data obtained is in agreement with recent theoretical calculations by Peralta et al.159 Two-bond C–F couplings across the double bond in fluorinated and partially fluorinated vinyl alkyl ethers measured by Brey160 have been found to depend very strongly on the electronegativity of the substituents attached to the double bond.

Fig. 4


c


It has been shown by Schraml et al.161 that long-range C–Si couplings can be very helpful in assignment of the lines in 29Si and 13C NMR spectra of silylated polyphenols and some other compounds. The procedure has been demonstrated on three trimethylsilylated phenols, 7-hydroxyflavone, ferulic acid and quercetin. High values for 2JCP and 2JHN couplings due to the ring strain have been observed by Gholivand et al.162 in the spectra of 4-F–C6H4C(O)N(H)P(O)(NHC6H4NH) and 4-CH3–C6H4N(H)P(O)(NHC6H4NH); the smaller coupling values are observed for the analogous compounds containing six-membered rings. 2 JNPt of 80 Hz and 4JHPt of 12 Hz have been recorded by Martellaro et al.163 for some mixed cyano and isocyano-platinum(II) complexes, Pt(CN)3(CNCH3), Pt(CN)2(CNCH3)2, Pt(CN)(CNCH3)3+ and Pt(CNCH3)42+. 2 JFF couplings varying from 107 to 126 Hz have been measured by Kareev et al.164 for 1,9-C60F(CF3), Cs–C60F17(CF3) and C1–C60F17(CF3) fluoro-substituted fullerenes. 2 JSiSi couplings have been measured by Cho et al.165 for a series of new silicate oligomers and compared with those already published in the literature. The MAS-J-HMQC experiment has been applied by Coelho et al.166 to a new pair of nuclei {29Si, 31P} in Si5O(PO4)6 and SiP2O7 polymorphs, which allowed them to evaluate the 2JSiOP couplings of 15 Hz for a crystalline silicophosphate phase Si5O(PO4)6. A very small 2JPP coupling of 37.1 Hz observed by Ito et al.167 for 3,3-diphenyl-1(2,4,6-tri-tert-butylphenyl)-2-(trimethylsilyl)-1,3-diphosphapropene has been used by the authors as an indication that the conformation of the C1 symmetry is kept in solution by this compound. The corresponding couplings in the 2-chloro- and 2methyl-1,3-diphosphapropene, which adopt the Cs conformation, are about ten times larger. Extensive use of 2JPP and 1JPP couplings has been made by Tattershall and Booth168 in their studies on the structure of three diastereoisomers of the diamide exo,exo-b-P4S3(NHCH(Me)Ph)2 which have been synthesized using enantiomericaly pure or racemic PhCH(Me)NH2. The 1JPP couplings have been used as diagnostics of chirality and 2JPP = 225.2 Hz has been observed in the spectrum of the unsymmetric diastereoisomer. 2,3 JPP couplings have been reported by Felicissimo et al.169 for two ruthenium complexes containing the hemilabile ligand PPh2(CH2)P(O)PPh2 (dppmo), RuCl2 (CO)(Z1,Z2-dppmO)2 and [RuCl(CO)(Z2-dppmO)2]PF6; the two-bond P–P couplings of 375.8 and 354.2 Hz, respectively, characteristic of the trans arrangement of phosphorous atoms have been observed in these compounds. 2 JPP couplings have been of diagnostic use in investigating solution structures of trans-RuH(Z1-BH4)(binap)(1,2-diamine) complexes studied by Sandoval et al.170 The structure of the (trichlorostannato)diphosphineplatinum(II) complexes in the (N-butyl-N 0 -methylimidazolium)[PF6] ionic liquid has been established by Rangits et al.171 with the help of 2JPP and 1JPPt couplings. 31 P MAS spectra of [Pd2X2(dppm)2], X = Cl, Br, I, complexes have been measured by Szalontai and Besenyei172 yielding 2JPP of ca. 450 Hz for all three compounds studied. A thorough analysis of 2JPW and 2JWW couplings has been performed by Lenoble et al.173 for two chiral polyoxotungstates, a1-[P2W17O61]10– and a1-[YbP2W17O61]7– in order to assign their 183W NMR spectra. 2 JPPb couplings have been observed by Larsson et al.174 in the 31P MAS NMR spectra of the two Pb(II) complexes, [Pb{S2P(OC2H5)2}] and [Pb{S2P(O-isoC4H9)2}], and used to confirm the assignment of the ligands.

7. Three-bond hydrogen–hydrogen couplings Van Gunsteren and co-workers175 have applied 3JHH couplings of different types in a molecular dynamics simulation study of the folding-unfolding equilibrium of Nucl. Magn. Reson., 2007, 36, 131–169 | 143 This journal is

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b-peptides. The authors analysed the influence of charged side chains on this equilibrium. The 3JHaHN couplings of the central alanine in a series of model peptides have been measured by Kallenbach and co-workers.176 The temperature profiles of these couplings revealed the presence of neighbour effect in Ala PPII peptides. The same types of couplings have been used by Evans and co-workers177 for probing the conformation of a linear 12-AA M13 phage pIII polypeptide that binds to singlewalled carbon nanohorns. A conformational analysis of a series of 24 XA and AX dipeptides has been performed by Schweitzer-Stenner and co-workers.178 The 3 JHaHN couplings have been analysed by a two state model encompassing PPII and a b-like conformation, allowing thus to estimate the PPII propensity of alanine. Dihedral scalar couplings, 3JHaHN, measured by Jennings and co-workers179 for the wild-type interleukin-1b and the four His mutant proteins have indicated both local and distal effects on the backbone angles upon mutation. A paper by Castiglione et al. 180 has been devoted to the elucidation of the 3D structure and solution conformation of enduracidin, a cyclic depsipeptide antibiotic obtained from the mycelium of Streptomyces fungidicus B-5477. Several examples of proteins for which 3JHaHN couplings have been used for structure elucidation are given in Table 1. A comparison of experimental and computed vicinal couplings made by Ronchi et al.211 for (a-L-rhamnopyranosyl)methylphosphonic acid and (2-O-methyl-a-Lrhamnopyranosyl)methylphosphonate has indicated a marked preference for the 1 C4 conformation for both compounds. The solution conformations of naturally occurring RNA nucleosides, 3-methyluridine and 3-methylpseudouridine, have been elucidated by Chow and co-workers212 by the use of a combination of sugar proton couplings from 1D NMR spectra and 1D NOE difference spectroscopy. The HexRot program has been developed by Herdewijn and co-workers213 to calculate the conformation of cyclohexenyl nucleosides from scalar 3JHH couplings. Stereoselective synthesis and conformational analysis of a series of aromatic C-thionucleosides by the use of vicinal proton– proton couplings have been performed by Jua´rez et al.214 The conformation of monosaccharide hydrazones by 3JHH couplings has been established by El Ashry et al.215 Table 2 lists the carbohydrates and nucleic acids for which vicinal proton–proton couplings have been used in structural studies. 3 JHH couplings have been applied in structural studies on a series of novel polyhydroxysterols220 isolated from a Red Sea marine sponge Lamellodysidea herbacea, six saponins from pericarp of Sapindus trifoliatus,221 condensation products derived from flavan-3-ol oak wood aldehydes reaction,222 and some 19b,28epoxy-18a-olean-5-ene derivatives.223 A stereochemical analysis by the use of vicinal proton–proton couplings has been performed by Zuber et al.224 in order to establish the structure of bistramide C, a marine natural product, by Ohta et al.225 who studied a new 20-membered macrolide, exiguolide, isolated from a marine sponge Geodia exigua, and by Shi et al.226 who performed a detailed NMR study for a novel enolate taxane isolated from Taxus canadensis needles. The 3JHH couplings have been reported for three lignans isolated from the pine (Pinus sylvestris L.) bark,227 salvadorin, a new dimeric dihydroisocoumarin isolated from Salvadora oleoides,228 and some new alkaloids from a series of oxoisoaporphines.229 Several new papers have been published by Wysocka and co-workers on the conformational studies of sparteine alkaloids.230–232 Among others, DFT calculations with the B3LYP hybrid functional have been performed to determine the equilibrium structures of a representative series of thiono-, oxo, thiono-, dioxo-, and dithiono-derivatives of sparteine.231 The relative stereochemistries of three new compounds, two homobotcinolide derivatives, 3-O-acetylhomobotcinolide and 8-methylhomobotcinolide, and a new 144 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Table 1 Peptides and proteins for which the solution structure has been calculated with 3JHH Name 2D block copolypeptide, Glu12-Ala12 RGD-hirudin

a

b

Ref.

24 66

21 39

181 182

6 6 6 3 8c 13 2 20 25 25 19 35 46 126

183 184 185 186 187 188 189 190 191 192 193 194 195 196

73 72 60 63

197 198 199 200

77 54 161

201 202 203

104

204

216

205

116 102 101 74 240

206 207 208 209 210

3D a series of aspartame-based sweeteners 2 AFA 3 hydroxyethylene dipeptide isostere 4 [Ac-CKPV]2 8 BL-DIS6, a model peptide 12 daptomycin, the calcium free cyclic lipopetide antibiotic 13 a linear precursor of SFTI-1 from sunflower seeds 14 violacin A, a linear cyclotide from Viola odorata 27 vhl-1, a leaf cyclotide-1 from Viola hederaceae 31 PcFK1, a spider peptide active against Plasmodium falciparum 33 HsTx1, a scorpion toxin 34 neuropetide K bound to dodecylphosphocholine micelles 36 [C/N] EGFR(644–697), the juxtamembrane domain of EGFR 54 [C/N] conkunitzin-S1, a neurotoxin from the venom of the cone snail 60 Conus striatus [C/N] calsensin, an invertebrate neuronal calcium-binding protein 82 [C/N] YggX, the oxidative stress-related protein from E. coli 91 [N] Sso AcP(13–115) from hyperthermophile Sulfolobus solfataricus 103 [D/C/N] Itk SH2 domain bound to phosphotyrosine-containing 110 + 5 peptide, pY [C/N] Grx4, a monothiol glutaredoxin from E. coli, reduced 105 [C/N] the HDGF PWWP domain 110 [C/N] scRPA70A(181–294), the DNA binding domain of RPA from 114 Saccharomyces cerevisiae [C/N] Pal/PG-P, the periplasmic domain of Pal complexed with a 115 + 7 peptidoglycan precursor [C/N] dsRNAbp-ZFa(2–128), the N-terminal zinc finger of the 127 X. laevis RNA-binding protein [C/N] HBP1 domain of AXH(208–345) 138 [C/N] ribosomal protein L11 from Thermotoga maritima 140 [C/N] MJ1529 from the thermophile Methanococcus jannaschii 154 [C/N] GNA1870-BC (101–255), the antigen of Neisseria meningitides 155 [C/N] S100A1, Ca2+-bound 93 2

a The number of amino acid residues. b The total number of vicinal backbone and side chain proton–proton couplings measured. c Measured only.

11-membered lactone studied by Reino et al.233 and two spirocyclic NK-1 antagonists studied by Herbert et al.234 have been established by the combined use of vicinal H–H couplings and NOE data. 3 JHH scalar couplings have been used for structure elucidation of a new compound, 3-normeridamycin, obtained from fermentation extracts of the soil actinomycete Streptomyces sp. LL-C31037 by Summers et al.,235 of products of dehydrogenative polymerization between pairs of hydroxycinnamic acids present in wound-healing plant tissues by Arrieta-Baez and Stark,236 and of a constrained chiral melatonin pharmacophore by Rivara et al.237 The LC-NMR technique has been applied by Wolfender et al.238 as a tool in their phytochemical studies. In particular, proton–proton couplings have been extensively Nucl. Magn. Reson., 2007, 36, 131–169 | 145 This journal is

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Table 2 Nucleosides, nucleotides, oligonucleotides and carbohydrates for which 3JHH has been used as a structural parameter Name

Ref.

[C/N] the Aquifex aeolicus tmRNA pseudoknot PK1 a series of 7-functionalized 7-deazapurine ribonucleosides

216 217

Carbohydrates large series of di- and monoalkynyl C-cellosides; mimics of cellulose I and cellulose II O-polysaccharide of Erwinia carotovora ssp. atroseptica GSPB 9205

218 219

used to elucidate the content and structure of the constituents of crude plant extracts. The tautomeric pairs of clusianone and 7-epi-clusianone have been isolated from the same source, i.e. Clusia torresii fruits.239 A relationship between H–H couplings and the equilibrium between the B ring chair and twist-boat forms of the bicyclo[3.3.1]-nonane system in these compounds has been shown. Experimental vicinal H–H couplings measured in a variety of solvents combined with molecular modelling have been applied by Vaz et al.240 in a quantitative study of the conformational equilibria of 7-benzyl-2-iodo-9-oxa-7-azabicyclo[4.3.0]nonan-8-one. A study of minimum energy conformers of several N-substituted derivatives of piperidine and pyrrolidine by the use of the 1H chemical shifts and vicinal proton– proton couplings has been carried out by Lobato-Garcia et al.241 providing evidence of weak H-bonding in these compounds. Vicinal proton–proton couplings have been applied to study the stereochemical properties of N-cyclohexylidene-N-(1-phenylethyl)amine derivatives,242 in structural elucidation of several new D2-pyrazoline derivatives,243 to estimate the dihedral angles in dicondensed indolinobenzospiropyrans,244 and to perform a conformational analysis of N-[((3 0 ,4 0 -dichlorophenyl)methyl)sulphonyl]-3-methyl-2,3,4,5tetrahydro-1H-2-benzazepin.245 Further examples include some N-substituted morpholines,246 a tricyclic derivative of a Diels-Alder adduct, 5-(acetyloxy)-3-hydroxy9,10-dimethoxy-6-oxo-11-oxatricyclo[6.2.1.02,7]undec-2-yl acetate,247 and 9-hydroxyphenalenone and its methyl derivatives studied by Honeyman et al.248 from the point of view of tautomerism. Vicinal–vicinal couplings and NOE experiments have been applied by Kumar and co-workers to establish the relative stereochemistries in 2,3-diphenyltetrahydrofuran derivatives obtained by intramolecular diastereoselective cyclization of homoallylic alcohols.249 Further examples include 3-hydroxy-3,4-dihydrofuran-2(5H)-ones synthesized from glycolic, mandelic and lactic acids,250 1,7-dioxa-2,6-dioxospiro [4.4]nonanes derived from 5-oxotetrahydrofuran-2-carboxylic acids,251 and a series of eight bicyclic sulfonium salts of the glycosidase inhibitor, australine.252 It has been established by Shavva et al.253 on the basis of 3JHH couplings and nonstationary NOE effects that the conformation of 17b-acetoxy-7a,18-dimethyl-3methoxy-6-oxaestra-1,3,5(10),8(9)-tetraene prevailing in solution with the 7a-methyl group in a quasiaxial position corresponds to the structure of the compound in the crystalline state. Vicinal proton–proton couplings have been applied by Abraham et al.254 in their studies on concentration and solvent effects on the conformational equilibrium in alcohols, diols and inositols. Further examples include cis-3-ethoxycycloheksanol studied by de Oliveira et al.,255 some new cis-1,3-disubstituted cyclohexanes by de Oliveira and Rittner,256 and trans-1,2-dihalocyclohexanes by Freitas et al.257 Experimental and MD simulation studies on the conformational preference of three cycloalkanols when included in b-cyclodextrin have been performed by Zubiaur et al.258 Proton–proton couplings, 3JHH, have been used by Fu¨lo¨p et al.259 to establish the stereochemistry of a series of hydroxylated 2-aminocyclohexanecarboxylic acids. 146 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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A detailed analysis of vicinal proton–proton couplings supported by molecular mechanics calculations performed by Hassner et al.260 for acylated hexahydrobenzazocines led to the conclusion that these compounds exist at room temperature as a mixture of fast-interconverting conformers of the octacycle. 3 JHH couplings have been used by Roberts and co-workers in a conformational analysis of succinamate monoanion in various solvents,261,262 and to determine the conformational preferences of 2,3-dihydroxypropanoic acid in various solvents and ionization state.263 An analysis of ring current and proton–proton coupling changes of dihydropyrene on annelation has been performed by Mitchell et al.264 to estimate the relative antiaromacity of cyclopentadienone. Conformational analysis based on an analysis of the vicinal a and b-proton couplings of (S)-tyrosinato ligands in diastereomers of the bis[(S)-tyrosinato](1,3diaminopropane)cobalt (III) complex has been applied by Miodragovic´ et al.265 to calculate the mol fractions of the three most stable rotamers (t, g, h) of the (S)tyronisato ligand’s side groups in D2O solution. An analysis of the vicinal couplings between the methylene protons located adjacent to the alkyne and the NH hydrogen in the 1H NMR spectra of bis(amino acid) derivatives of 1,4-diamino-2-butyne, of a general structure (t-BuOC(O)NHCHRC(O)NHCH2CR)2 where R = CH3, CH2Ph and CH2CH2SCH3, has shown that these compounds adopt a C2-symmetric turn conformation.266 Vicinal proton–proton couplings measured by Zheng et al.267 for bis(diarylamine) ‘‘bipolaron’’ obtained by two-electron oxidation of E,E-2,5-bis-{4-[di(p-anisyl) amino]styryl}-3,4-di(n-butoxy)thiophene have been used as an indication that the geometry of this compound is shifted towards a quinoidal pattern relative to that in the neutral species, but not to a fully quinoidal extent. 3 JHH couplings have been applied to establish a double bond configuration for two new polyketides, actinofuranones A and B isolated from the culture extract of a marine-derived Streptomyces strain designated CNQ766,268 in a series of novel 10deoxoartemisins,269 for several E-disubstituted alkenes obtained by vinylindiums coupling with diaryliodonium salts,270 for a series of stilbenes and chalcones,271 and for 1-substituted 1,3-dien-2-yl sulfides.272 Vicinal couplings, 3JHH, have been measured by Schott and Pregosin273 for [Rh(1,5-COD){(S,S)-4,4 0 -dibenzyl-2,2 0 -bis(2-oxazoline)}](X) and [Rh(1,5COD){(S,S)-2,2 0 -isopropylidene-bis(4-tert-butyl-2-oxazoline)}](X) salts, where X = CF3SO3, PF6, BArF and BF4. A marked difference observed between those found for the compounds containing small anions, 3J = ca. 2.5 Hz, and that observed for BArF, 3J = 8.6 Hz, has been interpreted in terms of the oxazoline ring conformation changes. The authors suggest that this is the first example of such an anion effect on a chelate ring conformation. 3JHH couplings have been measured by Ferna`ndez and Pregosin274 for two chiral cationic Pd(II) 1,3-diphenylallyl complexes: [Pd(Z3-PhCHCHCHPh)(Duphos)](CF3SO4) and [Pd(Z3-PhCHCHCHPh)(P,S)]BF4 where Duphos = 1,2-bis-((2R,5R)-2,5-dimethylphospholano)benzene) and P,S = [8-((o-(diphenylphosphino)benzyl)thiomethyl)]—(7,7 0 - dimethyl)-exo-norborneol. 3 JHH couplings have been extensively used by Maekawa et al.275 to characterize the electronic structures of a series of four mononuclear Rh-Cp(Me)5 and IrCp(Me)5 complexes with PAH’s, [M(Cp*)(Z6-PAH’s)](BF4)2, M = Rh and Ir; PAH’s = phenantrene, pyrene and triphenylene. The decrease of the proton–proton couplings has been observed in the Z6 coordinated benzene ring and no changes in the uncoordinated benzene rings have occurred.

8. Three-bond couplings to hydrogen It has been shown by Lindorff-Larsen and co-workers276 that the parameters in the Karplus relationships are better derived from ensembles representing the distribution of dihedral angles present in solution than from single conformations. The Nucl. Magn. Reson., 2007, 36, 131–169 | 147 This journal is

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Table 3 Peptides and proteins for which heteronuclear couplings have been used as a structural parameter in 3D structure calculations a

Name [C/N] L-alanyl-L-alanine

2

b

47

c 13 13

[D/N/C] P-gp411–30-DYKDDDK, 38 HIV-1 gp-41(1–30) fusion domain [C/N] WT drkN SH3 domain 59 [C/N] T22G drkN SH3 domain 59 [D/C/N] cGMP-dependent protein kinase Ia 59 2 [C/N] DPBD, human WRN(949–1092) 144 [C/N] murine gS-crystallin 177 [C/N] the cytoplasmic A(IIAMtl) 148 + 102 and phospho-IIBMtl post-transition state complex

23

13

JHC, JHN, JCC,13JCN, 3JNN 3 JCC, 3JCN

89 58 18 295 82 d

3

JHC JHC 3 JCC, 3JCN 3 JHN, 3JCC 3 JCC, 3JCN 3 JCC, 3JCN 3

Ref. 278 279 280 280 281 282 283 284

Number of residues. b Total number of vicinal couplings measured (homonuclear 3JHH couplings are also included if measured). c Types of heteronuclear couplings measured. d Number not reported. a

authors have presented a strategy to determine the parameters in a Karplus relationship for 3JHC, 3JCN and 3JHH couplings through the method that explicitly includes experimental information about the structural fluctuations of proteins. 3 JHC and 3JHH couplings have been used by Ruzza and co-workers277 in the structural analysis of synthetic peptides containing tyrosine analogues with different side chain orientations. The peptides were potential substrates of the nonreceptor tyrosine kinases. Further examples of proteins for which heteronuclear vicinal couplings have been applied in structural studies are listed in Table 3. Palleschi and co-workers285 have applied 3JHC couplings in molecular dynamics investigations of the polysaccharide scleroglucan. Carlomagno and co-workers286 have reported a conformational analysis of 2 0 -OH groups of the HIV-2 TAR RNA by means of 3J20 OHC1 0 , 3J2 0 OHC3 0 and 3J2 0 OHH2 0 couplings. This is the first conformational analysis of the H2 0 –C2 0 –O2 0 –H torsion angle in a medium sized RNA using a combination of scalar J-coupling and NOEdata. More examples of carbohydrates and nucleic acids whose structures have been found with the help of heteronuclear couplings have been included in Table 4. Gold and co-workers300 have used 3JHC, 1JCC and 1JHN couplings in the analysis of the oxidation products of [4-13C] and [7-15N]guanine under mild conditions. They proved that the sole isolable product in 71% yield was 5-carboxamido-5-formamido2-iminohydantoin. 3 JHC and 3JHH couplings have been used by de Castro et al.301 to obtain insight into the conformational parameters of [1-[2 0 ,5 0 -bis-O-(tert-butyldimethylsilyl)-b0 00 00 00 00 D-ribofuranosyl]-3-N-(methyl)thymine]-3 -spiro-5 -(4 -methoxalylamino-1 ,2 -oxathiole-200 ,200 -dioxide) and the model compound [5-O-(tert-butyldimethylsilyl)-1,2-Oisopropiliden-a-D-ribofuranosyl]-3 0 -spiro-5 0 -(4 0 -methoxalylamino-100 ,200 -oxathiole200 ,200 -dioxide) that may play a role in the exceptionally mild desilylation of the tert-butyldimethylsilyl ether group observed for [2 0 ,5 0 -bis-O-(tert-butyldimethylsilyl)-b-D-ribofuranosyl]-3-spiro-500 -(40 ’-amino-100 ,200 -oxathiole-200 ,200 -dioxide) nucleosides. Tautomerism in 6-mercaptopurine, 2,6-dimercaptopurine and 6-mercaptopurine9-riboside has been studied by Pazderski et al.302 The 15N NMR signals in these compounds have been assigned and the distribution of mobile protons proposed on the basis of 13C and 15N chemical shifts, nJHC (n = 1, 3, 4) and 2JHN couplings, determined by the use of the HECADE experiment; 3JHC couplings have been especially useful in this respect. 148 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Table 4 Nucleosides, nucleotides, oligonucleotides and carbohydrates for which heteronuclear vicinal couplings have been used as a structural parameter a

Name 0

0

A series of 16 diribonucleoside (3 –5 )-H-phosphonates the Tl+ form of d[G4T4G4]2 [C/N] class I GTP aptamer

a

Ref.

JHP JHTl+ 3 JCP

287 288 289

3

2 24 41

Carbohydrates [C/N] 2-acetamido-2-deoxy-D-aldohexoses and their methyl glycosides arabinogalactan from an immunostimulatory extract of Chlorella pyrenoidosa dPIM-8, a novel phosphatidylinositol manno-oligosaccharide from Gordonia sputi a series of Me b-[1-13C] and Me b-[3-13C] aldopyranosides trisaccharides containing N-acetylglucosamine a-L-Rhap-(1-2)[a-L-Rhap-(1-3)]-a-L-Rhap-OMe partially acetylated oligorhamnosides from Cleistopholis patens repeating unit of Enterobacter sakazakii ZORB A 741 O-polysaccharide endogenously O-acetylated oligosaccharides isolated from tomato xyloglucan the human milk oligosaccharide lacto-N-neotetraose

b

1

1

JHC, 1JHN, 290 JCC, 13JCN 1 JHC 291

13

1

JHC

292

JHC JHC 3 JHC 1 JHC 1 JHC

293 294 295 296 297

4,5

298

4 1

3

JHC, 3

JHH

JHC

299 3

b

The number of nucleotides. Type of vicinal heteronuclear couplings measured; JHH homonuclear couplings have also been measured in most cases. 3

JHC and 1JHH couplings have been used by Barrett et al.303 to prove the helical structure of tercyclopropanedimethanol in solution. It has been shown by Seroka et al.304 that D-glucose, D-mannose and D-rhamnose can be applied as chiral probes in elucidation of the absolute configuration of the chiral centre in 2-butanol. Dihedral angles f and c in these compounds have been calculated from the Karplus-type equation using 3JHC couplings (Fig. 5). 3 JHC couplings have been applied by Syakaev et al.305 to establish the conformation of a series of aryl- and heteroarylaldehyde 4-tert-butylphenoxyacetylhydrazones. 13JHC couplings have been reported by Claramunt et al.306 for three Nsubstituted pyrazoles and three N-substituted indazoles. 13JHC and 14JHH couplings have been computed by Jimeno et al.307 in X(CH3)nH(4n) compounds (X = C or N+, and n = 0–4) at two levels of theory, DFT B3LYP and EOM-CCSD//MP2.

Fig. 5


c


Fig. 6

In both cases good agreement between the experimental and computed values has been found. An analysis of 3JH5C3 and 3JH4H5 couplings has been performed by Gaziwoda et al.308 for a series of the novel 6-acetoxy, 6-hydroxy and 6-chloro derivatives of 4,5didehydro-L-ascorbic acid; the 3JH5C3 couplings measured for these compounds indicate the cis geometry along the C4–C5 double bond. 3JHC couplings have played a crucial role in structural studies of 2-substituted 2-tert-butyl-5-methyl-2,5-dihydrofurans, seco-derivatives of theaspiranes with pronounced blackcurrant notes.309 A three-bond H–C coupling has been used by Hametner et al.310 for determining the stereochemistry of the double bond in a series of twenty four 5-thio- or 5sulfonyl-substituted furyl-, thienyl- and N-methylpyrrolacrylonitriles, by Stanovnik and co-workers in order to establish the configuration around the double bond in some 3-aminomethylidenetetramic acids and their precursors,311 in dipodazine derivatives312 which have been synthesized starting from enaminones, in (1R,4E,5S)-4-{[2-(phtalazin-1-yl)hydrazino]methylidene}-1,8,8-trimethyl-2-oxabicyclo-[3.2.1]-octan-3-one and some related compounds.313 A conformational analysis of 2 0 -deoxy-2 0 -fluoro-5-methyl-4 0 -thioarabinouridine performed by Watts et al.314 by the use of 3JHF and 3JHH couplings combined with the PSEUROT program showed that it adopts a predominantly northern conformation in contrast to 2 0 -deoxy-2 0 -fluoro-5-methylarabinouridine which shows a dominantly southwest conformation. 3 JHP and 3JHC couplings have been used by Sakamoto et al.315 to determine the corresponding dihedral angles in 2-(diphenylphoshanyl)-N,N-dimethyl-1-benzamide and 2-(diphenylphoshanyl)-phenyl-pyrrolidin-1-yl-methanone. As follows from the analysis of 3JHP and 3JCP couplings performed by CruzGregorio et al.316 for six-membered cyclic phosphates, 2-phenoxy-2-oxo-1,3,2dioxaphosphorinanes bearing an internal protected or unprotected hydroxyl group exist mostly in a boat conformation. A cyclic phosphate with a free hydroxyl group oriented cis to the phosphoryl group shows a vicinal coupling 3JHP = 18.1 Hz which, according to the authors, is in accordance with the chair conformation. This is due to the formation of a seven-membered intramolecular hydrogen-bonded ring structure that stabilizes this less favourable conformation (Fig. 6). 3 JHP and 1JCP couplings have been very useful in elucidation of the preferred conformations of variously substituted trans and cis fused saturated 1,3,2-benzodiazaphosphinine 2-oxides studied by Zalań et al.317 A coupling between the imine proton and the cadmium atom, 3JHCd = 41.9 Hz, has been observed by Salehzadeh et al.318 in both the 1H and 113Cd NMR spectra of the [Cd(L333)](ClO4)2 complex where L333 = [N((CH2)3NQCH(o-C5H4N))3] is a new potentially heptadendate(N7) tripodal Schiff base ligand. Two mercury complexes [(bmppa)Hg(ClO4)]ClO4 and [(beppa)Hg(ClO4)]ClO4, where bmppa = N,N-bis(2-methylthio)ethyl-N-[(6-pivaloylamido-2-pirydyl)methyl]amine and beppa = N,N-bis(2-ethylthio)ethyl-N-[(6-pivaloylamido-2-pirydyl)methyl]amine, respectively have been characterized by the use of NMR spectroscopy and the JHHg and JCHg couplings associated with the HgS(R)CH3 group have been reported 150 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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for these compounds; for example, 3JHHg = 91 Hz has been found for the 2methylthio derivative.319 3 JHHg couplings in the range of 50–100 Hz have been observed by Helm et al.320 in the spectra of three homoleptic Hg(II) complexes with thiacrown ligands, [Hg(18S6)](PF6)2, [Hg(9S3)2](ClO4)2 and [Hg(16S4)](ClO4)2.

9. Three-bond couplings not involving hydrogen Bayesian inference has been applied by Habeck et al.321 to simultaneously determine protein torsion angles and the unknown Karplus parameters directly from experimental three-bond carbon–carbon, proton–carbon and proton–proton couplings without assuming prior knowledge of a pre-determined structure. Numerous examples of the application of small C–C couplings across two and three bonds to discrimination of stereochemical assignments have been presented in the paper by Fukushi and Kawabata.322 It has been suggested by Contreras et al.323 that long-range carbon–carbon couplings may serve as remarkable probes to gauge diamagnetic ring currents in fullerenes. Carbon–carbon couplings across one, two and three bonds in a series of pyridine carboxaldehydes have been measured by Taurian et al.324 and compared with the DFT-B3LYP calculated ones. 13 JCF couplings have been useful in assignments of the signals in 13C NMR spectra of a large series of substituted trifluoromethylcyclohexanes studied by Carcenac et al.325 JCF, JHF and JHH couplings have been applied by Tislerova et al.326 to establish the conformation of A-ring in a series of 2-fluoro-substituted 19b,28-epoxy-18aoleanane triterpenoids. The full multinuclear magnetic resonance analysis performed by Roche et al.327 for 4-amino-1,1,2,2,9,9,10,1-octafluoro[2.2]paracyclophane yielded a set of JCF, JFF, JHH, and JHF couplings including those across two and three bonds. A Karplusdependent 3JCF interaction has been found to be especially useful. nJCF (n = 1, 2, 3) have been very useful in the assignment of the 13C NMR chemical shifts in the spectra of androstane derivatives.328 A complete analysis of 1H, 13C and 19F NMR spectra has been performed by Ribet et al.329 for the fumaric acid salt of {[1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl]methyl}[(5-methylpyridin-2-yl)methyl]amine. In particular, a rigid chair conformation of the piperidine ring followed from the observed 3JCF coupling values. According to 3J data (1S,3S)dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosphonate studied by Wro´blewski and Gzowacka330 exists almost exclusively in a fully extended zig-zag conformation (3JCCCP = 11.3 Hz); the values of 3JH1H2 = 3.3 Hz and 3JH2P = 9.9 Hz correspond to ca. 60 dihedral angles attainable in this conformation in 1S diastereomer only (Fig. 7).

Fig. 7


c


A detailed analysis of the 1H and 13C NMR spectra of azidotriol, (1S,2R,3S)dibenzyl 4-azido-1,2,3-trihydroxybutylphosphonate and its triacetate performed by the same group of authors gave a set of spin–spin couplings including 3JCP and 3JHP, which allowed them to establish the conformation of both compounds.331 Relationship between the structure and 2JCP and 3JCP coupling values in phosphoroamidates containing five-, six- and seven-membered rings has been extensively studied by Gholivand et al.332 (see also ref. 162). Two new series of (3-methoxypropyl)stannanes, CH3O(CH2)3Ph3xSnClx, x = 0–2, and CH3O(CH2)3 Sn(S2CNEt2)3xClx, x = 0–2, have been studied by Le´bl et al.333 The authors point out that the best indicator of the O - Sn donor acceptor interaction in the compounds studied is the 3JCSn value. 2,3 JCPt couplings only slightly larger for trans than for cis isomers have been observed by Rochon and Buculei334 in the spectra of iodo-bridged dinuclear Pt(II) complexes with amines of the type I(amine)Pt(m-I)2Pt(amine)I. The same relationship is valid for 2JHPt couplings. The 3JHPt couplings measured for the dimethylamine compounds do not differ significantly, 46 Hz (trans) and 44 Hz (cis). An analysis of the spectra of 2-(trifluoromethyl)-2-oxazoline by Foris and Neumer335 gave a full set of the couplings in this compound including 3JNF, 3JHH and 3JHC. Locally dense basis sets have been developed by Sanchez et al.336 for correlated ab initio calculations of vicinal fluorine–fluorine couplings in several fluorinated compounds. The calculations have been carried out for difluoroethyne, trans- and cis-1,2-difluoroethenes and propenes, for antiperiplanar and synperiplanar 1,2-difluoroethanes and propanes. The authors found that the best choice of basis set for each atom belonging to the studied model compounds depends on its location with respect to those nuclei whose couplings are being calculated and on the conformation of the atoms involved. 3 JPP couplings of ca. 95 Hz have been reported by Mbaiwa and Becker337 for [Co(CNC6H3-i-Pr2-2,6)4PPh2(CH2)2PPh2]ClO4 and [Co(CNC6H3-Et2-2,6)4PPh2(CH2)2PPh2]ClO4 complexes; 2JPP coupling of 160.5 Hz has been found for the [Co(CNC6H3-Et2-2,6)4PPh2CH2PPh2]ClO4 compound.

10. Couplings over more than three bonds and through space All couplings including those between proton and carbon atoms across one, two, three and four bonds have been reported by Katritzky et al.338 for 3-cyano-339 and 3nitrosubstituted pyridines.338 Comparison has been made between the calculated and experimental data. 3,4 JHH couplings have been reported by Moon et al. for some flavonol340 and dihydroxyflavone derivatives,341 by Arciniegas et al.342 for the products of rearrangement of eremophilane esters of Robinsonecio gerberifolius, and applied by Bhavani et al.343 to elucidate the stereochemistry of r-2-alkoxycarbonyl-c-3-o-substituted phenyl-1,4-thiazane 1,1-dioxides. Proton–proton couplings across two, three and four bonds have been used by Nguyen et al.344 to characterize three quinamide– based disaccharide mimetics with unusual cyclohexane twist conformation. Measurements of 5JHH couplings in two 1,2-dimetylsubstituted stilbenes allowed Fluxa´ et al.345 to assign unambiguously the configuration around the double bond in these compounds: 5JHH = 1.5 Hz and 5JHH = 1.1 Hz have been found for E and Z isomers, respectively, (Fig. 8). The relative configuration of the stereogenic units in asymmetrically substituted bis- and tris-Tro¨ger’s bases has been unequivocally established by Elguero et al.346 on the basis of homoallylic, 5JHH, couplings and NOE effects. NMR parameters for the proton-exchange pathways in porphyrin and porphycene, which also included spin–spin couplings, have been calculated by Cybulski et al.347 by the use of the DFT method. The authors concentrated their attention on the JHN couplings between an inner proton and one of the four nitrogen nuclei and 152 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Fig. 8

the JHH through-space spin–spin coupling between the two inner protons; for both couplings diagrams representing variations with proton migration have been shown. Neither for porphyrin nor porphycene experimental J values are known and therefore additional calculations have been carried out for 1,3-bis(arylimino)isoindoline as a model compound; for this molecule, experimental NMR data including many spin–spin couplings has been reported recently by Schilf.348 5 JHC couplings between the methyl protons and the carbon atoms a to the carbonyl group have been observed by Araya-Maturana et al.349 in the spectra of some 3-(4-oxo-4H-chromen-3-yl)-acrylic acid ethyl esters. A Karplus-type relationship for 4JH/CF3 couplings based on the eight 4J values computed for hydrogenated 5-hydroxy-5-trifluoromethyl-D2-isoxazoline and -D2pyrazoline has been proposed by Sanz et al.;350 four of these couplings correspond to the higher energy conformations and therefore their values could not be confirmed by the experiment. Long-range H–F couplings have been determined and their glycosidic torsion dependence in 5-fluoropyrimidine-substituted RNA studied by Hennig et al.351 5 JHP coupling has been used by Nabi et al.352 as an indicator of metal complexation with aminophosphazene ring system. Slow molecular ligand-exchange conditions in acetonitrile-d3 solutions permitted detection of 35JHHg couplings in the spectra of Hg(ClO4)2/L complexes (L = 2,6bis(methylthiomethyl)pyridine) studied by Bebout and co-workers.353 14 JCF, 3,4JHF and 24JHH couplings have been measured by Wang et al.354 for the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman4,4 0 -imidazoline]-2 0 ,5 0 -dione and its synthetic intermediates. Experimental/theoretical approach has been applied by Contreras et al.355 to study transmission mechanisms in long-range couplings, 4,5JCF, in 1-F,4-X-cubanes (X are halogen atoms, among others). A large set of 14JCF and 26JFF couplings has been reported by Brey160 for fluorinated and partially fluorinated vinyl alkyl ethers. 25 JCSi couplings across Car–O–Si bonds have been measured by Sy´kora et al.356 for a large series of variously para substituted silylated phenols and the experimental values compared with the DFT calculated couplings. A low sensitivity of all couplings has been observed towards substitution both on the silicon atom and on the benzene ring. A coupling of 5.5 Hz between the three carbon atoms of the t-butyl group and the phosphorous atom bearing the isopropyl groups has been observed by Ivanov et al.357 in the spectrum of metalloligand 1,2-bis(diphenylphosphino)-1 0 -(diisopropylphosphino)-4-tert-butylferrocene. Its origin has been interpreted in terms of the through space mechanism. It has been suggested by Kareev et al.164 that the through space F F coupling is the largest contribution to the observed 4JFF and 5JFF values in 1,9-C60F(CF3), Cs-C60F17(CF3) and C1–C60F17(CF3). A similar interpretation has been offered by Dorozhkin et al.358 for the 7JFF couplings of 10.3–16.2 Hz observed in the spectra of C70(CF3)n, n = 2–10. Nucl. Magn. Reson., 2007, 36, 131–169 | 153 This journal is

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Ernst and co-workers359 have continued their studies on the through space fluor– fluor couplings. The results obtained for the Z and E isomers of 1,1 0 -difluoro-9,9 0 bifluoroenylidene led them to the conclusion that the size of F,F through-space coupling depends not only on the F,F distance but also on the angle between the C–F bonds. 5 JFP coupling of 4.1 Hz has been measured for P(p-FC6H4)3 by Micoli et al.360

11. Couplings through hydrogen bonds A number of papers have been devoted to spin–spin couplings across the hydrogen bonds. Alkorta et al.361 have confirmed their previous conclusion that neither the couplings nor the proton chemical shifts of oxygen- and nitrogen-containing systems that exhibit intramolecular hydrogen bonds provide evidence for the existence of any resonance-assisted stabilization. Several fundamental questions concerning the signs and mechanism of this type of coupling have been addressed by Del Bene and Elguero.362 Three papers published by these two authors have been devoted to ab initio calculations of spin–spin coupling across N–H–F hydrogen bonds.363–365 The papers on this topic have been recently published by Limbach and his group366 who were the first to observe this type of coupling experimentally in various FH collidine complexes. The monovalent ion position and hydrogen-bond network in guanine quartets have been characterized by van Mourik and Dingley367 by the use of DFT calculations of NMR parameters. The results obtained by these authors have shown that the sizes of the trans-hydrogen-bond couplings are influenced primarily by the hydrogen bond geometry and only slightly by the presence of the ion. The properties of six dihydrogen-bonded dimers with the BeH2 molecule as a proton acceptor have been calculated by Cybulski et al.368 by the use of MP2, CCSD(T) and B3LYP methods. The values of the 2hJHX and 3hJBeX couplings correlate well with the interaction energy and with the intermolecular distance. A CLOPPA-IPPP analysis of electronic mechanisms of intermolecular 1hJHA and 2h JAD spin–spin couplings in systems with D–H A hydrogen bonds has been performed by Giribet and de Azua.369 The couplings of ca. 3 Hz have been observed by Ding et al.370 between the protons of the methylenic groups a to the oxygen atoms of the macro-ring and the hydrogens on the sidearm of sodium/potassium ion complexes of lariat ethers and interpreted in terms of the hydrogen C–H O bonds. The authors suggest that these couplings can be used as a good indicator for the strength of the bonds. In Table 5 some other examples of the compounds are given for which scalar couplings through the hydrogen bond have been measured.

12. Residual dipolar couplings There is a continuous effort to improve the quality of information obtained from residual dipolar couplings measured for large biomolecules. This includes search for better understanding of the dynamics present in biomolecules and possible interactions between biomolecules and alignment media, application of new alignment media and developing new types of experiments. Annila and co-workers377 have demonstrated that the dilute liquid crystals and axial matrices routinely used in biomolecular NMR spectroscopy favour certain protein conformations. This variation is of importance and sometimes is quite large. It can also be regarded as dynamic orientation-dependent deformations. The fundamental reason for this is that the alignment phenomenon features free energy changes just as any other interaction phenomenon. However, in practice these variations are smaller than the precision by which RDCs can be measured experimentally. Based on ubiquitin 1DHN 154 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Table 5 Compounds for which scalar couplings have been measured through the hydrogen bond a

Name [D/C/N] Itk SH2 domain bound to phosphotyrosine-containing peptide, pY [C/N] the peptidoglycan binding domain of B. subtilis cell wall lytic enzyme [C/N] ribosomal protein L11 from Thermotoga maritima [C/N] Oxy-1.5 DNA guanine quadruplex in Na+, K+, and NH4+ bound forms [C/N] the Aquifex aeolicus tmRNA pseudoknot PK1 [C/N] D5-PL, a self-splicing group II intron catalytic effector domain 5 [N] deoxygunaosine derivatives, in solid state [C/N] V17A18 lac headpiece complexed with lac-gal operator [C/N] C384S phospho-IIBMtl (375–476)

c

Ref.

N–H OQC

3h

21

200

N–H OQC

3h

36

371

N–H OQC

3h

JCN

84

207

N–H N

2h

JNN

38

372

N–H N N–H N

2h

JNN JNN

7 60

216 373

N–H N N–H OQP

2h

JNN JNP

3 1

374 375

N–H OQP

3h

1

376

a

b

JCN JCN

2h

3h

JNP

Hydrogen bond type, symbols of nuclei involved are given in bold. measured. c Number of couplings measured.

b

Type of couplings

couplings measured in 31 different alignment conditions, Lakomek et al.378 have been able to detect the presence of motions slower than the inverse overall tumbling correlation time of this protein. Blackledge and co-workers379 have investigated directly the presence of correlated motion in protein G using a combined analysis of 1 DHC, 1DCC, 1DCN and 2DHC dipolar couplings and scalar couplings across hydrogen bonds. The authors have employed an unprecedented set of data comprising up to 27 RDCs per amino acid residue. The larger-amplitude slower motions have been found in the loops and in the b-sheet. In the latter an alternating pattern of dynamics along the peptide sequence has been found to form a long-range network across the bstrands, reminiscent of a standing wave. A composite medium composed of stretched polyacrylamide gels and ordered bacteriophage Pf1 has been employed by Ruan and Tolman380 for the measurement of independent sets of 1DHN couplings in 15N-labelled ubiquitin. It has been shown by Chou and co-workers381 that the relative subunit orientation of coiled-coil proteins in solution can be determined by comparison of RCDs measured in charged liquid-crystalline medium with values predicted from the three-dimensional charge distribution in protein. The method has been demonstrated for the coiled-coil domain of the cGMP-dependent protein kinase Ia. Zweckstetter382 has studied the charge-induced alignment of proteins in liquid crystalline phases at low pH. The experimental values of 1DHN couplings of Igg-binding domain of protein G and of ubiquitin are well fitted with simple electrostatic alignment model. This shows that steric and electrostatic interactions dominate weak alignment of biomolecules for a wide range of pH. Lancelot et al.383 have applied variable-angle sample spinning experiments to the measurement of scaled 1DHN couplings in 15N-labelled ubiquitin in solution. The novel ‘3P’ (periodicity, planarity, and pixels) method has been demonstrated by Wang and co-workers384 for secondary and tertiary structure determination of an a-helical protein using 1DHN, 1DCC and 1DCN couplings measured in a single alignment medium. It has been shown by Clore and Schwieters385 that high-resolution crystallographic B-factors and residual dipolar coupling data, 1DHN, 1DC0 N,1DHaCa,1DCaC0 , for a small a/b protein are entirely consistent with one another within experimental error. The data of the third immunoglobin binding domain (GB3) of streptococcal protein G of 56 residues served as an example. Mertens and Gooley386 have checked the validity of applying the Ramachandran database potential of mean force during simulated Nucl. Magn. Reson., 2007, 36, 131–169 | 155 This journal is

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annealing in structure calculations of five proteins. The authors have used multiple sets of residual dipolar couplings as quality assessment criteria for the calculated structures; they have shown that significant improvement is achieved in the Ramachandran map and in the accuracy of structures. Skrynnikov and co-workers387 have developed tools for estimating the true accuracy of protein structures based on RDC data. The authors compared 100 X-ray and NMR structures of proteins deposited in Protein Databank. Surprisingly, they found that the rmsd between structures obtained with these two methods systematically increases. There is a growing interest in the understanding of the unfolded state of proteins. Jha et al.388 have addressed the so-called ‘reconciliation problem’ between the random coil scaling behaviour and the presence of significant amounts of local structure in the unfolded state. The information on the latter is provided by means of RDCs. The authors have proposed their own statistical coil library that compares well with the experimental RDCs for chemically denatured proteins and reproduces the known coil scaling behaviour. The RDC values in this state are dominated by high aspect ratio chain configurations, which are predominantly composed of PPII and b conformers. Blackladge and co-workers389 have used 1DHN couplings to define the long-range order and local disorder in 140 residue-long natively unfolded protein, a-synuclein. 1 DHN couplings have been used by Kessler and co-workers390 for the characterization of ‘saposin fold’ in several 15N-labelled human saposins, by Sticht and coworkers391 to assess the relative domain orientation of the Lck SH3-SH2 domain pair, by Zweckstetter and co-workers392 to study the structural fluctuations in six neurotoxic mutants of a-synuclein, by Raybov and Fushman393 to provide information on the interdomain dynamics in Lys48-linked di-ubiquitin and by Ho and coworkers394 to investigate the solution quaternary structures of human normal adult recombinant hemoglobin and a low-oxygen-affinity mutant recombinant haemoglobin, both in carbonmonoxy form. Other examples of proteins and nucleic acids for which residual dipolar couplings have been used for structure calculation are listed in Tables 6 and 7, respectively. 1 DHC couplings have been used by Lorgian and co-workers414 to profile structural perturbations in different regions of phospholipid bilayers after incorporation of phospholamban, chain transmembrane peptide or cholesterol. A chiral liquid crystalline solution has been applied by Sugiura et al.415 for discriminating among enantiomers of chiral triazole fungicides, uniconazole and diniconazole; for both these compounds the splittings corresponding to the sum of the scalar JHC and residual dipolar DHC couplings have been measured and compared with each other for the enantiomer. A large set of 26 residual dipolar couplings has been measured by Concistre` et al.416 for all five singly labelled 13C isotopomers of 2-thiophenecarboxaldehyde. These have been used to determine the structure and the relative amounts of the cis and trans forms of this compound. The proton NMR spectrum of the doubly enriched acetophenone carbonyl, methyl–13C2 isotopomer dissolved in a liquidcrystalline solvent has been analysed by De Luca et al.417 It yielded a data set of dipolar couplings which have been used by the authors to investigate the international rotational motions in this molecule. Different values of residual dipolar couplings measured for enantiomers have been proposed by Luy and co-workers418 for the discrimination between the two forms. Stretched gelatin gels have served as chiral alignment media in these measurements. A nematogenic compound, 4-pentyl-4 0 -cyanobiphenyl, has been used by Merlet and co-workers419 to study the orientational order of this compound. NMR spectroscopy yielded values of field induced 1DHC dipolar couplings, which follow a divergence behaviour when the compound approaches the transition from the isotropic to the nematic phase. Maxwell and co-workers420 have employed residual dipolar couplings to assess changes in the network structure in a series of radiatively aged elastomers based on the Dow Corning DC745 gum stock. 156 | Nucl. Magn. Reson., 2007, 36, 131–169 This journal is

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Table 6 Proteins for which the solution structure has been calculated with RDCs a

Name glutatione tetraalanine [10%C/N] DPFFL bound to Ab1423 DPFFL bound to Ab140 hormaomycin cyclosporin A, refinement P-gp411–30-DYKDDDK, HIV-1 gp-41(1–30) fusion domain [C/N] EGFR(644–697), the juxtamembrane domain of EFGR nucleocapsid-binding domain of Sendai virus phosphoprotein, natively unfolded [C/N] WT drkN SH3 domain

b

c

Ref.

DHC DHH 1 DHC, 1DHN 1 DHC 1 DHC, 1DHN 1 DHC 1 DHN, 1DCC, 1 DCN 1 DHN

395 396 397 397 398 399 279

1

3 4 5+ 5+ 10 11 38

10 8 8 10 54 35 57

54

27

57

57

1

DHC, 1DHN

400

59

253

1

DHC, 1DHN, DCC, 1DCN 1 DHC, 1DHN, 1 DCC, 1DCN 1 DHC, 1DHN, 1 DCC, 1DCN 60+10bp

280

2,3

195

1

[C/N] T22G drkN SH3 domain

59

196

[C/N] conkunitzin-S1, a neurotoxin from the venom of the cone snail Conus striatus [C/N] V17A18 lac headpiece complexed with lac-gal operator 1 DHN [C/N] the peptidoglycan binding domain of B. subtilis cel wall lytic enzyme Cw1C [C/N] the Vts1p SAM domain (443–523) complexed with SRE RNA 1 DHC, 1DHN [C/N] the FYVE domain of LM5-1 protein from Leishmania major C/N] YggX, the oxidative stress-related protein from E. coli [C/N] D1-RAP, domain 1 of the receptor-associated protein [C/N] C384S phospho-IIBMtl (375–476)

60

201

[C/N] the HDGF PWWP domain

375 70

401 84

1

63

259

280 196 49

DHN

371

81+23nt

111

DHC, 1DHN, DCC, 1DCN 1 DHN

386

2

1

91

42

92

196

102

192

110

258

[D/C/N] cGMP-dependent protein kinase Ia

59 2

110

[C/N] Pal/PG-P, the periplasmic dom. of Pal complexed with a peptidoglycan prec. [C/N] HBP1 domain of AXH(208–345) [D/C/N] A30P a-synuclein

115+7

223

138 140

58 261

[D/C/N] A53T a-synuclein

140

261

[C/N] ribosomal protein L11 from Thermotoga maritime

140

429

[C/N] MJ1529 from the thermophile Methanococcus jannaschii [C/N] GNA1870-BC (101–255), the antigen of Neisseria meningitidis [C/N] human p47phox(151–286) complexed with human p22phox(149–168) [N] OMP, rat olfactory marker protein

154

71

155

114

1

DHN

209

136+20

91

1

DHN

403

163

80

1

DHN

404

1

198

DHN, 1DCC, 1 DCN 2 DHC, 1DHN, 1 DCN 2 DHC, 1DHN, 1 DCC, 1DCN 1 DHN, 1DCC, 1 DCN 1 DHN, 1DCN

384

1 DHN DHN, 1DCC, 1 DCN 1 DHN, 1DCC, 1 DCN 12 DHC, 1 DHN, 1DCC, 1 DCN 1 DHN

206 402

1

376 202 281 204

402 207

208


c


Table 6 (continued ) a

Name [D/C/N] SiR-FP (52–218) the sulfite reductase flavodoxin-like domain from E. coli [C/N] murine gS-crystallin [N] NiARD, acireductone dioxygenase from Klebsiella ATCC 8724 [N] VAT-N, valosine-containing protein-like ATPase of T. acidophilum, refinement [C/N] S100A1, Ca2+-bound [C/N] the cytoplasmic A(IIAMtl) and phospho-IIBMtl post-transition state complex 1 DHN [D/C/N] [1H-(methine/methyl)-L/V] enzyme IIAChitobiose [C/N] DnaK HSP70 chaperone protein of T. thermophilus

167 177 179

b 1

Ref. 1

DHN, DCC, 1 DCN 1 1376 DHN, 1DCC, 1 DCN 1 134 DHN 409

184

56

93 2

362

284 116 3

c

267

1

1

405 283 406

DHN

407

DHC, 1DHN, 1 DCC 148+102

210

1

DHC, 1DHN, DCC, 1DCN 1 DHN, 1DCC

d

408

1

501

308e

409

a Number of residues. b The total number of residual dipolar couplings measured. c Types of residual dipolar couplings measured. d Number not reported. e Global fold only.

Table 7 Oligonucleotides and carbohydrates for which the solution structure has been calculated with RDCs a

Name [C/N] Tar(17–45) complexed with neomycin B [C/N] Tar(17–45) complexed with acetylpromazine the ScYLV pseudoknot [C/N] D5-PL, a self-splicing group II intron catalytic effector domain 5 [C/N] class I GTP aptamer [C/N] the HIV-1 frameshift inducing element [C/N] GAAA tetraloop-receptor complex carbohydrates the human milk oligosaccharide lacto-N-neotetraose a

b

c

27+

41

1

27+

37

1

30 34

102 37

1

41 45 43 2

25 21 24

1

4

9

Ref. 1

DHC, DHN

410

DHC, 1DHN

410

DHC DHC

411 373

DHN DHC 1 DHN

289 412 413

1

299

1

1

DHC

b

The number of nucleotides or sugar units. The total number of residual dipolar couplings measured. c Types of residual dipolar couplings measured.

The structure and bond rotational potential of 1-chloro-2-bromoethane have been elucidated by Emsley and co-workers421 by the use of partially averaged dipolar couplings (also referred to as residual dipolar couplings) Dij obtained from an analysis of the NMR spectrum measured in the nematic liquid-crystalline solvent ZLI II 32.

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Nuclear spin relaxation in liquids and gases R. Ludwig DOI: 10.1039/b618328j

1. Introduction The aim of this report is to cover the progress of work in the field of magnetic relaxation and self-diffusion in liquids and gases over a period of twelve months from June 2005 to May 2006, and is a continuation of the report given last year.1 As in previous periods, this review is limited to work on comparatively simple liquids and solutions of physico-chemical and chemical interest, as publications in the field of macromolecules and biological chemistry are covered elsewhere in this volume. Of course, such a distinction is sometimes problematic, as innovative work dealing with solutions of complex molecules may be of interest for research in the field covered here. Thus, at the risk of duplication, some interesting studies dealing with more complex systems are mentioned briefly. The subsection ‘‘Molten Salts’’ is replaced by the subsection ‘‘Ionic Liquids and Molten Salts’’ taking into account the increasing importance of this new class of materials. At the beginning of this chapter it is convenient to quote some authoritative reviews in the subject area. More specialized reviews will be discussed in the corresponding subsections. Details will be discussed later in this chapter. The year 2006 represents the 60th anniversary of nuclear magnetic resonance (NMR) spectroscopy. It is therefore appropriate and indeed valuable to reflect on how this versatile methodology has developed, expanded, and evolved into a cornerstone of chemical research since 1946. Darbeau2 provided an overview of NMR spectroscopy including the basic principles of NMR the historical development of the field and a few unique applications of the methodology. Bagno et al.3 reviewed NMR techniques for the investigation of solvation phenomena and non-covalent interactions. Solvent effects; non-covalent interactions, spin–spin couplings; intermolecular NOE; spin–lattice relaxation and diffusion coefficients are discussed. Yonker and Linehan4 reported the use of supercritical fluids as solvents for NMR spectroscopy. The topics of high-pressure NMR; catalysis; phase equilibrium; molecular dynamics; diffusion coefficients and hydrogen bonding were considered. Brand et al.5 discussed intermolecular interaction as investigated by NOE and diffusion studies. Fantazzini and Brown6 reported the fact that distributions of relaxation times or rates may be misinterpreted or wrongly compared if units are not consistently used or not correctly identified. Multidimensional spectroscopy plays a number of essential roles in contemporary magnetic resonance. It brings a resolution enhancement without which numerous NMR applications in organic and inorganic chemistry would be unattainable, it serves as a basic tool in the assignment and structural elucidation of complex biological structures and it is an integral part of the image formation protocol in MRI. Frydman7 described a recent scheme enabling the acquisition of complete 2D NMR data sets within a single continuous acquisition. Diffusion NMR and in particular the DOSY processing method (Diffusion Ordered SpectroscopY), is an attractive technique to characterize mixtures without first having to separate the components. As a result, DOSY can yield a vast amount of analytical information. Cobas et al.8 reviewed general applications of DOSY. Arnesano et al.9 discussed recent advances in NMR on metalloproteins. Particular emphasis is given to those metalloproteins that belong to the same biochemical pathway. Gadolinium(III) complexes are often used in clinical MRI to increase Department of Physical Chemistry, University of Rostock, Dr-Lorenz-Weg 1, Rostock, 18051, Mecklenburg-Vorpommern, Germany


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contrast by selectively relaxing the water molecules near the complex. There is a desire to improve the sensitivity (relaxivity) of these contrast agents in order to detect molecular targets. Caravan10 described the molecular factors that contribute to relaxivity and illustrates with recent examples how these can be optimized. High resolution liquid state NMR is a powerful technique for in vitro studies of structure and dynamics of soluble biological macromolecules under physiological conditions. The unique combination of atomically resolved structural data with both local and global dynamic features covering the entire range of time scales from picoseconds to seconds makes NMR the method of choice in a very diverse and rapidly growing array of biochemical, biomedical, and pharmaceutical applications. Stangler et al.11 reviewed advances in high resolution liquid NMR. There is growing evidence that structural flexibility plays a central role in the function of protein molecules. Many of the experimental data come from NMR, a technique that allows internal motions to be probed with exquisite time and spatial resolution. Recent methodological advancements in NMR have extended the ability to characterize protein dynamics and promise to shed new light on the mechanisms by which these molecules function. Woods et al.12 reviewed the fundamental aspects of a new class of contrast media for MRI based upon the chemical shift saturation transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiological or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chemical shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.

2. General, physical and experimental aspects of nuclear spin relaxation 2.1 General aspects The effect of the magnetic field generated by the nuclear magnetization itself is generally neglected in NMR experiments since it is intrinsically weak and the net field produced by summing over the contributions of all the magnetizations in the sample often averages to zero. However, when the magnetization is spatially modulated, for example, by the application of magnetic-field gradients, the field no longer averages to zero and in highly polarized samples, the resulting dipolar field can significantly perturb the evolution of the magnetization. Deville et al.13 were the first to describe the occurrence of such effects in NMR experiments. In the early 1990s as high-field magnets became available it was shown that they could also be observed in liquids at room temperature.14 At a similar time, the presence of unexpected crosspeaks in two-dimensional (2D) spectra, corresponding to coherences between independent molecules in solution, was reported.15,16 In particular it was shown that crosspeaks occurred in spectra produced using the correlated, two-dimensional spectroscopy (COSY) revamped by asymmetric z-gradient echo detection (CRAZED) sequence, when the area of the second gradient pulse is a multiple of the area of the first pulse, with crosspeaks being largest for a 1:2 ratio of areas. These intermolecular multiple quantum coherences (iMQCs) were explained using a quantum-mechanical approach in which higher-order terms in the expansion of the equilibrium density matrix are retained and the effect of the dipole–dipole interaction between all spins is included in the Hamiltonian.15 The unexpected crosspeaks can also be explained via consideration of the effect of the DDF generated by the magnetization of one spin component on the evolution of magnetization of another spin component. In the recent years, it has been shown that these quantum and classical ‘‘pictures’’ produce consistent predictions.17 Marques et al.18 used the classical approach since it allows more straightforward introduction of the effects of diffusion and relaxation. The authors carried out experiments at magnetic-field strengths of 9.4, 14.1, and 17.6 T to explore the Nucl. Magn. Reson., 2007, 36, 170–195 | 171 This journal is

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evolution of intermolecular multiple quantum coherences in the nonlinear regime where the system evolves for times that are much greater than the characteristic time of action of the long-range dipolar field, td. The results show the expected Bessel function form of the recorded signal as a function of time of evolution, with evident zeros and sign changes. Although the theories and potential applications of intermolecular multiplequantum coherences (iMQCs) have been under active investigations for over a decade, discussion of iMQC NMR signal formation was mainly confined in the time domain. Zheng et al.19 developed a full line-shape theory to describe iMQC signals in the frequency domain. Relevant features of the line shape, such as peak height, linewidth, and phase, were investigated in detail. Predictions based on the theory agree well with experimental and simulated results. Since radiation-damping effects always couple with iMQCs in highly polarized liquid-state NMR systems, and strongly radiation-damped signals have many spectral characteristics similar to those of iMQCs, a detailed comparison was also made between them from different spectral aspects. Bouchard and Warren20 introduced a method for non-invasively mapping fiber orientation in materials and biological tissues using intermolecular multiple-quantum coherences. The nuclear magnetic dipole field of water molecules is configured by a CRAZED sequence to encode spatial distributions of material heterogeneities. Experiments in structured media confirm the structural sensitivity. This technique can probe length scales not accessible by conventional MRI and diffusion tensor imaging. Recovering the relaxation-time density function (or distribution) from NMR decay records requires inverting a Laplace transform based on noisy data, an illposed inverse problem. An important objective in the face of the consequent ambiguity in the solutions is to establish what reliable information is contained in the measurements. To this end Parker and Song21 described how upper and lower bounds on linear functionals of the density function, and ratios of linear functionals, can be calculated using optimization theory. Knowledge of the effective rotational correlation times, tc, for the modulation of anisotropic spin–spin interactions in macromolecules subject to Brownian motion in solution is of key interest for the practice of NMR spectroscopy in structural biology. The value of tc enables an estimate of the NMR spin relaxation rates, and indicates possible aggregation of the macromolecular species. Lee et al.22 reported a novel NMR pulse scheme, [15N,1H]-TRACT, which is based on transverse relaxation-optimized spectroscopy and permits to determine tc for 15N–1H bonds without interference from dipole–dipole coupling of the amide proton with remote protons. Solvent-localized NMR (SOLO) is a new method which allows the separation of NMR spectra of substances dissolved in different solvents. It uses the selective homogenized pulse sequence to produce a two-dimensional NMR spectrum resulting from intermolecular zero-quantum coherences in one distinct solvent. Faber23 demonstrated the method for the solvents water and DMSO on a length scale of 0.5 mm. Because signal in the spectra is refocused locally, SOLO is insensitive to variations in the magnetic field which may result from inhomogeneities or structures in the sample. This makes applications in strongly structured samples possible. SOLO is the first method that achieves localization of NMR signal with a single gradient pulse. Steinbeck and Chmelka24 showed that Hadamard-encoded heteronuclearresolved NMR diffusion and relaxation measurements allow overlapping signal decays to be resolved with substantially shorter measuring times than are generally associated with 2D heteronuclear cross-correlation experiments. Overall measuring time requirements can be reduced by approximately an order of magnitude, compared to typical 2D heteronuclear single-quantum correlation-resolved diffusion or relaxation measurements. Specifically, in cases where chemical shift correlation information provides enhanced spectral resolution, the use of Hadamard encoding can be used to overcome uniqueness challenges that are associated with the analysis 172 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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of concurrent dynamic processes and the extraction of time constants from overlapping exponential signal decays. This leads to substantially improved resolution of similar time constants than can be achieved solely through the use of postacquisition processing techniques. Hadamard-based pulse sequences have been used to determine 1H–13C-resolved diffusion coefficients and spin-relaxation time constants for the chemically similar components of an aqueous solution of ethanol, glycerol and poly(ethylene glycol), and a dye-containing block-copolymer solution, which exhibit significant spectral overlap in their 1H NMR spectra. To reliably measure NMR relaxation properties of macromolecules is a prerequisite for precise experiments that identify subtle variations in relaxation rates, as required for the determination of rotational diffusion anisotropy, CSA tensor determination, advanced motional modelling or entropy difference estimations. An underlying problem with current NMR relaxation measurement protocols is maintaining constant sample temperature throughout the execution of the relaxation series especially when rapid data acquisition is required. Armstrong and Bendiak25 reported four-dimensional nuclear magnetic resonance spectroscopy of oligosaccharides that correlates 1H–1H ROESY cross peaks to two additional 13C frequency dimensions. The 13C frequencies were introduced by derivatization of all free hydroxyl groups with doubly 13C-labeled acetyl isotags. Pulse sequences were optimized for processing with the filter diagonalization method. The extensive overlap typically observed in 2D ROESY 1 H–1H planes was alleviated by resolution of ROESY cross peaks in the two added dimensions associated with the carbon frequencies of the isotags. 2.2 Experimental aspects The spin–lattice relaxation dispersion may be probed in the laboratory frame through field-cycling NMR relaxometry. The experiment, as usually done, has the basic weakness that the low frequency end of the measured dispersion can be blurred by the presence of local fields. An understanding of the nature of such local fields was found to be essential to the interpretation of the dispersion profile. Perlo and Anoardo26 made an attempt to determine the extent to which specific information can be obtained from a rotating frame experiment. The technique consists in the study of the NMR signal dispersion at a fixed spin-lock time, as a function of the radio frequency field intensity. Within this scheme, a strong dispersion can be attributed to the presence of a non-zero magnetic field component along the laboratory-frame Zeeman-axis in the rotating-frame. At on-resonance condition, this component is exclusively due to the presence of local fields as projected on that axis. Mananga et al.27 presented a phase cycling scheme for suppressing spectral artifacts introduced in quadrupolar echo spectroscopy of spin-1 nuclei due to finite pulse width effects. The phase cycling scheme is developed using the formalism of average Hamiltonian theory and fictitious spin-1 operators. A simulation and experiment on deuterated polyethelene is performed highlighting the spectral artifact introduced by finite pulse widths and successful removal with the proposed phase cycling scheme. Yushmanov and Furo28 presented a simple stopped-flow design for rapid mixing of two liquids within the NMR probe. The device uses no switches or relays but exploits instead the torque exerted by the magnetic field on a current-leading-coil to open and close the start and stop valves. Presaturation utilizing relaxation gradients and echoes is an extremely easy and effective approach to solvent suppression in solution state nuclear magnetic resonance spectroscopy. The experiment produces flat baselines, excellent phase properties, and highly selective suppression that betters that of commonly used sequences. Furthermore, the only parameter that needs adjusting is the presaturation power, making it easy to implement even for non spectroscopists. Simpson and Brown29 envisaged the approach that will have wide spread applications. Zuckerstatter and Muller30 demonstrated that cogwheel phase cycling, which was previously only used in solid state NMR, can be applied to Nucl. Magn. Reson., 2007, 36, 170–195 | 173 This journal is

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optimize the efficiency of commonly used pulse sequences in multiple resonance liquid-state biomolecular NMR. In favourable cases the required minimum number of scans can be reduced by more than NIX as compared to a corresponding sequence with nested phase cycles. Since cogwheel phase cycling procedures can be designed for a range of scan numbers and can be combined with pulsed field gradients, the total experiment time can be adjusted closely to the required signal-to-noise ratio with minimal overhead. Examples are shown for 3D-TROSY-HNCO, 3D-TROSYHNCACO, and 3D-HACACO experiments on diamagnetic and paramagnetic proteins. Yushmanov and Furo31 described the design and performance of a simple probe insert for temperature-jump experiments in conventional NMR probes. The insert uses the output from conventional NMR amplifiers for heating conductive aqueous samples with a rate of 30–80 K/s for 200 W r.f. power. The observed dependence of the heating rate on sample conductivity is explained by the dominance of dielectric heating. Factors governing the temperature gradient within the sample are discussed. Miloushev and Palmer32 obtained analytic expressions for the nuclear magnetic spin relaxation rate constant for magnetization spin-locked in the rotating reference frame under an applied radiofrequency field, R1r, for two-site chemical exchange. The theoretical approach is motivated by Laguerre’s method. The general formula for R1r obtained by this approach is substantially simpler than existing expressions and is equally or slightly more accurate, in most cases. NMR microscopy is usually achieved at ultra-high-static magnetic field with the use of home-built coils adapted to the size of the sample. In that way, well-resolved images can be obtained with voxel size smaller than 50 mm. Miraux et al.33 showed that high-resolution imaging can be realized at lower field strength (4.7 Tesla) using 5and 10-mm probes initially dedicated to vertical magnets. These coils are easily adaptable to horizontal imaging systems. Excellent quality and filling factors permitted isotropic resolutions (450 mm) on a biomaterial and on mouse femoris. This study also demonstrates that spoiled-gradient echo sequence (FLASH) with low reception bandwidth or with the use of gadolinium are particularly effective for 3D MR microscopy. In comparison with most analytical chemistry techniques, nuclear magnetic resonance has an intrinsically low sensitivity, and many potential applications are therefore precluded by the limited available quantity of certain types of sample. In recent years, there has been a trend, both commercial and academic, towards miniaturization of the receiver coil in order to increase the mass sensitivity of NMR measurements. These small coils have also proved very useful in coupling NMR detection with commonly used microseparation techniques. A further development enabled by small detectors is parallel data acquisition from many samples simultaneously, made possible by incorporating multiple receiver coils into a single NMR probehead. Webb34 reviewed recent developments and applications of ‘‘microcoil’’ NMR spectroscopy.

2.3 Relaxation in coupled spin systems A product operator matrix to describe scalar couplings in liquid NMR is proposed by Cai et al.35 Combination of the product operator matrix and non-linear Bloch equations is employed to describe effects of chemical shift, translational diffusion, dipolar field, radiation damping, and relaxation in multiple spin systems with both scalar and dipolar couplings. A new simulation algorithm based on this approach is used to simulate NMR signals from dipolar field effects in the presence of scalar couplings. Several typical coupled spin systems with both intra-molecular scalar couplings and inter-molecular dipolar couplings are simulated. Monte Carlo methods are incorporated into simulations as well to analyze diffusion process in these complicated spin systems. The simulated results of diffusion and relaxation 174 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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parameters and 2D NMR spectra are coincident with the experimental measurements, and agree with theoretical predictions as well. The simulation algorithm presented herein therefore provides a convenient means for designing pulse sequences and quantifying experimental results in complex coupled spin systems. Carvetta and Levitt36 demonstrated the existence of exceptionally long-lived nuclear spin states in solution-state nuclear magnetic resonance. The lifetime of nuclear spin singlet states in systems containing coupled pairs of spins-1/2 may exceed the conventional relaxation time constant T1 by more than an order of magnitude. These long lifetimes may be observed if the long-lived singlet states are prevented from mixing with rapidly relaxing triplet states. The authors now provide the detailed theory of an experiment which uses magnetic field cycling to observe slow singlet relaxation. An approximate expression is given for the magnetic field dependence of the singlet relaxation rate constant, using a model of intramolecular dipole–dipole couplings and fluctuating external random fields. Nielsen and Robinson37 used spherical tensor operators to simplify the relaxation terms of the Redfield equation. A method for treating relaxation is developed using trace-normalized spherical tensor operators. The Redfield equation is recast as a set of coupled linear differential equations for the expectation values of a complete set of spherical tensor operators. A single spin-1/2 particle is treated, and the correspondence of the equation of motion with the Bloch equation is demonstrated. The advantage of the spherical tensor approach is that both the coherent and relaxation terms of the equation of motion are written as matrices that operate on a common vector consisting of the expectation values of spin variables. Wu et al.38 studied concerted double proton transfer in the hydrogen bonds of a carboxylic acid dimer by using 13C field-cycling NMR relaxometry. Heteronuclear 13C–1H dipolar interactions dominate the 13C spin–lattice relaxation which is significantly influenced by the polarisation state of the 1H Zeeman reservoir. The authors studied the methodology of field-cycling experiments for such heteronuclear spin-coupled systems experimentally and theoretically, including an investigation of various saturation-recovery and polarisation-recovery pulse sequence schemes. Kover et al.39 presented a modified CPMG-HSQMBC experiment which is capable to reduce the detrimental phase twists in the ‘‘long range’’ connectivity multiplets caused by proton–proton couplings. The authors demonstrated that concerted CPMG pulse trains applied on both nuclei in the starting CPMG-INEPT transfer step can considerably be improved by composite p pulses that compensate for pulse imperfections and off-resonance effects. Experimental optimization of the interpulse delay within the CPMG cycle was found to be crucial in order to achieve the best possible ‘‘decoupling’’ of homonuclear coupling modulation. Neves et al.40 explored the limits of polarization transfer efficiency for systems consisting of three isotropically coupled spins 1/2 in the absence of relaxation. An idealized free evolution and control Hamiltonian is studied, which provides an upper limit of transfer efficiency (in terms of transfer amplitude and transfer time) for realistic homonuclear spin systems with arbitrary Heisenberg-type coupling constants. It is shown that optimal control based pulse sequences have significantly improved transfer efficiencies compared to conventional transfer schemes.

2.4 Dipolar couplings and distance information In NMR applications for structural characterization of proteins and nucleic acids, nuclear spin relaxation is a critical factor for optimising the set-up of the NMR experiments,41,42 provides key data for de novo structure determination,43 and can provide a wealth of information on global and intramolecular molecular motions that may be crucial for macromolecules to adapt their structures to particular functions.43–51 Since most of the ‘classic’ treatments of relaxation theory were written before the advent of high polarizing magnetic fields and the availability of Nucl. Magn. Reson., 2007, 36, 170–195 | 175 This journal is

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isotope-labelled macromolecules, long-established facets of the theory have again and again led to novel structural biology applications. Examples include the fundamental role of proton–proton homonuclear Overhauser effects (NOE) in studies of macromolecular structures,43,52,53 the introduction of TROSY (transverse relaxation-optimised spectroscopy) and CRINEPT (cross-correlated relaxationenhanced polarization transfer) for studies of large molecular and supramolecular structures,46,54–57 and the observation of residual dipole–dipole couplings at high polarizing magnetic fields.58–60 Luginbu¨hl and Wu¨thrich61 discussed selected aspects of semi-classical relaxation theory that are considered to be of central interest for practical applications in macromolecular solution NMR. Nuclear spin relaxation provides useful information related to the dynamics of molecular systems. When relaxation is driven by intermolecular dipolar interactions, the relevant spectral density functions (SDFs) also have significant contributions, in principle, from distant spins all over the dynamic range typically probed by NMR experiments such as NOESY. Frezzato et al.62 investigate the intermolecular dipolar spin relaxation as driven by the relative diffusion of solvent and solute molecules taking place under a central force field and we examine the relevant implications for (preferential) solvation studies. For this purpose, the authors evaluate the SDFs by employing a numerical approach based on spatial discretization of the timepropagation equation, and they supply an analytical solution for the simplest case of a steplike mean-field potential. Several situations related to different solutesolvent pair correlation functions are examined in terms of static/dynamic effects and relaxation modes and some conclusions are drawn about the interpretation of NOE measurements. While the authors confirm previous results concerning the spoiling effect of long-range spins,63 they also show that SDFs are sufficiently sensitive to pair correlation functions that useful, yet rather complicated, inferences can be made on the nature of the solvation shell. The presence of long-range dipolar fields in liquids is known to introduce a nonlinear term in the Bloch-Torrey equations which is responsible for many interesting effects in nuclear magnetic resonance as well as in magnetic resonance imaging. Barros et al.64 show for the first time, that the diffusion coefficient D and the spin– spin relaxation time T2 can be obtained simultaneously from the time evolution profile of the long-range dipolar field refocused signal. In a COSY Revamped by Z-asymmetric Echo Detection sequence, the analytical first-order approximation solution of the Bloch-Torrey equations modified to include the effect of the distant dipolar field is used to demonstrate the technique in an experiment using doped water. Meriles and Dong65 report the indirect detection of the magnetization of one spin species via the NMR signal of a second species. Their method relies on the control of long-range dipolar fields between two separate objects, in this case, a water droplet (sensor) immersed in a tube containing mineral oil (sample). Unlike prior experiments, no gradient pulses are used; rather, the setup geometry is exploited to select the part of the sample to be probed and modulate the spin alignment in the sensor. The results are discussed in the context of Dipolar Field Microscopy, a proposed strategy in which the detector is a hyperpolarized tip. 2.5 Exchange spectroscopy High-resolution solution NMR experiments are extremely useful to characterize the location and the dynamics of hydrating water molecules at atomic resolution. However, these methods are severely limited by undesired incoherent transfer pathways such as those arising from exchange-relayed intra-molecular-cross-relaxation. Huang and Melacini66 reviewed several complementary exchange network editing methods that can be used in conjunction with other types of NMR hydration experiments such as magnetic relaxation dispersion. They also discuss several recent contributions illustrating how the original solution hydration NMR pulse sequence 176 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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architecture has inspired new approaches to map other types of non-covalent interactions going well beyond the initial scope of hydration. Sorce et al.67 considered the problem of the relaxation of identical spins 1/2 induced by chemical exchange between spins with different chemical shifts in the presence of timedependent r.f. irradiation (in the first rotating frame) for the fast exchange regime. The solution for the time evolution under the chemical exchange Hamiltonian in the tilted doubly rotating frame (TDRF) is presented. The authors specified detailed derivation to the case of a two-site chemical exchange system with complete randomization between jumps of the exchanging spins. The derived theory can be applied to describe the modulation of the chemical exchange relaxation rate constants when using a train of adiabatic pulses, such as the hyperbolic secant pulse. Theory presented is valid for quantification of the exchange-induced timedependent rotating frame longitudinal T1r, Tex and transverse T1r, Tex relaxations in the fast chemical exchange regime. Oregioni et al.68 considered the use of adiabatic half-passage pulses (AHP) for the uniform excitation of highly non-equilibrium spin-systems such as spin-exchange optically pumped (SEOP) 129Xe. The method simplifies a number of problems that are encountered for these systems, notably the non-renewable nature of the magnetization, the need for accurate pulse calibration and the influence of radiation damping. Plummer et al.69 used PFG-NMR to study the chemical exchange of poly(2-hydroxyethyl methacrylate) having a range of molecular weights with water in DMSO containing varying quantities of water. The aim was to investigate the use of PFG-NMR to study chemical exchange between a polymer with exchangeable protons and a small fast diffusing molecule to provide insight into the conformation adopted by a polymer in solution. Perrin et al.70 investigated the dynamic behavior of water within two types of ionomer membranes, Nafion and sulfonated polyimide, by field-cycling nuclear magnetic relaxation. This technique, applied to materials prepared at different hydration levels, allows the proton motion on a time scale of microseconds to be probed. The NMR longitudinal relaxation rate R1 measured over three decades of Larmor angular frequencies is particularly sensitive to the host-water interactions and thus well-suited to study fluid dynamics in restricted geometries.

2.6 Radiation damping Radiation damping arises from the field induced in the receiver coil by large bulk magnetization and tends to selectively drive this magnetization back to equilibrium much faster than relaxation processes. The demand for increased sensitivity in masslimited samples has led to the development of microcoil NMR probes that are capable of obtaining high quality NMR spectra with small sample volumes. Microcoil probes are optimized to increase sensitivity by increasing either the sample-to-coil ratio (filling factor) of the probe or quality factor of the detection coil. Though radiation damping effects have been studied in standard NMR probes, these effects have not been measured in the microcoil probes. Krishnan71 presented a systematic evaluation of radiation damping effects in a microcoil NMR probe. The results are compared with similar measurements in conventional large volume samples. These results show that radiation-damping effects in microcoil probe is much more pronounced than in 5 mm probes, and that it is critically important to optimize NMR experiments to minimize these effects. Datta et al.72 investigated the dynamics under the joint action of radiation damping and the distant dipolar field in high-field solution magnetic resonance. Different dynamical regimes during the evolution are identified and their individual features are discussed. In the steady state, the dynamics can be associated with a strange attractor in phase space on which the motion is chaotic. The possibility of the observed chaotic motion being spatiotemporal is examined. Nucl. Magn. Reson., 2007, 36, 170–195 | 177 This journal is

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Water suppression by selective preirradiation is increasingly difficult to achieve on probeheads with high quality factor because of the opposing forces of radiation damping. Wu and Otting73 showed that a simple scheme provides reliable water suppression in aqueous solutions of proteins and peptides with minimal saturation of the Ha protons. The scheme is shown to work also with dilute peptide solutions. The new water-suppression scheme suppresses the water magnetization by spatial scrambling. Traditional water suppression by preirradiation is similarly based more on water scrambling due to the radiofrequency inhomogeneity than on relaxation effects. 2.7 Quadrupolar interactions Oxygen-17 is the only stable oxygen isotope that can be detected by NMR. The quadrupolar moment of 17O spin (I = 5/2) can interact with local electric field gradients, resulting in extremely short T1 and T2 relaxation times which are in the range of several milliseconds. One unique NMR property of 17O spin is the independence of 17O relaxation times on the magnetic field strength and this makes it possible to achieve a large sensitivity gain for in vivo 17O NMR applications at high fields. Zhu et al.74 reported in vivo 17O NMR approaches for studies at high field. Latosinska75 gave an overview of the NQR capabilities in the search for a correlation between electronic structure and biological activity of certain compounds, mainly drugs. A correlation between the parameters characterising biological activity and the NQR spectral parameters describing chemical properties of a given compound, permits drawing conclusions on biological effectiveness of compounds from a certain group. The quadrupole coupling constants, which are very well correlated with atomic charges, can be treated as descriptors in QSAR. The information inferred from NQR study on local electron density distribution together with analysis of charge distribution, provides excellent means for determination of reactive sites and hence, can indicate possible promising directions to be followed in drugs design. Rotational correlation times of metal ion aqua complexes can be determined from 17 O NMR relaxation rates if the quadrupole coupling constant of the bound water oxygen-17 nucleus is known. The rotational correlation time is an important parameter for the efficiency of Gd3+ complexes as magnetic resonance imaging contrast agents. Yazyev and Helm76 used a combination of density functional theory with classical and Car-Parrinello molecular dynamics simulations to perform a computational study of the 17O quadrupole coupling constants in model aqua ions and the [Gd(DOTA)(H2O)] complex used in clinical diagnostics. For the inner sphere water molecule in the [Gd(DOTA)(H2O)] complex the determined quadrupole coupling parameter chi root 1 + (Z2/3) of 8.7 MHz is very similar to that of the liquid water (9.0 MHz). Tanase and Boada77 analyzed the dynamics of spin 3/2 systems by using the density matrix theory of relaxation. By using the superoperator formalism, an algebraic formulation of the density matrix’s evolution is obtained, in which the contributions from free relaxation and RF application are easily factored out. As an intermediate step, an exact form for the propagator of the density matrix for a spin 3/2 system, in the presence of static quadrupolar coupling, inhomogeneous static magnetic field, and relaxation is demonstrated. Using this algebraic formulation, exact expressions for the behaviour of the density matrix in the classical one-, two- and three-pulse experiments are derived. These theoretical formulas are then used to illustrate the bias introduced on the measured relaxation parameters by the presence of large spatial variations in the B0 and B1 fields. Antonijevic and Bodenhausen78 proposed a set of graphical conventions called quadrapolar transfer pathways to describe a wide range of experiments designed for the study of quadrupolar nuclei with spin quantum numbers I = 1, 3/2, 2, 5/2, etc. These pathways allow one to appreciate the distinction between quadrupolar and Zeeman echoes, represent a generalization of the well-known coherence transfer pathways. 178 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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2.8 Intermolecular dipolar interaction in diamagnetic and paramagnetic solution NMR resonance frequencies and relaxation properties of nuclear spins residing in paramagnetic transition metal complexes in solution are strongly influenced by the presence of unpaired electron spin.79 In particular, the nuclear spin relaxation rates in paramagnetic solutions are very much higher than in the diamagnetic counterparts. In the context of nuclear spin–lattice relaxation, one commonly speaks about the paramagnetic relaxation enhancement, PRE. Strong PRE effects can also be seen for nuclear spins belonging to the solvent or to ligands that spend only a small portion of the time in the coordination sphere of the paramagnetic metal ion. The PRE effect, especially when studied as a function of the magnetic field (the nuclear magnetic relaxation dispersion, NMRD, experiment) can be an important source of information on structural as well as dynamic properties of a system, provided that an adequate theoretical model is available. The NMRD profiles are an important and commonly used tool in the characterisation of paramagnetic complexes, such as Gd(III) chelates, considered for possible applications as contrast agents for magnetic resonance imaging, MRI.80,81 Schaefle and Sharp82 described four theoretical and computational approaches to analyze NMR paramagnetic relaxation enhancement (NMR-PRE). The primary objective of the theory is to describe the relationship of the NMR-PRE phenomenon to the electron spin Hamiltonian and the spin energy level structure when zero field splitting interactions are significant. Four formulations of theory are discussed: (1) spin dynamics simulation; (2) the laboratory frame ‘‘constant H(S)’’ formulation; (3) the Molecular Frame ‘‘constant H(S)’’ formulation; and (4) the z.f.s.-limit ‘‘constant H(S)’’ formulation. No single theoretical approach describes all important aspects of the relaxation mechanism in a fully satisfactory way. The authors uses the four formulations in a complementary manner to provide as complete a picture of the relaxation mechanism as possible. Metal ion complexes provide flexible paramagnetic centers that may be used to define intermolecular contacts in a variety of solution phase environments because both the charge and electronic relaxation properties of the complex may be varied. For most complex ions, there are several proton equilibria that may change the effective charge on the complex as a function of pH which in turn affects the efficacy of application for defining the electrostatic surfaces of co-solute molecules. Diakova et al.83 reported spectrophotometric and nuclear spin relaxation studies on aqueous solutions of chromium(III) complexes of EDTA, DTPA and bis-arnides of both. Transferring from laboratory frame to off-resonance rotating frame for the 1H spin can compensate the relaxivity loss for paramagnetic agents at the magnetic field strength higher than 3 Tesla and enhance water relaxation rate constant significantly. Zhang and Xie84 described a comprehensive theory for calculating the relaxation rate constants in the off-resonance rotating frame. This theory considers the contributions from both inner shell and outer shell water. The derived relaxation rate constants and relaxation enhancement efficiency as a function of the magnetic field strength and the effective field parameters are directly correlated to the structures, dynamics and environments of paramagnetic agents. To validate the theoretical predictions, the authors have measured the relaxation enhancement efficiency for a series of macromolecule conjugated gadolinium chelates at 9.4 Tesla. The experimental results confirmed the theoretical predictions. The theory also predicts the relaxation enhancement for T-type paramagnetic agents at high magnetic fields. Promising fields of applications include situations where T1- or T2-type paramagnetic agents are used for labeling molecular/cellular events. Teng and Bryant85 utilized the paramagnetic contribution to proton spin–lattice relaxation rate constants induced by freely diffusing charged paramagnetic centers to investigate the effect of charge on the intermolecular exploration of a protein by the small molecule. Priqueler86 described some basic theoretical aspects of 195Pt nuclear magnetic resonance spectroscopy and also the empirical approach used by the Nucl. Magn. Reson., 2007, 36, 170–195 | 179 This journal is

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researchers in the field. 195Pt NMR spectroscopy in the liquid state has been used successfully in many research fields, e.g., the determination of enantiomeric composition and absolute configuration, in the area of biosensors and biomarkers, in cluster chemistry, in cancer research and in kinetic studies. 2.9 Slow motions in glasses Studies of slow molecular motions in supercooled and glassy systems using NMR techniques have become more popular and the number of papers increased steadily during the past few years. In particular the homogeneous versus heterogeneous scenario for the dynamics of glass-forming polymers was discussed intensively. In the heterogeneous scenario the nonexponentiality of the a-relaxation is attributed to a superposition of relaxation rates, whereas in the homogeneous scenario the nonexponentiality is intrinsic in nature. The origin of the nonexponential relaxation found in supercooled liquids has been studied extensively in the past ten years. Two possibilities exist.87,88 Either all the particles undergo nonexponential relaxation (homogeneous scenario), or the relaxation of each particle is exponential and there is a large variation in the relaxation time of the particles (heterogeneous scenario). There have been many simulations89–97 and experiments98–102 which imply heterogeneous relaxation. The heterogeneous relaxation scenario suggests that the particles in a supercooled liquid can be categorized by their relaxation time. The particles with the shortest relaxation times are referred to as ‘‘fast’’ particles, and the particles with the longest relaxation times are ‘‘slow’’ particles. Winterlich et al.103 measured spin– lattice and spin–spin-relaxation times, one- and two-dimensional spectra as well as two- and four-time correlation functions for the molecular crystals ortho- and metacarborane using deuteron nuclear magnetic resonance. It is found that in their noncubic phases these crystals exhibit highly anisotropic motions. In order to allow for a quantitative description of the motional geometry of the carboranes several stochastic models are formulated. By comparison of the model calculations with the experimental results it is found that the dynamics of these quasi-icosahedrally shaped molecules is governed by a composite reorientation process. Somma et al.104 investigated orientation molecular dynamics in a series of ‘‘defectfree’’ oligofluorenes by depolarized dynamic light scattering and dynamic NMR spectroscopy. Typical liquid crystalline pretransitional dynamics were observed upon cooling the isotropic phase to the liquid crystalline phase with strong increase of the scattered intensity and slowing down of the characteristic time of the probed collective relaxation. Kiczenski et al.105 examined the variation of the structure of E-glass with fictive temperature with high resolution, multinuclear (11B, 27Al, 29Si, 17 O and 19F) MAS NMR. The previously observed decrease in 4-coordinated boron with increasing fictive temperature is confirmed and, for the first time, is directly correlated with an increase in non-bridging oxygens. An increase in 5-coordinated Al is also observed. Blinc et al.106 studied the proton motion in bulk and highly drawn fiber polyamide-6 by field cycling relaxometry and proton line shape measurements. The dips in the T, dispersion allowed for the determination of the nitrogen-14 quadrupole coupling tensor. A striking difference in the main line width transition and the low-frequency molecular dynamics has been observed between a slowly cooled ‘‘bulk’’ polyamide-6 sample and a rapidly cooled and highly drawn ‘‘fiber’’ sample by wide line proton nuclear magnetic resonance line shape and spin–lattice relaxation time measurements. Ramanuja et al.107 report the results of 1H NMR spin–lattice relaxation time T1 studies in betaine phosphate. The experiments have been carried out in the temperature range 300 to 4 K, at two Larmor frequencies 11.4 and 23.3 MHz. The T1 data (300–100 K) has been analysed using modified BPP equation based on Ikeda’s model. CH3 protons are found to relax other protons via spin diffusion. Giordani et al.108 measured self-diffusion coefficients for normal and deuterated cholesterol-d6 (C26 and C27 methyl groups deuterated) in 1-octanol, chloroform and 180 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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cyclohexane by varying the impurity water concentration and temperature. The pulsed field gradient spin-echo (PGSE) 1H and 2H NMR were used, respectively, at 600 and 92 MHz. At 30 1C, the hydrodynamic radius obtained from the D value and solvent viscosity is 5.09, 7.07 and 6.17 A˚, respectively, in 1-octanol, chloroform, and cyclohexane when the impurity water is negligible. The aggregate structure is confirmed by comparing NOESY spectra in chloroform and 1-octanol. The NOESY analysis reveals the presence of one extra cross peak (C4–C19) in chloroform compared to 1-octanol. 2.10 Models for molecular dynamics The liquid state of matter is of great importance in nature and technology. Almost all reactions in biological and chemical systems proceed in solution or liquid like environments. Therefore, it is of interest to develop further the existing models and theories for describing the molecular structure and dynamics of liquids. These models and theories should mediate a better understanding, for example, of the arrangement of the molecules relative to each other or of the dynamic behaviour of the molecules and thus of the route of chemical reactions in liquid systems. In recent years NMR spectroscopy has proven extremely useful for the study of macromolecular dynamics. Relaxation rate measurements have opened new avenues to the understanding of internal motions in macromolecules. Thus, measurements of T1 and T2 relaxation times as well as heteronuclear Overhauser effects, rotating frame relaxation, and cross-correlated relaxation experiments have generated a wealth of data for the study of molecular motions, requiring sophisticated models to interpret them. Halle109 presented a molecular theory for the field-dependent spin–lattice relaxation time of water in tissue. The theory attributes the large relaxation enhancement observed at low frequencies to intermediary protons in labile groups or internal water molecules that act as relaxation sinks for the bulk water protons. Exchange of intermediary protons not only transfers magnetization to bulk water protons, it also drives relaxation by a mechanism of exchange-mediated orientational randomization (EMOR). An analytical expression for T, is derived that remains valid outside the motional-narrowing regime. Cross-relaxation between intermediary protons and polymer protons plays an important role, whereas spin diffusion among polymer protons can be neglected. For sufficiently slow exchange, the dispersion midpoint is determined by the local dipolar field rather than by molecular motions, which makes the dispersion frequency insensitive to temperature and system composition. The EMOR model differs fundamentally from previous models that identify collective polymer vibrations or hydration water dynamics as the molecular motion responsible for spin relaxation. Unlike previous models, the EMOR model accounts quantitatively for 1H magnetic relaxation dispersion (MRD) profiles from tissue model systems without invoking unrealistic parameter values. Chavez and Halle110 demonstrated that the EMOR model accounts for the dependence of the water-H spin–lattice relaxation rate on resonance frequency over more than four decades and on pH. The parameter values deduced from analysis of the 1H MRD data are consistent with values derived from 2H MRD profiles from the same gels and with small-molecule reference data. This agreement indicates that the water-1H relaxation dispersion in aqueous biopolymer gels is produced directly by exchange-mediated orientational randomization of internal water molecules or labile biopolymer protons, with little or no role played by collective biopolymer vibrations or coherent spin diffusion. This ubiquitous mechanism is proposed to be the principal source of water-1H spin–lattice relaxation at low magnetic fields in all aqueous systems with rotationally immobile biopolymers, including biological tissue. The same mechanism also contributes to transverse and rotating-frame relaxation and magnetization transfer at high fields. Molecular dynamics (MD) simulations are a convenient tool to follow molecular motion in realistic pure systems and mixtures in detail. Therefore, these simulations Nucl. Magn. Reson., 2007, 36, 170–195 | 181 This journal is

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are frequently used as a basis for designing models describing diffusion.111–126 When developing a model describing intra-diffusion in mixtures based on MD simulations usually a rather large number of simulated conditions is necessary, where the term condition refers to thermodynamic conditions and molecular parameters as well. In the literature such data are unfortunately only scarcely available with all information required. Also the conditions found have been chosen by the authors to give information on the specific questions to be answered in these publications. Thus, the conditions are rarely chosen, such as to give maximum information on parameters of diffusion models. If simulations are usually chosen as basis for parameter estimation the conditions are distributed arbitrarily in a region as large as possible while physically feasible. Since MD simulations are rather time consuming, it is desirable to reduce the number of simulations as much as possible while not sacrificing significance of parameters determined. Based on this model Merzliak et al.127 presented an improved set of coefficients obtained from optimized molecular dynamics simulations. In these simulations, the thermodynamic states were planned with the help of optimal experimental design, which allows to reduce the number of simulations necessary for significant determination of the coefficients by roughly a decade. The model was then applied to the real liquid mixtures toluene/cyclohexane, toluene/1,4-dioxane, n-hexane/toluene, 1,4-dioxane/cyclohexane and cyclohexane/ n-hexane, which have molecular properties that correspond to the model assumptions. Experimental intra-diffusion coefficients for these mixtures were determined with nuclear magnetic resonance (NMR) techniques. Even without additional parameters for the mixture the proposed model can describe the diffusion coefficients with an average accuracy of 5%. Grivet128 studied NMR relaxation parameters of Lennard-Jones fluids from molecular-dynamics simulation. The measured correlation functions were compared with theoretical expressions derived by Ayant129 and by Hwang and Freed.130 Grivet showed that, in order to recover the long-time behaviour characteristic of diffusion-controlled relaxation processes, the simulation must comprise at least 10 000 particles. By fitting the simulation results to the Hwang-Freed function, independent values of the diffusion coefficient were obtained, similar but not identical to those computed using the Green-Kubo formalism. The spectral densities of the dipole–dipole interaction were computed as Fourier transforms of the correlation functions. These quantities are less sensitive to model imperfections and reproduce quite well the values derived from theory. The dimensionless spin– lattice and spin–spin relaxation rates were derived from the spectral densities. It was shown that the spin–lattice (longitudinal) relaxation rate goes through a maximum as the temperature increases, while the spin–spin (transverse) rate decreases monotonously. Estimating the amplitudes and decay rate constants of exponentially decaying signals is an important problem in NMR. Understanding how the uncertainty in the parameter estimates depends on the data acquisition parameters and on the ‘‘true’’ but unknown values of the exponential signal parameters is an important step in designing experiments and determining the amount and quality of the data that must be gathered to make good parameter estimates. Bretthorst131 applied Bayesian probability theory to this problem. Data modelled as sums of exponentials arise in many areas of science and are common in NMR. However, exponential parameter estimation is fundamentally a difficult problem. Bretthorst et al.132 used Bayesian probability theory to obtain optimal exponential parameter estimates. The calculations are implemented using Markov chain Monte Carlo with simulated annealing to draw samples from the joint posterior probability for all of the parameters appearing in the exponential model. Monte Carlo integration is then used to approximate the marginal posterior probabilities for each of the parameters. The authors give numerical examples taken from simulated data and NMR relaxation experiments to illustrate the calculations and the effect of prior information on the parameter estimates. 182 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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3. Selected applications of nuclear spin relaxation 3.1 Pure liquids Singh and Mehrotra133 reported the experimental values of NMR spin–lattice relaxation time T1 and mutual viscosity of p-nitrotoluene, alpha-chlorotoluene, o-toluidine, m-toluidine and p-toluidine. The experimental values of NMR spin– lattice relaxation time T1 and dielectric relaxation time have been correlated with calculated values obtained using various equations of dielectric relaxation time. Singh et al.134 report NMR spin–lattice relaxation times and dielectric relaxation times of alpha-naphthol, beta-naphthol, o-aminophenol, benzyl alcohol, phenol, pyrogallol, catechol and the experimental values of mutual viscosity of o-aminophenol, m-aminophenol and p-aminophenol. Using a combination of density functional calculations of molecular clusters with a quantum cluster equilibrium (QCE) model Ludwig135 showed that liquid methanol is dominated by cyclic and/or lasso structures. Only cluster populations including these structures fit the measured thermodynamic and spectroscopic properties, such as heat of vaporization, heat capacity, NMR chemical shifts, and quadrupole coupling constants. On the other hand, cluster populations comprising open-chain structures fail to reach the experimental values. Korb136 shows that the measurement of nuclear spin–lattice relaxation rates 1/T1 as a function of magnetic field strength or nuclear Larmor frequency allows to probe directly the microdynamics of liquids in confinement. This method was applied to characterize the diffusion of various aprotic liquids as well as water at the surface of nanopores in calibrated systems. 3.2 Non-electrolyte solutions The structure and dynamics of hydrogen-bonded complexes of H2O/D2O and dimethyl sulfoxide (DMSO) have been studied by Wulf and Ludwig137 using infrared spectroscopy, NMR spectroscopy and ab initio calculations. NMR deuteron relaxation rates and calculated deuteron quadrupole coupling constants yield rotational correlation times of water. The molecular reorientation of water monomers in DMSO is two-and-a-half times slower than in bulk water. This result can be explained by local structure behavior. Perrin et al.138 investigated the dynamic behaviour of water within two types of ionomer membranes, Nafion and sulfonated polyimide, by field-cycling nuclear magnetic relaxation. This technique, applied to materials prepared at different hydration levels, allows the proton motion on a time scale of microseconds to be probed. The NMR longitudinal relaxation rate R1 measured over three decades of Larmor angular frequencies omega is particularly sensitive to the host-water interactions and thus well-suited to study fluid dynamics in restricted geometries. Kassab et al.139 present the magnetic-field dependence of the proton and deuteron spin–lattice relaxation rate of water confined in reverse micelles. After a plateau at very low fields, R, decreases as a power law when the Larmor frequency increases. These typical relaxation features have been interpreted according to a model of molecular reorientations coupled with translational diffusion in spherical confinement. A numerical simulation of Brownian dynamics of water molecules confined in a sphere is proposed to support this model. Yamaguchi et al.140 calculated the dynamic properties of both the solute and solvent of the aqueous solution of benzene, xenon and neon by the mode-coupling theory for molecular liquids based on the interaction-site model. The B-coefficients of the reorientational relaxation and the translational diffusion of the solvent are evaluated from their dependence on the concentration of the solute and the reorientational relaxation time of water within the hydration shell is estimated based on the two-state model. The reorientational relaxation times of water in the bulk and within the hydration shell, that of solute and the translational diffusion coefficients of solute and solvent, are calculated at 30 1C. The temperature Nucl. Magn. Reson., 2007, 36, 170–195 | 183 This journal is

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dependence of these dynamic properties is in qualitative agreement with that of NMR experiment reported by Nakahara et al.,141 although the agreement of the absolute values is not so good. The B-coefficients of the reorientational relaxation times for benzene, xenon and neon solution are correlated with the hydration number and the partial molar volume of the solute. Erdem and Michel142 applied proton spin relaxation to study the dynamics of ethylene glycol (EG) adsorbed in NaX, EG/NaX. The molecular mobility strongly depends on the pore filling factor which may be controlled by high-resolution 1H MAS NMR measurements. Although EG in bulk shows a Vogel-Fulcher-Tammann type of activation, temperature dependent relaxation rate measurements for the EG/NaX systems always follow an Arrhenius plot, independent of the loading degree. There is no hint to a glass-forming behaviour of EG/NaX which could be understood in terms of the strong influence of surface–molecule interactions playing a dominant role compared to the molecule–molecule interactions. Madhurima et al.143 compared dielectric relaxation and NMR spin–lattice relaxation times of hydrogen-bonded binary systems. Sanna et al.144 investigated the aggregation properties of two classes of aromatic and hydrophobic compounds, namely chloroacetamides and ethyl 3-phenyl-2-nitropropionates, in moderately concentrated aqueous solution. The identification of all species present in solution under specific experimental conditions was performed by 1D and 2D NMR, pulsed gradient spin-echo NMR, and dynamic light scattering techniques. Some physical-chemical properties of the aqueous solutions were also determined. Both classes of compounds behave quite similarly: in solution, three distinct species, namely a monomeric species, small and mobile aggregates and large and stiff aggregates, are observed. Sinibaldi et al.145 investigated two binary aqueous mixtures which contain the small amphiphilic molecules TMAO (trimethylamine-N-oxide) and TBA (tert-butyl alcohol) by molecular dynamics simulations and NMR chemical shift and selfdiffusion measurements. Langer and Mayer146 measured 31P-NMR spectra on aqueous solutions and gels of phosphorylated polyvinyl alcohol in absence and in presence of dispersed magnetic nanoparticles. In this system, the rotational diffusion is still rapid enough for a sufficient averaging of the CSA tensor of the 31P nucleus. At the same time, the lateral diffusion of the 31P nuclei is significantly reduced. 3.3 Electrolyte solutions Pavlova and Chizhik147 established peculiarities of quadrupolar relaxation in electrolyte solutions via comparison of the data obtained from proton and deuteron resonances. It has been shown that quadrupole coupling constants (QCC) of deuterons depend not only on internal electron structure of molecule or ion, but on solution structure as well. To interpret the experimental results quantumchemical calculations of QCC of deuterons in different molecular complexes simulating different solution substructures were carried out. Hayamizu148 studied polyethylene oxide (PEO) electrolytes doped with lithium salts by the multi-nuclear NMR methods for the glymes of the small molecular weights and the cross-linked solid polymers. The segmental motions of the PEO chain and the lithium hopping motions were analyzed from the spin–lattice relaxation times T1 of the 1H and 7Li NMR. The diffusion phenomena were measured by the pulsed-gradient spin-echo (PGSE) NMR method for the individual components by 1H, 7Li and 19F NMR (anions). When the solvents are liquids, all the components diffuse almost freely in the large temperature range. Silbs and Furo149 discussed the current status of electrophoretic NMR and its applications in the fields of colloid and surfactant science. Kushnarev et al.150 studied water clusters of Na+, K+ and NH4+ ions with Cl and I counterions are studied using 17O NMR spectroscopy. It was found that, in the range of electrolyte concentrations 0.001–5 mol/l, the concentration dependence of the spin–spin relaxation time of oxygen nuclei in water molecules varies widely, depending on 184 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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the nature of the cation. The influence of the electrolyte concentration on the chemical shifts and relaxation times of 17O nuclei is analyzed. 3.4 Ionic liquids and molten salts Ionic Liquids (ILs) present a new class of interesting materials. Giernoth et al.151 developed NMR techniques for investigating ionic liquids. After thorough optimisation, a resolution comparable to classical solvents was achieved. The technique is usable for a wide range of ILs. Observed nuclei are 1H and 13C and potentially 2H and 19F. Measurements of T1 values show multipulse experiments to be feasible. Protonated ionic liquids cause large NMR signals arising from solvent resonances. Ionic liquids (ILs) with long side chains possess signals throughout the spectral range of protons, thus rendering simple solvent signal suppression techniques ineffective. Giernoth and Bankmann152 present solvent signal suppression based on diffusionordered NMR spectroscopy (DOSY). In contrast to the well established usage of DOSY to filter water resonances from biological systems, the authors filtered out the slower moving molecules. This method allows in many cases for the complete removal of the solvent signals from 1H spectra of solutes and may become a useful tool for in situ studies of reactions performed in ILs. Anthony et al.153 applied a new method of obtaining molecular reorientational dynamics from 13C spin–lattice relaxation data of aromatic carbons in viscous solutions to 13C relaxation data of the ionic liquid, 1-methyl-3-nonylimidazolium hexafluorophosphate ([MNIM]PF6). spin–lattice relaxation times are used to determine pseudorotational correlation times for the [MNIM]PF6 ionic liquid. Pseudorotational correlation times are used to calculate corrected maximum NOE factors from a combined isotropic dipolar and nuclear Overhauser effect (NOE) equation. Nama et al.154 reported 1H, 19F-HOESY studies on the ionic liquid based on 1-butyl-3-methylimidazolium tetrafluoroborate, [BMIM]BF4, [BMIM]–[N(OTf)2], and, partially, [BMIM]PF6. The addition of methanol separates the ions. In dichloromethane solution the anions and cations show strong HOESY contacts even after dilution and taken together with the PGSE diffusion measurements, the data suggest strong ion pairing in this solvent. Tokuda et al.155 measured a series of room-temperature ionic liquids (RTILs) were prepared with different cationic structures, 1-butyl-3-methylimidazolium ([bmim]), 1-butylpyridinium ([bpy]), N-butyl-N-methylpyrrolidinium, ([bmpro]) and N-butyl-N,N,N-trimethylammonium ([(n-C4H9)(CH3)3N]) combined with an anion, bis(trifluoromethane sulfonyl) imide ([(CF3SO2)2N]) and the thermal property, density, self-diffusion coefficients of the cation and anion, viscosity and ionic conductivity. The self-diffusion coefficient, viscosity, ionic conductivity and molar conductivity follow the Vogel-FulcherTamman equation for temperature dependencies and the best-fit parameters have been estimated. Mele et al.156 studied the local structure of ionic liquids. Cation– cation NOE interactions and internuclear distances in neat [BMIM][BF4] and [BDMIM]-[BF4] were measured. Tokuda et al.157 explored ion-transport properties of room-temperature ionic liquids (RTILs), N,N-diethyl-N-methoxyethyl-N-methyl ammonium (DEME) with different anions, BF4 and (CF3SO2)2N, as well as their mixed systems with two different organic solvents, propylene carbonate and 1,2-dichloroethane by means of conductometry and pulsed-field-gradient spin-echo (PGSE) NMR diffusivity measurements. Umecky et al.158 determined self-diffusion coefficients of the cation and anion species in 1-butyl-3-methylimidazolium hexafluorophosphate, [BMIM] [PF6], were independently determined over a wide temperature range by observing 1H and 19F nuclei with the pulsed-field gradient spin-echo NMR technique. On the basis of the hydrodynamic model the self-diffusion coefficients of [BMIM][PF6] were discussed in terms of intermolecular interactions. Umecky et al.159 studied the transport properties in a series of 1-alkyl-3-methylimidazolium hexafluorophosphates with the alkyl side chains being butyl, hexyl and octyl, which are expressed by [BMIM][PF6], Nucl. Magn. Reson., 2007, 36, 170–195 | 185 This journal is

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[HMIM][PF6] and [OMIM][PF6], respectively. The self-diffusion coefficients of the cation (D-cation) and anion (D-anion) species in the ionic liquids were independently determined. Based on these experimental results, the effects of alkyl side chain on transport properties in 1-alkyl-3-methylimidazolium hexafluorophosphates were discussed in terms of interionic interactions. Heimer et al.160 applied a new method for obtaining molecular reorientational dynamics from 13C spin–lattice relaxation data of aromatic carbons in viscous solutions is applied to 13C relaxation data of both the cation and anion in the ionic liquid, 1-ethyl-3-methylimidazolium butanesulfonate ([EMIM]BSO3). 13C pseudorotational correlation times are used to calculate corrected maximum NOE factors from a combined isotropic dipolar and nuclear Overhauser effect (NOE) equation. These corrected maximum NOE factors are then used to determine the dipolar relaxation rate part of the total relaxation rate for each aromatic 13C nucleus in the imidazolium ring. Rotational correlation times are compared with viscosity data and indicate several [EMIM]BSO3 phase changes over the temperature range from 278 to 328 K. Modifications of the Stokes-EinsteinDebye (SED) model are used to determine molecular radii for the 1-ethyl-3methylimidazolium cation. Fernandez et al.161 reported 1H, 31P and 7Li pulsedgradient spin-echo (PGSE) diffusion and variable-temperature NMR results for THF solutions of the lithium and potassium salts derived from diphenylphosphino (o-cyanophenyl)aniline. The structures of the products from reactions of these salts with crown ethers are determined via PGSE and 1H Overhauser NMR methods. Zhaia et al.162 studied 1H NMR, 13C NMR and 13C spin–lattice relaxation time T1 of the mixtures of room temperature ionic liquid [OMIM][BF4] and acetone with different proportions. The results indicated that the interaction between the protons of the ring, the methyl and methylene next to the nitrogen of ionic liquids and the carbonyl oxygen of acetone weakened the strong interaction between the cation and anion of the ionic liquid, thus increased the motion and decreased the viscosity of the ionic liquid.

4. Nuclear spin relaxation in gases Gas-phase NMR has great potential as a probe for a variety of interesting physical and biomedical problems that are not amenable to study by water or similar liquid. However, NMR of gases was largely neglected due to the low signal obtained from the thermally polarized gases with very low sample density. The advent pf optical pumping techniques for enhancing polarization of the noble gas 3He and 129Xe has bought new life in this field, especially in medical imaging where 3He lung inhalation imaging is approaching a clinical application. However, there are numerous applications in materials science that also benefit from the uses of these gases. While MRI at very low magnetic fields has certain potential advantages, it may also face problems that are not typical for MRI at conventional and high field (0.1–10 T). Major differences arise due to the presence of concomitant components of inhomogeneous magnetic field (gradients) that are transverse to the major Bz field, B0. These concomitant transverse field components are inevitably generated by the same gradient coils that generate desired B, imaging gradients as routinely used in MRI for spatial encoding. In the hypothetical case (linear spatial variation of B field amplitude due to the imaging gradients, no concomitant transverse field components, no B0 and B, field inhomogeneities, etc.), Fourier transform MRI preserves the shape of the real object being examined. In certain systems, the application of resonant optical fields may be used to enhance the nuclear spin polarization by several orders of magnitude. Such large, non-equilibrium enhancements can translate directly into dramatic improvements in NMR detection sensitivity and thus offer a variety of novel experimental possibilities. Goodson163 described the development of optically enhanced NMR and MRI, spanning applicable systems that include noble gases, semiconductors and molecular and ionic crystals, as well as the exploitation of photo-initiated radical pairs in 186 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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solution and biological solids. Realized and potential NMR applications include void-space imaging of materials and living organisms; probing structure and dynamics in proteins and inclusion complexes. Ishikawa et al.164 measured the spin relaxation of polarized xenon atoms dissolved in deuterated ethanol. Surface relaxation was suppressed by coating the cell walls with deuterated eicosane. From the dependence of the decay rate on temperature and static magnetic field, we obtained the correlation time of random fluctuations of the local field at the liquidsolid interface. By varying the cell volume, the wall coating and the surface area of the eicosane, we measured the contribution of the spin–rotation interaction to the relaxation. Stupic et al.165 report the first systematic study of relaxation experienced by the hyperpolarized noble gas isotope 83Kr (I = 9/2) in contact with surfaces. The spin– lattice relaxation of 83Kr is found to depend strongly on the chemical composition of the surfaces in the vicinity of the gas. This effect is caused by quadrupolar interactions during brief periods of surface adsorption that are the dominating source of longitudinal spin relaxation in the 83Kr atoms. Simple model systems of closest packed glass beads with uniform but variable bead sizes are used for the relaxation measurements. The observed relaxation rates depend strongly on the chemical treatment of the glass surfaces and on the surface to volume ratio. Lung functional magnetic resonance imaging (MRI) has become a reality using different inert hyperpolarized gases, such as 3He and 129Xe, which have provided an extraordinary boost in lung imaging and has also attracted interest to other chemically inert gaseous contrast agents. Ruiz-Cabello et al.166 demonstrated the first diffusion-weighted images using thermally polarized inhaled sulfur hexafluoride (SF6) in small animals. The aim of this study was to evaluate whether or not the diffusion coefficient of this fluorinated gas is sensitive to pulmonary structure, gas concentration and air pressure in the airways. Chang and Conradi167 report measurements of free diffusivity D and relaxation times T1 and T2 for pure C2F6 and C3F8 and their mixtures with oxygen. A simplified relaxation theory is presented and used to fit the data. The results enable spatially localized relaxation time measurements to determine the local gas concentration in lung MR images, so the free diffusivity D0 is then known. Comparison of the measured diffusion to D0 will express the extent of diffusion restriction and allow the local surface-to-volume ratio to be found. Kuethe et al.168 studied the physics of spin–rotation interaction in roughly spherical perfluorinated gas molecules. Given a pressure, temperature and mixture composition, they could calculate T1 for common laboratory conditions with a known accuracy, typically 0.5%. The model’s formulaic structure is likely to apply to even broader ranges of physical conditions and to other gases that relax by spin–rotation interaction. Ter Horst et al.169 measured spin–lattice relaxation times for the deuterons in CD4 in pure gas and in mixtures with the following buffer gases: Ar, Kr, Xe, HCl, N2, CO, CO2, CF4 and SF6. Effective collision cross sections for the molecular reorientation of CD4 in collisions with these ten molecules are obtained as a function of temperature. The authors compared these cross sections with the corresponding cross sections obtained from 1H spin–rotation relaxation in mixtures of CH4 with the same set of buffer gases. Various classical reorientation models typically applied in liquids predict different ratios of the reduced correlation times for the reorientation of spherical tops. Terekhov et al.170 investigated the effects of embedding gaseous SF6 into EPDM rubber using NMR methods. It was found that observed sorption and desorption processes follow the behaviour of the dual mode sorption model. A strong correlation was found between EPDM cross-linking and transversal relaxation time of embedded SF6. First experiments on probing the swelling effects in EPDM due to its contact with polar liquids have been performed. Baker and Conradi171 described an apparatus for hydrogen NMR in an electromagnet for temperatures up to 1300 K and pressures to 55 atm. A crucial feature for studies of transition-metal hydrides and complex hydrides of light metals is the Nucl. Magn. Reson., 2007, 36, 170–195 | 187 This journal is

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ability to add or remove hydrogen or other gases at operating conditions, enabling in situ NMR. The sample is held in a long, closed-end ceramic tube; the tube is supported against rupture by a greater external pressure of argon gas. Knagge et al.172 monitored the substrate and field dependencies of surface SPINOE enhancements using optical pumping and magic angle spinning. Relaxation rates and enhancements were examined to gain an understanding of the parameters that determine the SPINOE enhancement. NMR of some nuclei (e.g. 1H, 13C, 19F, 29Si or 31 P, I = 1/2) gives strong signals which allow analytical studies of gaseous compounds. The other magnetic nuclei have low natural abundance or/and contain an electric quadrupole moment and their NMR signals are rather weak. Jackowski173 presents new experimental techniques which allow the detection of small amounts of chemical compounds in gaseous matrices.

5. Self-diffusion in liquids 5.1 Experimental and theoretical aspects Measurement of molecular diffusion coefficients in solution by nuclear magnetic resonance (NMR) was first introduced by Stejskal and Tanner in 1965174 where a theoretical foundation was also laid down. Since then, this method has evolved into a number of versions for different purposes.175–177 In particular, it was extended significantly by Johnson et al.178,179 to multidimensional NMR, where the diffusion coefficient serves as a new dimension of various NMR spectra to distinguish the molecules of different sizes or diffusion coefficients. Due to the non-uniform PFG and RF fields across the sample, considerable deviation may occur when comparing diffusion data obtained from different NMR instruments. Some efforts have been made to reduce the errors180–182 and are effective under certain conditions. Zhang183 described a new approach is described with an offset-independent adiabatic inversion pulse184,185 to uniformly excite a central region of the sample, where the RF field is assumed to be uniform and the PFG strength can be expressed by a linear approximation. Experimental studies of the unrestricted translational diffusion coefficient of molecules in a liquid provide information1186–188 about the organization of their immediate environment and a way to test the models of intermolecular forces and the theories of transport. In porous media and biological tissues, the translational diffusion coefficient is important to correlate the long-range apparent diffusion189–191 of the molecules explored by pulsed gradient spin-echo (PGSE) NMR with their interactions with the fluid/matrix interfaces and/or macromolecules in a crowded environment. Melchior and Fries192 proposed a simple method to measure the relative diffusion coefficient of a pair of small molecules at the nanometer scale. Rata et al.193 discussed a simple and fast method of measuring self-diffusion coefficients of protonated systems with a mobile single-sided NMR sensor. The NMR sensor uses a magnet geometry that generates a highly flat sensitive volume where a strong and highly uniform static magnetic field gradient is defined. Selfdiffusion coefficients were measured by Hahn- and stimulated echoes detected in the presence of the uniform magnetic field gradient of the static field. To improve the sensitivity of these experiments, a Carr-Purcell-Meiboom-Gill pulse sequence was applied after the main diffusion-encoding period. Bedet et al.194 addressed the problem of measuring accurately and as quickly as possible a self-diffusion coefficient by the so-called pulsed gradient stimulated echo experiment or, equivalently, by using a sequence involving radio-frequency field gradients. The discussion deals with the smallest diffusion coefficient which can be measured with a reasonable accuracy, possibly taking into account the values of longitudinal and transverse relaxation times along with the nature of gradients. It is shown theoretically and experimentally that the diffusion coefficient can be measured accurately via only two experiments provided that the ratio of the signal amplitudes lies in the range 0.2–0.6. Oscillating188 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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gradient spin echo (OGSE) diffusion experiments have long been used to measure the short-time apparent diffusion coefficient in the presence of restricted diffusion, as well as the spectrum of the slow-motion velocity autocorrelation function. Momot et al.195 focused on two previously unexplored aspects of OGSE experiments: convection compensation and acquisition of pure-phase diffusion spectra in the presence of homonuclear scalar couplings. The authors demonstrated that convection compensation afforded by single-echo OGSE compares well with that in doubleecho convection-compensated PGSE experiments. Mohoric196 showed that with a proper timing of p pulses, it is possible to reduce the effect of the static internal magnetic field gradient on the measurement of diffusion with the pulsed gradient spin echo (PGSE). The author introduced a pulse sequence that in the first order eliminates the effect of weak internal static gradients in a standard PGSE experiment. The method should be applied in the cases, where strong and short magnetic gradient pulses are used to investigate the motion of liquid in heterogeneous samples with large susceptibility differences such as porous media. Signal overlap in the NMR dimension significantly complicates the construction and analysis of 2D diffusion-ordered (DOSY) spectra. Such problems can often be reduced or even eliminated by extending the NMR domain of a DOSY experiment into two dimensions, giving a 3D-DOSY spectrum. To date such experiments have generally sacrificed some signal-to-noise ratio and have C required extensive and time-consuming phase cycling. Nilsson and Morris197 introduced a new family or pulse sequences with internal diffusion encoding (IDOSY) which avoids both of these problems. It is often straightforward to incorporate convection compensation in such sequences at no cost in signal-to-noise ratio. Many practical applications of diffusion NMR, ranging from biomedical to industrial, entail the measurement of low-concentration solutes in nondeuterated, compositionally complex systems. Momot and Kuchel198 presented examples of robust, versatile diffusion experiments that can be used with nondeuterated solvents at nonambient temperatures. Specifically, three experiments are presented in detail: CONVEX, which combines excitation-sculpting solvent suppression with doubleecho convection-compensating PGSE; DQDiff, which implements double-quantum filtered diffusion measurements in a convection-compensating mode; and applications of oscillating-gradient spin-echo (OGSE) to systems with homonuclear scalar couplings. Lutti and Callaghan199 demonstrated a method whereby molecular diffusion coefficients may be measured in the presence of the deformational flow field of a rheo-NMR cell. The method, which uses a repetitive CPMG train of r.f. pulses interspersed with magnetic field gradient pulses, allows the anisotropic diffusion spectrum to be directly probed. The authors focus on the cylindrical Couette cell, for which the radial, tangential and axial directions correspond to the hydrodynamic velocity gradient, velocity and vorticity directions. Antalek200 discussed the importance of spin relaxation in quantitative pulse gradient spin echo NMR mixture analysis. Kato et al.201 measured diffusion coefficients for various solvent molecules using the PFG-NMR method. Accurate diffusion coefficients were obtained using the Shigemi NMR tube. The relative combined standard uncertainties of the diffusion coefficients were found to be within approximately 0.4%. The three uncertainty sources (signal decay of the standard and the solvent and diffusion coefficient of standard) equally affect the combined standard uncertainties. Unreliable data were obtained using a normal NMR tube, indicating that convection and background gradient effects significantly affected the accurate measurement of the diffusion coefficients. Tillich et al.202 introduced a new NMR method which allows within local small volumes the determination of integral structural parameters like the surface-to-pore volume ratio or the tortuosity of a fluid-filled porous medium. A combination of conventional imaging (MRI) with measurements of observation-time dependent self-diffusion (dynamic imaging) was used. Nucl. Magn. Reson., 2007, 36, 170–195 | 189 This journal is

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The standard method of diffusion tensor imaging (DTI) involves one diffusionsensitizing gradient direction per acquired signal. Sigmund and Song203 described an alternative method in which the entire direction set required for calculating the diffusion tenser is captured in a few scans. In this method, a series of radiofrequency (RF) pulses are applied, resulting in a train of spin echoes. A pattern of applied magnetic field gradients between the RF pulses generates a different diffusion weighting in both magnitude and direction for each echo, resulting in a dataset sufficient to determine the tenser. This significantly reduces the time required for a full DTI scan and potentially allows a tradeoff of this time for image quality. 5.2 Selected examples Van der Elst et al.204 determined the self-diffusion coefficients of various lanthanum(III) diamagnetic analogues of open-chain and macrocyclic complexes of gadolinium used as MRI contrast agents were determined in dilute aqueous solutions by pulsed-field-gradient (PFG) high-resolution 1H-NMR spectroscopy. The self-diffusion coefficient of H2O was obtained for the same samples to derive the relative diffusion constant, a parameter involved in the outersphere paramagnetic-relaxation mechanism. Thureau et al.205 measured NMR diffusion and nuclear Overhauser enhancement to study the hydration properties of thymine. Thureau et al.206 used DOSY-NMR experiments were used to characterize two structural isomers that have different shapes, but identical moss fragmentation patterns, from an organic mixture. It is shown that the spherical molecule diffuses faster than the ellipsoidal one. This distinct behaviour is tentatively explained in terms of microfriction effects from the solvent. Mayer207 discussed experimental approaches for the application of NMR spectroscopy to dispersed nanoparticles. A general numeric approach for the analysis of the obtained data is introduced which accounts for rotational and lateral diffusion of the particles in a fluid medium. The applicability of the NMR experiments together with the numerical analysis of the resulting spectra is demonstrated on various examples which cover the particle structure, phase transitions, decomposition, pathways, molecular exchange at phase boundaries and release processes. Shimada et al.208 measured diffusion coefficients for separated uniform poly (ethylene glycol) oligomers in dilute solutions of deuterium oxide (D2O) at 30 1C, using pulsed-field gradient nuclear magnetic resonance. The measured D for each molecular weight was extrapolated to infinite dilution. Diffusion coefficients obtained at infinite dilution follow the scaling behavior of Zimm-type diffusion, even in the lower molecular weight range. The transverse relaxation rate R2 of many biological tissues are altered by endogenous magnetized particles and may be sensitive to the pathological progression of neurodegenerative disorders associated with altered brain-iron stores. Nikolova et al.209 validated a T2r transverse relaxation model using Carr-Purcell-Meiboom-Gill (CPMG). Galvosas and Callaghan210 demonstrated the use of NMR velocity imaging techniques to measure flow in a free falling jet of water at speeds up to and on the order of 1 m/s. In particular, they show how to adapt the RARE imaging method, based on a CPMG multiple r.f. pulse train, so that the real and imaginary parts of the signal may be suitably acquired, enabling pulsed gradient spin echo encoding for flow. Volkov and Volkov211 applied pulsed field gradient nuclear magnetic resonance technique to investigate the selfdiffusion mechanism of water, alcohol molecules and Li+ counterions in sulfocation exchangers with different structures of the polymeric matrix. It could be shown that in the homogeneous perfluorinated sulfocation exchange membranes the ionic and water translation motions are controlled by the hydrogen bond network forming in ionogenic channels at the high water content. At the low solvent content, the selfdiffusion coefficients of methanol and ethanol are higher than the water self-diffusion coefficients. 190 | Nucl. Magn. Reson., 2007, 36, 170–195 This journal is

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Solid-state NMR spectroscopy A. E. Alieva and R. V. Lawb DOI: 10.1039/b618332h

1

Introduction

The aim of our contribution is to outline important recent advances and applications achieved in the area of solid-state NMR based on the literature published between July 2005 and June 2006. Large number of papers making use of solid-state NMR techniques has been published during this period, however, only some of these have been included in this report. Specifically, over 600 references that include solid-state NMR and related terms in the title were initially retrieved for the preparation of this report, and approximately half of these were included in the final report. In choosing sources for this report we have aimed at highlighting publications that uses solidstate NMR as the only or the primary technique for structural and/or dynamics studies of solid materials as well as those that have applied the technique in an innovative manner. In selecting references, we have also aimed at illustrating diversity of problems and subject areas covered by modern solid-state NMR applications. The format used in this report is similar to that used in the previous years. The following section of the report includes review articles (Section 2) on both general and specific aspects of solid-state NMR spectroscopy and its applications. Publications about recent experimental developments and novel applications that are of general methodological interest are arranged in sections 3–5. With regard to experimental aspects (Section 3), the high resolution achieved in proton solid-state NMR spectra at high levels of deuteration has attracted considerable attention.25,26 Other remarkable developments include: efficient through-bond 1H–13C INEPT,40 significant NOEs in 11B{1H} experiments,41 MAS NMR of 33S and 35/37Cl,46,47 considerable RF heating of samples in the presence of water53,54 and new software for simulations of NMR experiments.58 In addition, the number of publications describing solid-state 17O NMR technique developments and its applications (Sections 3, 5 and 6) has increased compared to previous years. In respect to distance and structure determinations (Section 4), some interesting examples include highly accurate measurements of 13C–15N distances (0.002 A˚)71 and zeolite crystal structure solutions.75 As in previous years, DFT calculations of NMR parameters remain very popular (Section 5). Various examples of solid-state NMR applications are collected in the final Section 6. This section is divided into 16 subsections depending on the type of the material studied. Sections 1–6.5 and 6.6–6.16 have been prepared by A. E. Aliev and R. V. Law, respectively.

2

Reviews

Some new developments and applications in the field of NMR of solids appearing in the literature between 2003 and 2005 have been reviewed by Dybowski and Bai.1 Reviews section highlights important new articles published in the recent years. Other sections of this review include new NMR technique and instrumentation developments, as well as applications of solid-state NMR techniques to study a

Department of Chemistry, University College London, 20 Gordon Street, London, UK WC1H OAJ b Department of Chemistry, Imperial College of Science and Technology, London, UK SW7 2AY


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inorganic solids, semiconductors and solid ionic conductors, glasses, polymers and biological materials. A short review titled ‘‘Solid-state NMR spectroscopy: molecular structure and organisation at the atomic level’’ has been published by Baldus.2 This review highlights some new techniques aimed at assembling complete three-dimensional molecular structures from solid-state NMR data using a single sample or a small number of compounds under MAS conditions. Selected techniques considered include chemical shift selective pulse schemes and the direct or indirect detection of proton-proton interactions. This review has also focused on the recent studies of amyloid fibril structures using high-resolution solid-state NMR and other techniques. Specific applications of NMR to the study of polymorphs and related forms (such as solvates) of organic and pharmaceutical compounds have been reviewed by Harris.3 The nature of the systems covered and the solid-state NMR techniques used are briefly introduced. The methodologies involved are reviewed under a number of different headings, ranging from spectral editing through relaxation times to shielding tensors and NMR crystallography. In each case the relevant applications are described. A special section in this review discusses studies of solvates (especially hydrates), and another reviews quantitative analysis. A brief description of the REDOR and REAPDOR experiments that are suitable for (I = 1/2, S 4 1/2) spin pairs has been provided by Gullion and Vega in their review article.4 Both REDOR and REAPDOR provide the opportunity to measure dipolar couplings accurately and provide internuclear separations with minimal effort. The main focus of the article is to present the conditions for which the dipolar evolution of each of these two experiments is described by universal dipolar dephasing curves, which depend only on the dipolar coupling and are independent of the quadrupolar interaction and relative orientation between dipolar and quadrupolar tensors. Applications of optical pumping and polarisation techniques in NMR have been reviewed by Goodson.5 In general, the application of resonant optical fields may be used to enhance the nuclear spin polarisation by several orders of magnitude in certain systems. Such large, non-equilibrium enhancements can translate directly into dramatic improvements in NMR detection sensitivity, and thus offer a variety of novel experimental possibilities. The article by Goodson considers the principles and practice of optical nuclear polarisation (ONP) in organic molecular crystals. Work over the 35-year history of ONP-enhanced NMR is reviewed, with particular emphasis on recent developments including: the use of field-ramping in ONP experiments; microwave- and RF-driven ONP; enhanced high-resolution NMR of single crystals; the observation of high 1H polarisation; and ONP in polycrystalline substances. The review concludes with a brief discussion of future possibilities provided by ONP, including the expansion of such approaches to other (e.g., biological) systems. An overview of 195Pt NMR has been presented by Priqueler et al.6 This brief, nonexhaustive review describes some basic theoretical aspects of 195Pt NMR spectroscopy and also the empirical approach used by the researchers in the field. The different factors which influence the 195Pt chemical shifts are discussed. It is shown that while liquid-state 195Pt NMR spectroscopy encompasses a wide range of areas, the parallel solid-state technique has only been employed over the past few years, mainly in studies of heterogeneous catalysis and is more industrially oriented. A thorough review of 35/37Cl, 79/81Br and 127I solid-state NMR data is presented by Bryce and Sward.7 Isotropic chemical shifts, quadrupolar coupling constants and other available information on the magnitude and orientation of the chemical shift and electric field gradient tensors for chlorine, bromine and iodine in diverse chemical compounds is tabulated on the basis of over 200 references. Special emphasis is placed on the information available from the study of powdered diamagnetic solids in high magnetic fields. The survey provided by the authors Nucl. Magn. Reson., 2007, 36, 196–243 | 197 This journal is

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indicates a recent notable increase in the number of applications of solid-state quadrupolar halogen NMR, particularly 35Cl NMR, as high magnetic fields have become more widely available to solid-state NMR spectroscopists. Possible future directions for research involving 35/37Cl, 79/81Br and 127I solid-state NMR spectroscopy are also discussed. Ashbrook and Duer have reviewed various aspects of structural information available from solid-state NMR of quadrupolar nuclei.8 Briefly, this review assesses what is currently possible, from achieving high-resolution spectra for quadrupolar nuclei, to forming correlation spectra which give qualitative details of spatial proximity of nuclei and the determination of internuclear distances between quadrupolar-quadrupolar and quadrupolar-spin-1/2 nuclei. Examples are given of each technique discussed and the advantages and disadvantages of the various experiments for different possible applications are assessed. Three population transfer techniques for improving the sensitivity of the central transition of NMR spectra from half-integer quadrupolar nuclei in the solid-state have been described by Siegel et al.9 Two of the methods considered are intended for inverting the populations of energy levels associated with the satellite transitions either by employing double frequency sweeps or hyperbolic secant pulses. The third method, rotor-assisted population transfer, is designed to saturate the satellite transitions. The effect of various experimental parameters on the resulting sensitivity enhancement is also discussed. Studies of dynamic processes in organic solids by NMR (up to 2003) have been reviewed by Reichert.10 This article covers the major experimental methods and briefly comments on their applications in a variety of materials. Merging concepts from liquid- and solid-state NMR spectroscopy for the investigation of supra- and biomolecular systems have been reviewed by Schnell.11 New NMR methods and experiments developed recently are considered in this review. A possibility of using recoupling techniques in HRMAS studies is also considered. Hughes and Baldus have reviewed the topic of polypeptide structure elucidation using solid-state MAS NMR.12 They discuss various aspects of sample preparation and recent progress in establishing high-resolution conditions for MAS-based structural studies. In addition, approaches for obtaining structural parameters in multiply or uniformly labelled polypeptides are reviewed and recent applications to globular membrane-associated proteins are summarised. Exchange NMR spectroscopy in solids and its applications to large-scale conformational studies in biopolymers have been reviewed by Krushelnitsky.13 In general, the exchange NMR experiment compares resonant frequencies of a magnetic nucleus before and after the so-called mixing time, thereby gaining information about molecular dynamics on millisecond and second time scales. In this review, major methodological advances in the field are examined and various applications of exchange NMR experiments to conformational dynamics in solid biopolymers are described. In another related article, Krushelnitsky and Reichert provide a survey of solidstate NMR techniques and their applications for protein dynamics studies.14 The most important techniques used in solid-state NMR studies of protein dynamics and their comparison with each other as well as with their solution NMR counterparts are presented. Some of the most significant results obtained with the help of solidstate NMR methods are also described. Finally, the main methodological problems and possible solutions are also outlined. Structural and dynamic studies of proteins by high-resolution solid-state NMR have been reviewed by Bockmann.15 The recent progress made in resonances assignments, structure and dynamics determination, as well as the detection of protein interaction partners by solid-state NMR methods have been discussed.


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Structural models for amyloid fibrils built using information from a wide variety of techniques, including XRD, electron microscopy, solid-state NMR and EPR have been reviewd by Makin and Serpell.16 They describe and compare postulated structural models for the mature amyloid fibril and discuss how the ordered structure of amyloid contributes to its stability. The knowledge of the structure of these fibrils is essential for understanding the process of pathology of the amyloidoses (Alzheimer’s disease and Creutzfeldt-Jakob disease) and for the rational design of drugs to inhibit or reverse amyloid formation. In another article on the subject of amyloid structure, Tycko reviews the newly developed solid-state NMR techniques.17 In this article, essential aspects of solidstate NMR methods are described briefly and new results regarding the supramolecular organisation of amyloid fibrils and the conformations of peptides within amyloid fibrils are reviewed. Current applications of bicelles in NMR studies of membrane-associated amphiphiles and proteins have been surveyed by Prosser et al.18 This review article covers current trends in studies of membrane amphiphiles and membrane proteins using both fast tumbling bicelles and magnetically aligned bicelle media for both solution and solid-state NMR. The fast tumbling bicelles provide a versatile biologically mimetic membrane model, which in many cases is preferable to micelles, both because of the range of lipids and amphiphiles that may be combined and because radius of curvature effects and strain effects common with micelles may be avoided. It is shown that drug and small molecule binding and partitioning studies may benefit from their application in fast tumbling bicelles, tailored to mimic specific membranes. Solid-state NMR studies of polytopic transmembrane proteins are also reviewed. Solid-state NMR applications in drug design have been reviewed by Watts.19 It is shown that observation of drugs and ligands at their site of action in membrane proteins is now possible through the use of solid-state NMR, with structural details being resolved at a sub-nanometre level. These solid-state NMR results can be further supplemented by detailed dynamic and electronic information about the surrounding ligand environment and provide surprising new insights into ligand binding useful for drug design. Monitoring fluoropyrimidine metabolism in solid tumors with in vivo 19F NMR spectroscopy has been reviewed by van Laarhoven et al.20 The technique considered offers unique possibilities for monitoring the pharmacokinetics of fluoropyrimidines in vivo in tumors and normal tissue in a non-invasive way, both in animals and in patients. It is shown that the recent introduction of clinical MR scanners with magnetic fields above 1.5 T may stimulate increased clinical use of 19F NMR. Motional phase disorder of polymer chains as crystallized to hexagonal lattices has been reviewed by Sozzani et al.21 Several examples using multinuclear solid-state NMR techniques have been surveyed, where motion is induced by high temperature and pressure or favored by inclusion of moderate amounts of comonomer units in the main chain and by the use of monomers containing mobile side chains. Molecular dynamics studies in solid polymers by NMR have been reviewed in the article by DeAzevedo et al.22 Some of the advanced NMR methods and their applications for studying molecular dynamics are discussed. These, however, do not include NMR relaxation methods. The main focus of this article is on the NMR methods suitable for molecular dynamics studies of synthetic polymers. Recent NMR studies of nanoparticles have been surveyed by Mayer.23 Different experimental approaches for the application of NMR spectroscopy to dispersed nanoparticles are summarised and briefly discussed regarding their specific advantages and disadvantages. A general numerical approach for the analysis of the obtained data is introduced which accounts for rotational and lateral diffusion of the particles in a fluid medium. The applicability of the NMR experiments together with the numerical analysis of the resulting spectra is demonstrated on various examples, Nucl. Magn. Reson., 2007, 36, 196–243 | 199 This journal is

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which cover the particle structure, phase transitions, decomposition pathways, molecular exchange at phase boundaries and other processes. Finally, some of the applications of 13C, 29Si and 31P solid-state NMR techniques in the area of catalysis have been reviewed by Blu¨mel.24

3. Experimental developments 3.1 Proton NMR A systematic study of proton line widths in rigid solids as a function of sample spinning frequency and proton density, with the latter controlled by the ratio of protonated and perdeuterated model compounds, has been described.25 It is shown that the line width correlates more closely with the overall proton density than the size of local clusters of 1H spins. At relatively high MAS rates, the line width is shown to be dependent linearly upon the inverse MAS rate. In the limit of infinite spinning rate and/or zero proton concentration, the line width extrapolates to a nonzero value, owing to contributions from scalar couplings, chemical shift dispersion and B0 field inhomogeneity. At up to 30% protonation levels, proton detection experiments are demonstrated to have a substantial (2- to 3-fold) sensitivity gain over corresponding 13C-detected experiments. The use of dilute protons for polarisation transfer to and from low-gamma spins within 5 A˚ has been demonstrated. Ultrahigh resolution achieved in proton solid-state NMR spectroscopy at high levels of deuteration has been presented by Chevelkov et al.26 It is shown that a 1H line width on the order of 17–35 Hz can be achieved at moderate spinning frequencies (8–24 kHz) without application of homonuclear decoupling. The experiments were carried out using a perdeuterated 15N-enriched microcrystalline sample of the SH3 domain from chicken a-spectrin. 1 H NMR spectra of the methyl group in an oriented crystal sample of methylmalonic acid with all three non-methyl protons replaced by deuterons have been interpreted in terms of the damped quantum rotation (DQR) theory of NMR line shapes.27 In general, the DQR approach offers a theoretical reproduction of the observed spectra while the conventional Alexander-Binsch line-shape model shows evident defects in the present case. The temperature trends of the quantities characterizing the coherent and incoherent dynamics of the methyl group in the DQR approach derived from the spectra are fairly reproduced using a model reported previously. The reported findings provide further evidence of limitations to the validity of the common belief that molecular rate processes in condensed phases are necessarily classical. 3.2 Decoupling and recoupling SPINAL modulated decoupling scheme in high field double- and triple-resonance solid-state NMR experiments on stationary samples has been described.28 CW irradiation has been shown to have limited bandwidth for heteronuclear 1H decoupling at high fields and for 13C decoupling in 1H/13C/15N-triple-resonance experiments. The new decoupling technique is used to improve the efficiency of 1H and 13C heteronuclear decoupling on single crystals of peptides and magnetically aligned samples of membrane proteins in bicelles. The latter is of particular importance since aqueous samples of biomolecules are lossy at high fields, which further limits the strengths of the RF fields that can be applied. Novel low-power pulse sequences for homonuclear dipolar recoupling in biological solid-state NMR spectroscopy have been presented.29 The pulse sequences are developed numerically using the SIMPSON simulation program in combination with optimal control procedures. The new dipolar recoupling methods are demonstrated numerically and experimentally by double quantum filtration MAS NMR experiments for which sensitivity gains approaching a factor of 2 is observed. 200 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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A unified bimodal Floquet description of decoupling and recoupling using CW irradiation in solid-state MAS NMR has been presented by Ernst et al.30 The theoretical treatment used by the authors leads to a time-independent effective Hamiltonian in Hilbert space and can be looked at as a generalisation of average Hamiltonian theory to several incommensurate time dependencies. As a prototype experiment the application of CW RF irradiation in combination with MAS is considered. It is shown that perturbations up to the third order must be taken into account to explain all experimentally observed resonance conditions. The influence of CW heteronuclear decoupling on symmetry-based double quantum homonuclear dipolar recoupling, using experimental measurements, numerical simulations and average Hamiltonian theory has been examined.31 It has been shown that there are two distinct regimes in which the heteronuclear interference effects are minimized. The first regime utilizes a moderate homonuclear recoupling field and a strong heteronuclear decoupling field, whereas the second regime utilizes a strong homonuclear recoupling field and a weak or absent heteronuclear decoupling field. The second regime is experimentally accessible at moderate or high MAS frequencies and is particularly relevant for many applications of solidstate NMR recoupling experiments to organic or biological materials. An approach to design modulated RF sequences under sample spinning which decouple/recouple a specific nuclear-spin interaction in solid-state NMR has been presented.32 In the new approach the Euler angles of the spin rotation caused by a general RF field are forced to fulfill the symmetry principle theory for selecting an interaction of interest. Then, modulated RF sequences are directly obtained from the Euler angles with a large degree of freedom. As an example of this approach, an amplitude- and phase-modulated RF sequence to recouple chemical shift anisotropy (CSA) is developed, which is robust with respect to RF inhomogeneity. Two-dimensional experiments with this RF sequence under on- and off-MAS provide 1D and 2D powder patterns, respectively. The latter enables determination of the CSA principal values more accurately, even for overlapped signals in MAS spectra. The effectiveness of this modulated RF sequence is experimentally demonstrated on [15N]-N-acetyl-D,Lalanine for determination of the 15N and 13CO CSA principal values. A comparison of three different implementations of the chemical shift recoupling experiment of Tycko et at. [J. Magn. Reson., 1989, 85, 265–274] has been presented.33 An optimised and constant time implementations are shown to give welldefined and artefact-free powder pattern line shapes in the indirectly observed dimension for both sp2 and sp3 carbon sites. Experimental setup has been shown to be no more demanding than for the original experiment and can be implemented using standard commercial hardware. A new approach to frequency-selective homonuclear dipolar recoupling in solidstate MAS NMR has been presented.34 This approach, referred to as SEASHORE, employs alternating periods of double quantum recoupling and chemical shift evolution to produce phase modulations of the recoupled dipole-dipole interactions that average out undesired interactions, leaving only dipole-dipole couplings between nuclear spins with a selected pair of NMR frequencies. It is shown that SEASHORE is in principle applicable to systems with arbitrary coupling strengths and arbitrary sets of NMR frequencies. Arbitrary MAS frequencies are also possible, subject only to restrictions imposed by the pulse sequence chosen for double quantum recoupling. The efficacy of SEASHORE has been demonstrated in experimental 13C NMR measurements of uniformly 15N, 13C-labelled L-valine powder and in amyloid fibrils formed by a synthetic decapeptide containing uniformly 15N,13C-labelled residues. 3.3 Cross polarisation and polarisation transfer A recently proposed experimental scheme for achieving uniform CP enhancement of low-gamma nuclear species in solids under MAS conditions, termed quantitative Nucl. Magn. Reson., 2007, 36, 196–243 | 201 This journal is

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cross polarisation (QUCP), has been described using comprehensive theoretical analysis, numerical simulation and experimental investigation with both uniformly labelled and naturally abundant solids.35 This method combines CP with dipolarassisted rotational resonance (DARR) broadband homonuclear recoupling technique to achieve quantitative CP spectra under fast MAS. In addition to the previously reported interpretation, a number of general guidelines for performing QUCP experiments are presented in this work. It is established that while the enhancement factor in QUCP depends on the CP contact time, uniform enhancement can nevertheless be realized for all types of carbons. For natural abundance samples, the polarisation transfer rate was found to be slower than that in labelled samples. Various representative systems, including uniformly 13C-labelled DL-alanine and 13C, 15 N-labelled L-tyrosine, as well as naturally abundant alanine, tyrosine and monoethyl fumarate, were used to verify the validity of the theoretical analysis. The method of integrated cross polarisation utilized for electron-to-nucleus polarisation transfer has been applied to nucleus-to-nucleus polarisation transfer.36 Instead of using a p/2 pulse followed by a p/2 phase-shifted locking pulse like in the conventional CP, irradiation with a single phase is applied together with adiabatic frequency sweep. This is shown to be useful for locking individual spin packets even in the presence of considerable spectral distribution and/or line broadening, thus providing efficient polarisation transfer for spin species having large chemical shifts, especially at high static fields. Some triple resonance experiments in solid-state CP MAS NMR have been described.37 It is shown that phenylphosphinic acid and octavinylsilsequioxane are useful for the set-up of the Hartmann-Hahn condition under MAS condition for 31 P - 13C and 29Si - 13C CP transfer, respectively. The effect of 51V decoupling during 29Si acquisition has also been described. The examples presented are useful for studies of inorganic compounds and hybrid materials by triple resonance solidstate NMR experiments. Using 1H–103Rh cross-polarization, solid-state 103Rh NMR spectra have been reported for diamagnetic Rh(III) compounds.38 The isotropic chemical shift and CSA were determined for a crystalline form of the dihydroxy-bridged Rh(III) dimer and for a salt of the oxo-centered acetate-bridged Rh(III) trimer using 1H–103Rh CP MAS NMR. A new strategy has been presented by Eden for achieving selective heteronuclear polarisation transfers from half-integer quadrupolar spins in MAS NMR.39 By combining CP with a recently introduced RAPT pulse sequence that selectively excites the signal of a half-integer quadrupolar nucleus based on the magnitude of its quadrupolar coupling constant, it has been shown that heteronuclei may be selectively excited. Selective 23Na - 1H polarisation transfers have been demonstrated in Na2MoO4 2H2O, Na2HPO4 2H2O and a mixture of NaHCO3 and Na2HPO4 2H2O. A refocused INEPT through-bond coherence transfer technique has been demonstrated for NMR of rigid organic solids and is shown to provide a valuable building block for the development of NMR correlation experiments in biological solids.40 The use of efficient proton homonuclear dipolar decoupling in combination with a direct spectral optimisation procedure provides minimisation of the transverse dephasing of coherences and leads to very efficient through-bond 1H–13C INEPT for crystalline organic compounds. Application of this technique to 2D heteronuclear correlation spectroscopy leads to up to a factor of 3 increase in sensitivity for a 13C-enriched sample in comparison to standard through-bond experiments and provides excellent selectivity for one-bond transfer. The method is demonstrated on a microcrystalline protein sample. 3.4 Quadrupolar nuclei Ashbrook et al. have demonstrated that a strong 11B{1H} NOE enhancement can be observed in solid-state 11B NMR spectra of borane adducts, yielding fractional 202 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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enhancements, fI{S} = (II0)/I0, of the MAS NMR signal of up to 155%.41 This is an interesting and unusual observation as 11B (spin I = 3/2) is a quadrupolar nucleus and the corresponding NOE is completely absent in solution. More generally, it shows that the NOE may have a wider role to play in solid-state NMR studies of dynamics. The question of the homogeneous broadening that occurs in 2D solid-state NMR experiments has been examined.42 This homogeneous broadening is mathematically introduced in a simple way, versus the irreversible decay rates related to the coherences that are involved during t1 and t2. The pulse sequences and coherence transfer pathways that are used to measure these decay rates are presented. Using AlPO4 berlinite the 27Al echo-type relaxation times have been measured for the central and satellite transitions. It has been shown that the choice of the highresolution method should be done according to the spin value and the corresponding homogeneous broadening. The sidebands observed in the MAS NMR spectrum of a spin-1 2H nucleus may be very strongly broadened if motion is present in the solid. The broadening arises from interference between the line-narrowing effects of MAS and the dynamicsdriven reorientation of the 2H quadrupole tensor. It has been shown that this motional broadening is absent or much reduced in the corresponding double quantum MAS NMR spectrum.43 This observation suggests a new approach to studying dynamics in solids and examples are drawn from 2H MAS NMR of oxalic acid dihydrate, sodium tetrathionate dihydrate and the synthetic polymer PMMA. Recently available ultrahigh magnetic fields offer new opportunities for studies of quadrupole nuclei in biological solids because of the dramatic enhancement in sensitivity and resolution associated with the reduction of second-order quadrupole interactions. A new approach has been presented for understanding the function and energetics of ion solvation in channels using solid-state 17O NMR spectroscopy of single-site 17O-labelled gramicidin A.44 The chemical shift and quadrupole coupling parameters obtained in powder samples of lyophilized material are shown to be similar to those reported in the literature for carbonyl oxygens. In lipid bilayers, it is found that the carbonyl 17O anisotropic chemical shift of Leu10, one of the three carbonyl oxygens contributing to the ion binding site in gramicidin A, is altered by 40 ppm when K+ ion binds to the channel, demonstrating a high sensitivity to such interactions. Moreover, considering the large breadth of the carbonyl 17O chemical shift (4500 ppm), the recording of anisotropic 17O chemical shifts in bilayers aligned with respect to magnetic field B0 is shown to offer high-quality structural restraints similar to 15N and 13C anisotropic chemical shifts. Solid-state 17O NMR is known to be a highly sensitive probe of structural detail of organic solids. Hence, its improvements in sensitivity and resolution are crucial for the applications to larger biological molecules. It has been shown that high resolution (B1 ppm) and significant signal enhancement can be achieved by combining 1H decoupling with double rotation, which narrows the lines by a factor of B100 compared to conventional MAS and by manipulation of the satellite transition populations to transfer magnetisation to the central transition, which doubles the sensitivity of the technique.45 Experiences obtained from recent improvements in the performance of solid-state 14 N MAS NMR spectroscopy have been used in a natural abundance 33S MAS NMR investigation of the satellite transitions for this spin I = 3/2 isotope.46 The study reports the first observation of manifolds of spinning sidebands for the transitions in 33S MAS NMR as observed for the two alums with NH4 and K. For the NH4-alum a variable temperature 33S MAS NMR study, employing the satellite transitions, shows that the 33S quadrupole coupling constant exhibits a linear temperature dependence and undergoes a sign change with zero-crossing at 277 K. For the isostructural K-alum a quite similar increase in the magnitude of the 33 S quadrupole coupling constant with increasing temperature is observed. A study of the effect of the applied pulse widths at constant RF field strength on the intensity Nucl. Magn. Reson., 2007, 36, 196–243 | 203 This journal is

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and variation in second-order quadrupolar line shape for the central transition of the K-alum has also been reported. The results of a detailed systematic chlorine solid-state NMR study of several hydrochloride salts of amino acids implicated in chloride ion transport channel selectivity have been reported.47 35Cl and 37Cl NMR spectra have been obtained for stationary and magic-angle spinning powdered samples of the hydrochlorides of the following compounds on 500 and 900 MHz spectrometers: D,L-arginine monohydrate, L-lysine, L-serine, L-glutamic acid, L-proline, L-isoleucine, L-valine, L-phenylalanine and glycine. Spectral analyses provided information on the anisotropic properties and relative orientations of the chlorine electric field gradient and chemical shift tensors, which are intimately related to the local molecular and electronic structure. Data obtained using the 900 MHz spectrometer provided unique examples of the effects of CSA on the NMR spectrum of a quadrupolar nucleus. The range of chlorine quadrupolar coupling constants measured, 6.42 to 2.03 MHz, demonstrated the sensitivity of this parameter to the chloride ion environment and suggested the applicability of chlorine solid-state NMR as a novel experimental tool for determining chloride binding environments in larger ion channel systems. Salts of hydrophobic amino acids were observed to exhibit larger values of quadrupolar couplings than salts of hydrophilic amino acids. A simple model for rationalizing the observed trend in quadrupolar couplings has been proposed. For salts for which neutron diffraction structures are available, a quantum chemical method has been identified which reproduces experimental values of quadrupolar couplings with a root-mean-square deviation of 0.1 MHz and a correlation coefficient of 0.9998. On the basis of these studies, chlorine NMR tensors were predicted for the Cl-binding site in chloride ion transport channels. Multifrequency pulsed NMR experiments on quadrupole-perturbed I = 3/2 spins in single crystals have been shown to be useful for measuring spin-lattice relaxation parameters even for a mixture of quadrupolar plus magnetic relaxation mechanisms.48 It has been shown that such measurements can be related to other MAS NMR experiments on powders. This strategy is demonstrated by studies of 71Ga and 69 Ga (both I = 3/2) spin-lattice relaxation behaviour in a single crystal (film) sample of gallium nitride, GaN, at various orientations of the axially symmetric nuclear quadrupole coupling tensor. A strategy of multifrequency irradiation with observation of satellite and/or central transitions, incorporating different initial conditions for the level populations, has been shown to provide a means of obtaining three different relaxation time constants from single crystal 71Ga data alone. The 69Ga results provided a further check of internal consistency, since magnetic and quadrupolar contributions to its relaxation scale in opposite directions compared to 71Ga. It was found that introduction of MAS leads to a number of complications into the measurement and interpretation of the spin-lattice relaxation. The recently introduced concept of soft pulse added mixing (SPAM) has been used in 2D HETCOR NMR experiments between half-integer quadrupolar and spin-1/2 nuclei. The experiments employ MQ MAS to remove the second order quadrupolar broadening and CP or refocused INEPT for magnetisation transfer.49 By using previously unexploited coherence pathways, the efficiency of SPAM MQ HETCOR NMR is shown to increase by a factor of almost two without additional optimization. The sensitivity gain is demonstrated on a test sample, AlPO4-14, using CP and INEPT to correlate 27Al and 31P nuclei. The new method allowed the acquisition of the first high-resolution solid-state (27Al, 29Si)-correlation spectra. It has been shown that through-bond homonuclear correlation experiments can be used in solids between spins of type X, separated by four chemical bonds in X–O–Y– O–X motifs, provided a J-coupling between X and Y exists.50 In particular, it has been demonstrated that central transitions of quadrupolar 27Al spins can be correlated via the 2J scalar coupling between 27Al (X) and 31P (Y) in materials containing Al–O–P–O–Al motifs. 204 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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The use of hyperbolic secant (HS) pulses to obtain NMR signal enhancements for the central transition of spin-5/2 quadrupolar nuclei in solids has been explored.51 By inverting the populations of nuclear-spin energy levels prior to applying a selective observe pulse, enhancements near the theoretical maximum are obtained for the central 27Al NMR transition in a single crystal of a-Al2O3. The experimental enhancements obtained using HS inversion pulses for powder samples are compared to those obtained using the double-frequency sweep method. For every sample investigated, the HS enhancement factors are shown to be equal to or superior to those previously reported using other enhancement techniques. A new approach for resolution enhancement in solid-state NMR spectra of spin9/2 quadrupolar nuclei has been reported, which allows the observation of 1D spectra with a much better resolution than that observed in the isotropic projection of 2D MQ ST1 MAS spectra.52 The enhanced resolution is shown to result from the much smaller homogeneous broadening that occurs on using the SATRAS ST2 method as compared to MQ ST1 MAS.

3.5 RF heating effects Dissipation of RF energy as heat during CW decoupling in solid-state NMR experiment has been examined.53 It was found that a significant temperature increase could occur while performing dynamic NMR measurements provided the sample contains polar molecules and the sequence calls for relatively long applications of RF power. Furthermore, the methyl flip motion in dimethylsulfone (DMS) was shown to be activated by the decoupling RF energy conversion to heat during a CODEX pulse sequence. This introduced a significant bias in the correlation timetemperature dependency measurement used to obtain the activation energy of the motion. By investigating the dependency of the temperature increase in hydrated lead nitrate on experimental parameters during high-power decoupling one-pulse experiments, the mechanisms for the RF energy deposition was identified. The samples were heated due to dissipation of the energy absorbed by dielectric losses, a phenomenon commonly known as ‘‘microwave’’ heating. It was thus established that during solid-state NMR experiments at moderate B0 fields, RF heating could lead to the heating of samples containing polar molecules such as hydrated polymers and inorganic solids, thus resulting in systematic errors for slow dynamics measurements by solid-state NMR. A new, simple approach for estimating sample temperature has been used to show that, at 9.4 T, sample heating depends mostly on 1H decoupling power rather than on 15N irradiation in PISEMA experiments.54 Such heating for different sample preparations, including lipid composition, salt concentration and hydration level was assessed and the hydration level was found to be the primary parameter correlated with sample heating. The contribution to RF heating from the dielectric loss appears to be dominant under the experimental conditions used. The heat generated by a single scan was approximately calculated from the Q values of the probe, to be a 1.7 K elevation per single pulse sequence iteration under typical sample conditions. It has been shown that the steady-state sample temperature during PISEMA experiments can be estimated based on the new method, which correlates the loss factor with the temperature rise induced by the RF heating of the sample.

3.6 Probe developments A simple hardware modification of a Bruker 7 mm MAS NMR probe to a single crystal goniometer probe has been described.55 Chemical shift 31P tensors of Na4P2O7 10H2O have been determined to demonstrate the functionality of the rebuilt probehead. Nucl. Magn. Reson., 2007, 36, 196–243 | 205 This journal is

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A micro-MAS probehead has been developed for high-resolution solid-state NMR observation of mass-limited samples.56 This probehead has been shown to give extremely high sensitivity of the spectra and largely improves the limit of detection for solid-state NMR. As a result, the NMR spectra of mg order samples could be successfully observed using conventional 400 MHz NMR within a few hours. The feasibility of a minicoil for solid-state 19F–1H NMR experiments has been demonstrated that has short pulse widths, good RF homogeneity, and excellent signal-to-noise for small samples while using low power amplifiers typical to liquidstate NMR.57 3.7 Software developments A new protocol (SOLARIA, a MAS NMR version of ARIA used in solution NMR) has been presented for automated cross-peak assignment in solid-state 2D MAS NMR spectra with a high level of resonance overlap and for further structure calculations.58 A highly optimized computer program for the simulation of solution and solidstate NMR experiments, SPINEVOLUTION, has been described by Veshtort and Griffin.59 Although particularly efficient for the simulation of experiments with complex pulse sequences and multi-spin systems in solids, SPINEVOLUTION has been shown to be a versatile and easy to use tool for the simulation and optimisation of virtually any NMR experiment. The performance of SPINEVOLUTION was compared with that of another recently developed NMR simulation package, SIMPSON. Benchmarked on a series of examples, SPINEVOLUTION was consistently found to be orders of magnitude faster. 3.8 Other technique related developments A robust new solid-state NMR method for selecting CH2 signals in MAS 13C NMR spectra has been presented.60 Heteronuclear dipolar evolution under MREV-8 homonuclear proton decoupling has been used to convert 13C magnetisation of methylene groups into two- and three-spin coherences. The two-spin coherences of the type SyIz were removed by a 13C 90x1 pulse. The three-spin coherence is reconverted into magnetisation during the remainder of the rotation period, still under MREV-8 decoupling. The required elimination of 13C chemical shift precession is achieved by a 1801 pulse bracketed by two rotation periods. The selection of the desired three-spin coherence has an efficiency of 13% theoretically and of 8% experimentally relative to the standard CP MAS spectrum. The new experiment has been demonstrated using cholesteryl acetate and two humic acids. A new method for the characterisation of orientational order in organic solids based on MAS NMR spectroscopy has been introduced.61 The method is related to the rotor-synchronized MAS experiment proposed by Harbison and Spiess [Chem. Phys. Lett., 1986, 124, 128], but exploits the anisotropy of the deuterium quadrupolar coupling instead of the 13C chemical shielding anisotropy. MAS provides a sensitivity advantage over pseudostatic techniques; using the deuterium quadrupolar coupling makes the method applicable to systems that do not exhibit large carbon CSAs, such as aliphatic polymers. It has been shown that due to the magnitude of the deuterium quadrupolar coupling, a large number of spinning sidebands can be reliably observed, allowing for a precise determination of the orientational distribution function. Experimental data are analyzed in terms of Wigner matrix basis functions as well as the conjugate orthogonal functions framework. Unidirectionally cold-drawn poly(ethylene) has been used as an example to demonstrate the new method. Single crystal REDOR experiments can be used to determine the three-dimensional orientation of heteronuclear bond vectors in an amino acid, as well as the crystal’s orientation relative to the rotor fixed frame (RFF). It has been shown that 206 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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for samples uniaxially aligned along the rotor axis, the polar tilt angle of a bond vector relative to the RFF can be measured by use of an analytical expression that describes the REDOR curve for that system.62 These bond orientations were verified by X-ray indexing of the single crystal sample and were shown to be as accurate as 11. 15 N solid-state NMR refocused INADEQUATE spectra of two lipophilic deoxyguanosine derivatives have been used to unambiguously identify different intermolecular hydrogen-bonding arrangements that direct the self-assembly of modified DNA bases and are indicative of either guanine ribbon or quartet self-assembly.63 A new protocol has been proposed for performing quantitative measurements in solid-state NMR, by calibration of the circuit response through a low-power pulse injected during the acquisition (the so-called ERETIC method).64 Some peculiarities of the new approach and useful applications typical of solids have been considered. A novel approach to markedly reduce RF power for both 1H and observed nuclei during spin exchange for separated local field experiments has been proposed.65 The RF power to satisfy the Hartmann-Hahn matching conditions during spin exchange for observed nuclei was arbitrarily reduced by alternating the directions of effective fields for 1H nuclei with unequal duration times and amplitudes. The proposed techniques were compared experimentally with those developed previously by the authors. Order parameters describing conformational exchange processes on the nanosecond to microsecond timescale can be obtained from powder patterns in solid-state NMR experiments. Extensions of these experiments to MAS based high-resolution experiments have shown a great promise for site-specific probes of biopolymers. In a new study, a detailed comparison of two pulse sequences, transverse ManfieldRhim-Elleman-Vaughn (T-MREV) and Lee-Goldburg cross polarisation (LGCP), has been presented using experimental and simulation tools to explore their utility in the study of order parameters.66 Systematic errors due to passively coupled 13C or 1 H nuclei, as well as due to B1 inhomogeneity have also been discussed. Both pulse sequences are shown to be useful for quantitative measurements of the order parameter, but the LGCP experiment is found to be of greater accuracy provided that the B1 field is highly homogeneous. The T-MREV experiment is far better compensated for B1 inhomogeneity and it also performs better in situations with limited signal. It has been shown that the polymorphic form of a material (sodium acetate) obtained by a solid-state dehydration process (starting from sodium acetate trihydrate) can be altered by carrying out the dehydration process under conditions of rapid (several kilohertz) sample rotation in a solid-state MAS NMR probe, providing a new opportunity to influence the outcome of solid-state dehydration/desolvation processes and, in particular, to alter the polymorphic form of the product obtained.67 A new experimental investigation of the NMR FID in a lattice of spin-1/2 nuclei in a strong Zeeman field has been presented.68 Following a p/2 pulse, evolution under the secular dipolar Hamiltonian preserves the coherence number in the Zeeman eigenbasis, but changes the number of correlated spins. In order to probe the multiple-spin dynamics during the FID, the growth of coherence orders has been measured in a basis other than the usual Zeeman eigenbasis. This measurement provides the first direct experimental observation of the growth of coherent multiplespin correlations during the FID. Experiments were performed with a cubic lattice of spins (19F in calcium fluoride) and a linear spin chain (19F in fluorapatite). It is found that the geometrical arrangement of the spins plays a significant role in the development of higher-order correlations.

4. Distance and angle measurements by solid-state NMR The results of two techniques of dipolar recoupling, REDOR and CP MAS, have been compared in the case of a coupled multiple-spin system.69 A fundamentally Nucl. Magn. Reson., 2007, 36, 196–243 | 207 This journal is

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different behavior is observed for these two techniques. In REDOR, the terms associated with each interaction SIk, commute with each other and no truncation takes place so that each addition of spin Ik causes a splitting with its dipolar frequency. In CP MAS, the flip-flop terms of the dipolar Hamiltonian do not commute with the dominant term from the strongly coupled spin pair so that the weak coupling terms from the neighbouring spin Ik are effectively truncated by the dominant pair interaction. Spin dynamics calculations are shown to be in agreement with the experimental data in a cubane shaped cluster. It has been shown that in solid-state NMR deuteron spectroscopy can be performed in full analogy to 1H spectroscopy, including 2H chemical shift resolution and 2H–X dipolar correlation schemes, when the NMR experiments are conducted in a ‘‘rotor-synchronized’’ fashion under fast MAS conditions.70 Solid-state 2H–X NMR experiments of this type, including 2H–15N and 2H–1H chemical shift correlations and distance measurements, are introduced and demonstrated on cytosine monohydrate, whose acidic protons can readily be replaced by deuterons by recrystallisation from D2O. In this way, 2H NMR spectroscopy provides information complementary to 1H NMR data, which is particularly useful for studying hydrogen bonds in supra- or biomolecular systems. REDOR solid-state NMR experiments on lyophilized samples of HIV-1 TAR have been used to measure conformational changes in the tat-binding site concomitant with binding of a short peptide comprising the residues of the tat basic binding domain.71 Peptide binding was observed to produce a nearly 4 A˚ decrease in the separation between phosphorothioate and fluorine labels incorporated at A27 in the upper helix and U23 in the bulge, respectively, consistent with distance changes observed in previous solution NMR studies and with models showing significant rearrangement in position of bulge residue U23 in the bound-form RNA. In addition to providing long-range constraints on free TAR and the TAR-tat complex, these results suggest that in RNAs known to undergo large deformations upon ligand binding, 31P–19F REDOR measurements can also serve as an assay for complex formation in solid-state samples. These experiments provide the first example of a solid-state NMR distance measurement in an RNA-peptide complex. A novel technique for measuring distances between heteronuclei in static powder samples has been described.72 The new approach is based on a two-dimensional single-echo scheme enhanced with adiabatic CP. As an example, the results for intramolecular distances in a-crystalline form of glycine are presented. The measured NMR distances 13Ca–15N and 13CO-15N are 1.496 0.002 and 2.50 0.02 A˚, respectively. Through incorporation of phosphorothioate groups in the nucleic acid backbone and mono-fluorinated nucleotides 31P{19F} REDOR has been used to study the binding of DNA to drugs and RNA to proteins through the detection of internuclear distances as large as 13–14 A˚.73 The technique applied is further refined for use in nucleic acids by the combined use of selective placement of phosphorothioate groups and the introduction of nucleotides containing trifluoromethyl (–CF3) groups. To ascertain the REDOR-detectable distance limit between a unique phosphorous spin and a trifluoromethyl group and to assess interference from intermolecular couplings, a series of model compounds and DNA dodecamers were synthesized each containing a unique phosphorous label and trifluoromethyl group or a single 19F nucleus. The dipolar coupling constants of the various 31P and 19F containing compounds were compared using experimental and theoretical dephasing curves involving several models for intermolecular interactions. Possibilities provided by double quantum POST-C7 measurements have been explored for semi-quantitative measurements of 31P–31P distances in disodium ATP hydrates.74 A new NMR experiment to measure heteronuclear dipolar couplings in the solidstate has been proposed.75 In this technique, a spin-lock based on a multiple pulse sequence, BLEW, is used in both RF channels to suppress the chemical shift and 208 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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homonuclear dipolar coupling interactions. The spin part of the zeroth-order average Hamiltonian is isotropic at on-resonance and renders the heteronuclear isotropic mixing leading to spin exchange via the local field (HIMSELF) for an in phase transfer of magnetization. Theoretical, simulated and experimental results demonstrating the performance of the HIMSELF technique are also reported. A new method for structure determination of zeolite crystal structures has been described that combines powder XRD and NMR spectroscopy in which the crucial step of structure solution is achieved using solid-state 29Si double quantum dipolar recoupling, which probes the distance-dependent dipolar interactions between naturally abundant 29Si nuclei in the zeolite framework.76 Using two purely siliceous zeolite test samples, it has been shown that the NMR data can be combined with the unit cell parameters and space group to solve structural models that refine successfully against the powder XRD data.

5. NMR parameters: experimental and theoretical studies 5.1 Spin

1 2

nuclei

The principal 13C chemical shift values for the p-[TCNE]22 dimer anion within an array of counterions have been measured to understand better the electronic structure of these atypical chemical species in several related TCNE-based structures.77 The structure of p-[TCNE]22 is unusual as it contains two very long C–C bonds (ca. 2.9 A˚) between the two monomeric units and has been found to exist as a singlet state. A systematic study of several oxidation states of [TCNE]z (z = 0, 1-, 2-) was conducted to determine how the NMR chemical shift tensor values change as a function of electronic structure and to understand the interactions that lead to spinpairing of the monomer units. The DFT calculated nuclear shielding tensors are correlated with the experimentally determined principal chemical shift values. Both theoretical and experimental ethylenic chemical shielding tensors revealed high sensitivity in the component, d>, lying in the monomer molecular plane and perpendicular to the p-electron plane. This largest shift dependence on charge density is observed to be about 111 ppm/e for d>. The component in the molecular plane but parallel to the central CQC bond, d//, exhibits a sensitivity of approximately 43 ppm/e. The results support the claim that it is changes within the ethylenic p-electrons and not the s-electrons that best account for the dramatic variations in bonding and shift tensors in this series of compounds. An investigation of the chemical shift tensors of the 13C-labelled carbons in Ph13CR13CPh and (Z2-Ph13CR13CPh)Pt(PPh3)2 (C6H6) has been carried out via analysis of 13C NMR spectra from stationary solid samples.78 The principal components of the chemical shift tensors as well as their orientations with respect to the 13C,13C internuclear vector have been determined. DFT calculations of these tensors have been found to be in close agreement with the experimental values. For diphenylacetylene (tolane), the orientations and principal-component magnitudes of the alkynyl carbon chemical shift tensors were comparable to those for other alkynyl carbons, although the chemical shift tensor is not axially symmetric in this case. The measured carbon shift tensors in the platinum complex bear a striking similarity to those of the alkenyl carbons in trans-Ph(H)CQC(H)Ph and a short theoretical discussion of these observations has been presented. Solid-state 207Pb NMR studies have been conducted on binary lead group 16 and mixed transition metal/lead group 16 materials, correlating the NMR chemical shifts of the materials with their structures.79 The experimental results show that the 207Pb chemical shifts are strongly influenced by the local electronic structure. Data are reported for lead selenide, lead selenate, calcium plumbate, strontium plumbite, barium plumbite, lead borate, lead zirconate, lead tungstate, lead meta-tantalate, lead niobate, lead molybdate, lead meta-vanadate, lead sulfite and lead sulfate. Nucl. Magn. Reson., 2007, 36, 196–243 | 209 This journal is

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A combined solid-state NMR and ZORA DFT study of one-bond nuclear spinspin coupling between group-14 nuclei and quadrupolar 35/37Cl nuclei in triphenyl chlorides, Ph3XCl (X = C, Si, Ge, Sn and Pb), has been presented.80 Solid-state NMR spectra have been acquired for all compounds in which X is a spin-1/2 isotope [13C, 29Si, 117/119Sn and 207Pb] at applied magnetic fields of 4.70, 7.05 and 11.75 T. From simulations of these spectra, values describing the indirect spin-spin coupling tensor, the isotropic indirect spin-spin coupling constant, 1J(X,35/37Cl)iso and the anisotropy of the J tensor, D1J(X,35/37Cl), have been determined for all but the leadchlorine spin-pair. To better compare the indirect spin-spin coupling parameters between spin pairs, 1Jiso and D1J values were converted to their reduced coupling constants, 1Kiso and D1K. From experiment, the sign of 1Kiso was found to be negative while the sign of D1K is positive for all spin pairs investigated. The magnitude of both 1Kiso and D1K was found to increase as one moves down group-14. Theoretical values of the magnitude and sign of 1Kiso and D1K were obtained from ZORA-DFT calculations and were in agreement with the available experimental data. From the calculations, the Fermi-contact mechanism was determined to provide the largest contribution to 1Kiso for all spin pairs while spin-dipolar and paramagnetic spin-orbit mechanisms were found to make significant contributions to the anisotropy of K. The inclusion of relativistic effects was found to influence K(Sn, Cl) and K(Pb, Cl). A new double quantum solid-state NMR pulse sequence has been presented and used to measure one-bond 13C–13C J-couplings in a set of 13C2-labelled rhodopsin isotopomers.81 The measured J-couplings revealed a perturbation of the electronic structure at the terminus of the conjugated chain but showed no evidence for protein-induced electronic perturbation near the C11–C12 isomerisation site. In general, this work establishes NMR methodology for measuring accurate 1JCC values in noncrystalline macromolecules and shows that the measured J-couplings may reveal local electronic perturbations of mechanistic significance. 5.2 Quadrupolar nuclei Dynamic processes such as chemical exchange or rotations between inequivalent orientations can affect the MAS and MQ MAS NMR spectra of half-integer quadrupolar nuclei. The paper presented by Kotecha et al. discusses such dynamic multisite MAS and MQ MAS effects and applies them to study the dynamic processes that occur in the double perovskite cryolite, Na3AlF6.82 Dynamic line shape simulations invoking a second-order broadening of the central transition and relying on the semiclassical Bloch-McConnell formalism for chemical exchange were performed for a variety of exchange models possessing different symmetries. Fitting experimental variable temperature cryolite 23Na NMR data with this formalism revealed that the two inequivalent sodium sites in this mineral undergo an exchange characterized by a broad distribution of rates. To further assess this dynamic process a variety of 27Al and 19F MAS NMR studies were also undertaken. Quantitative 27 Al–19F dipolar coupling measurements then revealed a dynamic motion of the AlF6 octahedra that were qualitatively consistent with predictions stemming from molecular dynamic simulations on this double perovskite. Ab initio calculations have been used to compute all of the tensor elements of the electric field gradient for each carbon-deuterium bond in the ring of deuterated 3-methyl-indole.83 Previous analyses have ignored the smaller tensor elements perpendicular to principal component Vzz which is aligned with the C–2H bond (local bond z-axis). At each ring position, the smallest element Vxx is in the molecular plane and Vyy is normal to the plane of the ring. The asymmetry parameter Z ranges from 0.07 at C4 to 0.11 at C2. The perpendicular (off-bond) tensor elements were used in concert with an improved understanding of the indole ring geometry to analyze prototype 2H NMR spectra from oriented hydrated peptide/lipid samples. 210 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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The high resolution offered by MAS when compared to the static condition in solid-state NMR of powders has been used to full advantage in a 14N MAS NMR study of some ammonium salts.84 It has been shown that the high-quality 14N MAS NMR spectra, which can be obtained for these salts, allow determination of the 14N quadrupole coupling constant and the asymmetry parameter with very high precision. The detection of the number of sites has been confirmed by the corresponding crystal structures determined from single crystal XRD. The magnitudes of the 14N quadrupole coupling constants for the ammonium salts studied were in the range from B20 kHz to 1 MHz while the asymmetry parameters span the full range between 0 and 1. The 14N quadrupole coupling parameters for ammonium ions appeared to be highly sensitive to crystal structure and therefore appreciably more informative for the characterisation of ammonium salts in comparison to the isotropic 14N (or 15N) chemical shifts. A solid-state 17O NMR 1H-decoupled double angle rotation (DOR) study of monosodium L-glutamate monohydrate has been reported.85 It has been shown that all eight inequivalent sites can be resolved with DOR line widths (B65 Hz) about 120 times narrower than those observed in the MAS spectrum. The lines were tentatively assigned on the basis of their behaviour under proton decoupling. With a shift range of B45 ppm for the similar oxygen sites and spectral resolution under DOR comparable to that for spin-1/2 nuclei, solid-state 17O NMR is predicted to have tremendous potential in the study of biomolecules. The method for analyzing the 2H NMR spectrum affected by strong paramagnetic interaction has been discussed.86 The 2H NMR spectral simulation including the effects of paramagnetic shift and paramagnetic spin-spin relaxation was performed for several molecular motions. The contribution of distant paramagnetic ions to the paramagnetic shift and the effect of anisotropic spin-spin relaxation on the line shape of the 2H NMR spectrum were investigated by the spectral simulation. The temperature variation of 2H NMR spectrum of [Mn(H2O)6][SiF6] observed by the quadrupole-echo sequence was well reproduced using the proposed method. Solid-state NMR has been used to analyze the chemical environments of sodium sites in powdered crystalline samples of sodium nucleotide complexes.87 Three of the studied complexes have been previously characterized structurally by crystallography (disodium deoxycytidine-5 0 -monophosphate heptahydrate, disodium deoxyuridine-5 0 -monophosphate pentahydrate and disodium adensoine-5 0 -triphosphate trihydrate). For these salts, the nuclear quadrupole coupling parameters measured by 23Na MQ MAS NMR are shown to be correlated with sodium ion coordination environments. Furthermore, two complexes that had not been previously characterized structurally, disodium uridine-3 0 -monophosphate and a disodium uridine-3 0 monophosphate/disodium uridine-2 0 -monophosphate mix, were identified by solidstate NMR. A spectroscopic assignment of the four sites of an additional salt, disodium adensoine-5 0 -triphosphate trihydrate, has also been presented and discussed within the context of creating a general approach for the spectroscopic assignment of multiple sites in sodium nucleotide complexes. Experimental procedures have been proposed and demonstrated that separate the spectroscopic contribution from both 47Ti and 49Ti in solid-state NMR spectra.88 These take advantage of the different nuclear spin quantum numbers of these isotopes that lead to different ‘effective’ RF fields for the central transition nutation frequencies when these nuclei occur in sites with a significant electric field gradient. Numerical simulations and solid-state NMR experiments were performed on the TiO2 polymorphs anatase and rutile. For anatase, the separation of the two isotopes at high field (21.1 T) facilitated accurate determination of the EFG and CSA tensors. This was accomplished by taking advantage of the quadrupolar interaction between the EFG at the titanium site and the different magnitudes of the nuclear quadrupole moments of the two isotopes. Rutile, having a larger quadrupolar coupling constant, was examined by 49Ti-selective experiments at different magnetic fields to obtain Nucl. Magn. Reson., 2007, 36, 196–243 | 211 This journal is

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spectra with different scalings of the two anisotropic tensors. A small CSA of 30 ppm was determined. Solid-state 95Mo NMR spectroscopy has been shown to be an efficient and effective tool for analyzing the diamagnetic octacyanomolybdate(IV) anions, Mo(CN)84, of approximate dodecahedral, D2d, and square antiprismatic, D4d, symmetry.89 The sensitivity of the Mo magnetic shielding (s) and EFG tensors to small changes in the local structure of these anions allows the approximate D2d and D4d Mo(CN)84 anions to be readily distinguished. The use of high applied magnetic fields, 11.75, 17.63 and 21.1 T, has been shown to amplify the overall sensitivity of the NMR experiment and enables more accurate characterisation of the Mo s and EFG tensors. Although the magnitudes of the Mo s and EFG interactions are comparable for the D2d and D4d Mo(CN)84 anions, the relative values and orientations of the principal components of the Mo s and EFG tensors gave rise to 95Mo NMR line shapes that are significantly different at the fields used. Quantum chemical calculations of the Mo s and EFG tensors, using ZORA DFT and restricted Hartree-Fock methods, were also carried out and were in good agreement with experiment.

6. Applications 6.1 Organic solids Studies on the solid-state structure of two polymorphs of 4-methyl-2-nitroacetanilide were conducted using MAS 13C, 15N and 1H NMR spectroscopy, together with firstprinciples computations of NMR shielding (including use of a program that takes explicit account of the translational symmetry inherent in crystalline structures).90 The effects on 13C chemical shifts of side chain rotations have been explored. Information derived from these studies was then incorporated within a systematic space-search methodology for elucidation of trial crystallographic structures from powder XRD. Three N-substituted pyrazoles and three N-substituted indazoles have been studied by NMR spectroscopy in solution (1H, 13C, 15N) and in the solid-state (13C, 15N).91 The chemical shifts have been compared with GIAO DFT calculated absolute shieldings. Some discrepancies have been analyzed. 1 H and 19F nuclear spin relaxation processes in polycrystalline 3-(trifluoromethyl)phenanthrene have been observed and modelled.92 The relaxation rates for the two spin species were observed from 85 to 300 K at the low NMR frequencies of o/2p = 22.5 and 53.0 MHz where CF3 rotation, characterized by a mean time t between hops, is the only motion on the NMR time scale. All motional time scales (ot { 1, ot E 1,) and ot c 1) were observed. The 1H spins were found to be immobile on the NMR time scale but were coupled to the 19F spins via the dipoledipole interaction. The temperature dependence of the observed relaxation rates (biexponential) showed considerable structure and a thorough analysis of BlochWangsness-Redfield theory for this coupled spin system has been provided. The activation energy for CF3 rotation was found to be 11.5 0.7 kJ/mol, in excellent agreement with the calculation in a 13-molecule cluster using detailed ab initio electronic structure calculations. The reaction between p-(LiC2)2C6H4 and BPh3 has been reported to afford high yields of [Li(THF)4]2[p-(Ph3BC2)2C6H4], a heretofore missing member of the isoelectronic [p-(Ph3EC2)2C6H4] (E = groups 13–15 element) series.93 The central phenylene linker was found to be free to rotate in the solid-state, as determined by a variable-temperature solid-state 2H spin-echo NMR spectroscopic study. At room temperature, the rate of rotation was shown to be at least 20 times faster than that of its carbon-based analogue, presumably a result of Coulombic repulsions minimizing noncovalent interactions between rotating units in the borate salt. 212 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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The 5,5 0 -disubstituted-3,3 0 -diindolylmethanes have been prepared and their structures have been analyzed using XRD and NMR techniques.94 The XRD studies revealed interesting C–H p intermolecular interactions which may play role in characterisation of their biological features. In 1H and 13C NMR spectra in solution and 13C CP MAS NMR spectra in the solid-state only a single pattern of signals was observed. Two-dimensional 1H–13C MAS J-HMQC solid-state NMR spectra of the two anomeric forms of maltose at natural abundance have been presented.95 The experimental 1H chemical shifts of the CH and CH2 protons were assigned using first-principles chemical shift calculations that employ a plane-wave pseudo-potential approach. Further calculations show that the calculated change in the 1H chemical shift when comparing the full crystal and an isolated molecule is a quantitative measure of intermolecular C–H O weak hydrogen bonding. Notably, a clear correlation between a large chemical shift change (up to 2 ppm) and both a short H O distance (o2.7 A˚) and a CHO bond angle greater than 1301 was observed, thus showing that directionality is important in C–H O hydrogen bonding. Synchrotron powder XRD and solid-state 13C NMR shift tensor data have been combined to provide a unique path to structure in microcrystalline organic solids.96 Analysis is demonstrated on ambuic acid powder, a widely occurring natural product, to provide the complete crystal structure. The NMR data verified phase purity, specify one molecule per asymmetric unit and provide an initial structural model including relative stereochemistry and molecular conformation. A refinement of X-ray data from the initial model established that ambuic acid crystallizes in the P21 space group. The combined analysis yielded structural improvements at two dihedral angles over prior NMR predictions. Predicted hydroxyl hydrogen-bonding orientations also agreed with NMR predictions within 6.91. This work has demonstrated that the combination of long-range order information from synchrotron powder diffraction data together with the accurate shorter range structure given by solid-state NMR measurements is a powerful tool for studying complex organic solids. The topochemical photoconversion process in which a-trans-cinnamic acid becomes a-truxillic acid has been investigated.97 The results from 13C CP MAS NMR experiments suggested that the Johnson, Mehl, Avrami and Kolmogorov model of phase transformation kinetics can be applied to this system. The model elucidates parameters of the reaction, such as the nucleation rate, diffusion rate and dimensionality of the reaction. It was concluded that this reaction follows onedimensional growth with a decreasing nucleation rate. Single crystal XRD and 13C and 15N CP MAS NMR studies of conformational isomerism in zinc diethyldithiocarbamate adducts with dialkylamines have been described.98 Solid-state NMR spectroscopy has been applied to establish the dynamic processes of aliphatic groups and the phosphorus skeleton in unsymmetrical thiopyrophosphate.99 Variable 13C and 31P temperature NMR studies as well as T1 and T1r measurements revealed the different mode of molecular motion for each neopentyl residue directly bonded to phosphorus. It was concluded that molecular dynamics of aliphatic groups causes different van der Waals interactions in the crystal lattice and is the driving force of phase transition. The thermally annealed solid-state polymerisation of 2,3-dicyano-5,7-dimethyl6H-1,4-diazepine has been studied by 1H, 13C and 15N MAS solid-state NMR.100 The obtained NMR data suggested that a tautomeric form of the monomer is responsible for the solid-state reactivity of the crystalline monomer. It was found that the solid-state polymerisation of crystalline 2,3-dicyano-5,7-dimethyl-6H-1,4diazepine proceeds as a heterogeneous decomposition of the crystalline lattice resulting in an insoluble, amorphous material. A plausible reaction scheme involving a tautomeric form (consistent with the NMR results) has been proposed. Nucl. Magn. Reson., 2007, 36, 196–243 | 213 This journal is

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In another related work, crystalline 2,3-dicyano-5,7-dimethyl-6H-1,4-diazepine was investigated by solid-state NMR, XRD and spectral simulations.101 The solidstate 13C NMR spectra displayed unusual splittings for the methyl and cyano resonances. The crystal structure indicated that the methyl doublet is a consequence of two crystallographically inequivalent environments. The methyl motions associated with each site was examined via T1 measurements. The complex cyano splittings, however, were a result of both crystallographic inequivalence and residual 13 C–14N dipolar coupling. Spectral simulations, using the perturbation method of the centre bands and first-order sidebands were used to demonstrate and elucidate the observed MAS rate-dependent multiplet patterns of the cyano signals. Schiff base derivatives of 2-hydroxynaphthylaldehyde were studied by means of 13 C and 15N CP MAS NMR and deuterium isotope effects on 15N chemical shifts in the solid-state.102 The latter provided evidence for the presence of a dynamic proton transfer equilibrium in the solid-state at the room temperature. The X-ray structure and the solid-state NMR measurements (mainly 15N CP MAS) of the labelled compound, has allowed to determine the static and dynamic properties of 3(5)-ethyl-5(3)-phenyl-1H-pyrazole, a tetramer formed by three 5-ethyl-3-phenyl-1H-pyrazole and one 3-ethyl-5-phenyl-1H-pyrazole tautomers.103 Solid-state acid-base interactions in complexes of heterocyclic bases with dicarboxylic acids have been studied using XRD, hydrogen bond analysis and 15N NMR spectroscopy.104 The findings in this study provide insight into the structural characteristics of complexes involving heterocyclic bases and carboxylic acids and demonstrate that X-ray crystallography and 15N solid-state NMR are complementary in elucidating hydrogen bonding interactions and the degree of proton transfer of the hydrogen bonded complexes. A systematic solid-state 17O NMR study of a series of carboxylic compounds, maleic acid, chloromaleic acid, KH maleate, KH chloromaleate, K2 chloromaleate and LiH phthalate MeOH has been reported.105 MAS, 3Q MAS and DOR 17O NMR spectra were recorded at high magnetic fields (14.1 and 18.8 T). 17O MAS NMR for metal-free carboxylic acids and metal-containing carboxylic salts demonstrate that site-specific information for samples containing multiple oxygen sites can be obtained. In addition to 17O NMR, extensive quantum mechanical calculations were carried out to explore the influence of hydrogen bonding at the oxygen sites. B3LYP/6-311G++(d,p) calculations of 17O NMR parameters yielded good agreement with the experimental values. Linear correlations were observed between the calculated 17O NMR parameters and the hydrogen bond strengths, suggesting the possibility of estimating hydrogen bonding information from 17O NMR data. The calculations also revealed intermolecular hydrogen bond effects on the 17O NMR shielding tensors. It was found that the d11 and d22 components of the chemical shift tensor at O–H and CQO, respectively, are aligned nearly parallel with the strong hydrogen bond and shift away from this direction as the hydrogen bond interaction weakens. 13 C NMR and 2H NMR techniques have been used to investigate structural and dynamic properties of the 1,4-dicyanobutane/urea and 1,5-dicyanopentane/urea 1:1 hydrogen bonded complexes and the 1,6-dicyanohexane/urea inclusion compound.106 The pure crystalline phase of urea has also been investigated. The 13C NMR studies have focused on 13C CSA and second order quadrupolar effects (arising from 13C–14N interaction) for the urea molecules and the cyano groups of the a,o-dicyanoalkanes. Parameters describing these interactions are derived and are discussed in relation to the known structures of these solids. Comparison of 13C CSAs of the cyano carbons and rates of 13C dipolar dephasing suggests that 1,4-dicyanobutane and 1,5-dicyanopentane are effectively static, whereas 1,6-dicyanohexane has greater mobility. 2H NMR line shape analysis for the 1,4-dicyanobutane/urea-d4 and 1,5-dicyanopentane/urea-d4 complexes indicates that the only motion of the urea molecules that is effective on the 2H NMR timescale is a rapid libration about the CQO bond over an angular range of ca. 261. For the 1,6214 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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dicyanohexane/urea-d4 inclusion compound, the 2H NMR line shape is consistent with a motion comprising 1801 jumps about the CQO bond at rates that are intermediate on the 2H NMR timescale. The dynamic properties of the urea molecules in these materials are compared with those of urea molecules in other crystalline environments. The tautomerism of the enol form of acetylacetone (pentane-2,4-dione) inside a host cavity has been studied by means of solid-state 13C NMR spectroscopy using the variable temperature CP MAS technique.107 It was found that the enol form, 4 hydroxypent-3-en-2-one, exists in an equilibrium with an identical tautomer through O–H O proton transfer. The experimental results (energy barrier and chemical shifts) were rationalized by using MP2 and GIAO calculations. Variable temperature 2H NMR experiments (line shape analysis, relaxation studies) were carried out on the pyridine-d5-tris-(1,2-dioxyphenyl)-cyclotriphosphazene inclusion compound in the temperature range between 110–300 K.108 It was found that the pyridine guests are highly mobile throughout the whole temperature range covered here. The observation of three superimposed 2H NMR signals was interpreted in terms of a particular (motionally averaged) orientation of the pyridine molecules, which is a consequence of the molecular symmetry of the pyridine guests and the imposed channel restrictions. The experimental data were consistent with a combined rotation on cone-small angle fluctuation model, which assumes a fast molecular reorientation between two superimposed cones with an opening angle for the inner cone between 59–731. On the basis of this model assumption, it was possible to reproduce both the experimental 2H NMR line shapes and the spin– lattice relaxation data in a quantitative way. The analysis of the partially relaxed spectra (inversion recovery experiments) yielded the correlation times for this overall motional process. They followed an Arrhenius behavior from which an activation energy of 8.7 0.4 kJ mol1 was derived. The results were discussed in the framework of the published data for related systems. The relationship between DSC profiles and changes in 13C and 31P the spin-lattice relaxation times of the host and 1H T1 of guest in inclusion complexes of bis[6-O,6O 0 -(1,2:3,4-diisopropylidene-a-D-galactopyranosyl)thiophosphoryl] disulfide (DGTD) with n-propanol has been discussed in term of guest migration in the crystal lattice.109 1H–13C FSLG HETCOR experiment recorded with different contact times was employed to establish the guest localisation in the crystal lattice for different modifications of the inclusion complex. The migration pathway of the guest was verified by means of theoretical DFT calculations. 6.2 Amino acids 13

C, 14N, 15N, 17O and 35Cl NMR parameters, including chemical shift tensors and quadrupolar tensors for 14N, 17O and 35Cl, have been calculated for the crystalline forms of various amino acids under periodic boundary conditions and complemented by experiment where necessary.110 The 13C shift tensors and 14N EFG tensors were in excellent agreement with experiment. It has been shown that static 17O NMR spectra could be precisely simulated using the calculation of the full chemical shift tensors and their relative orientation with the EFG tensors. This study allows correlations to be found between hydrogen bonding in the crystal structures and the 17 O NMR shielding parameters and the 35Cl quadrupolar parameters, respectively. Calculations using the two experimental structures for L-alanine have shown that, while the calculated isotropic chemical shift values of 13C and 15N are relatively insensitive to small differences in the experimental structure, the 17O shift is markedly affected. Gravimetric analysis and 13C solid-state NMR have been applied to study solidphase transition from the transparent single crystal of L-serine monohydrate to a turbid powder.111 It was found that L-serine monohydrate loses water molecules and transforms into an anhydrate, thus experimentally demonstrating Frey’s assumption Nucl. Magn. Reson., 2007, 36, 196–243 | 215 This journal is

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(Acta Cryst., B29, 876, 1973). The CP NMR studies of the oriented crystal of the L-serine monohydrate revealed the dehydration mechanism. Furthermore, the chemical shift tensor components of the carboxyl carbon in L-serine monohydrate were determined. The difference in the tensor component of d22 between the monohydrate and anhydrate forms was more than 7 ppm, probably owing to differences in the hydrogen-bonding structure of each form. The application of rotor-assisted population transfer (RAPT) technique to measure the quadrupolar coupling constant for spin 5/2 nuclei has been described.112 Experimental 17O RAPT profile is traced for the amino acid L-leucine. In addition, results from MQ MAS experiments are incorporated to determine the quadrupolar asymmetry parameter. Unlike previous reports, the 17O NMR parameters for an amino acid, L-leucine, is reported at a relatively low field of 9.4 T. A study of polymorphism using a range of solid-state NMR techniques has been presented.113 The existence of at least six polymorphs in a sample of N-benzoyl-Lphenylalanine has been demonstrated. In addition, a new methodology has been described for the characterisation of the protonation state, hydrogen bonding and molecular conformation for the polymorphs. DFT modelling was used to investigate the separate effects of hydrogen bonding and molecular conformation on the chemical shift tensor. 6.3 Peptides The solid-state NMR, crystallographic and quantum chemical investigation of the origins of the 13C NMR chemical shifts of the imidazole group in histidinecontaining dipeptides have been reported.114 The chemical shift ranges for Cg and Cd2 seen in eight crystalline dipeptides were very large (12.7–13.8 ppm); the shifts were highly correlated (R2 = 0.90) and were dominated by ring tautomer effects and intermolecular interactions. A similar correlation was found in proteins, but only for buried residues. The imidazole 13C NMR chemical shifts were predicted with an overall rms error of 1.6–1.9 ppm over a 26 ppm range, by using quantum chemical methods. Incorporation of hydrogen bond partner molecules was found to be essential in order to reproduce the chemical shifts observed experimentally. Using AIM (atoms in molecules) theory it was found that essentially all interactions were of a closed shell nature and the hydrogen bond critical point properties were highly correlated with the N H O (average R2 = 0.93) and Ne2 H N (average R2 = 0.98) hydrogen bond lengths. For Ce2, the 13C chemical shifts were also highly correlated with each of these properties, indicating the dominance of intermolecular interactions for Ce1. The structure of an elastin-mimetic model peptide, (Val–Pro–Gly–Val–Gly)6 or (VPGVG)6, was proposed by combining data obtained from quantitative use of the conformation-dependent 13C NMR chemical shifts, 2D off MAS diffusion solidstate NMR with 13C double labelling of the peptides, rotational-echo doubleresonance of 13C, 15N double labelling peptides and statistical distribution of the backbone torsion angles of Val–Pro, Pro–Gly and Gly–Val–Gly sequences from PDB.115 The resulting model was presented as a distribution of conformations in this polypeptide. It was found that the Val-16 residue adopts torsion angles (f,c) = (90 151, 120 151). Torsion angles for other amino acid residues have also been determined. To reconcile the torsion angles corresponding to the main component in the conformational distributions, a type-IIb-turn structure was assigned to about 40% of the Pro–Gly pair. 13 C high-resolution solid-state NMR coupled with selective 13C isotope-labelling of different Ala methyl carbons was used to clarify the structure of (AG)15 peptide in the silk II structure as a model for the crystalline domain of Bombyx mori silk fibre.116 Two-dimensional spin-diffusion solid-state NMR spectra of 13C double-labelled model peptides (GPGGA)6G [(Gly–Pro–Gly–Gly–Ala)6–Gly] of flagelliform silk 216 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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were observed for studying the local structure in the solid-state.117 It was found that the spin-diffusion NMR spectra calculated by assuming the torsion angles of the b-spiral structure exclusively could not reproduce the observed spectra. In contrast, the spectra calculated by taking into account the statistical distribution of the torsion angles of the individual central residues in the sequences Ala–Gly–Pro, Gly–Pro– Gly, Pro–Gly–Gly, Gly–Gly–Ala and Gly–Ala–Gly from PDB data could reproduce the observed spectra well. This indicated that the statistical distribution of the torsion angles should be considered for the structural model of (GPGGA)6G similar to the case of the model peptide of elastin. 2 H,13C MAS correlation experiments have been described that are performed on a uniformly 2H,13C,15N labelled sample of Nac–Val and on the uniformly 2H,15N labelled dipeptide Nac–Val–Leu–OH.118 The experiments involve the measurement of 2H T1 relaxation times at two different magnetic fields, as well as the measurement of the 2H tensor parameters by evolution of the 2H chemical shift. The data are interpreted quantitatively to differentiate between different side chain motional models. The structural analysis of natural protein fibres with mixed parallel and antiparallel b-sheet structures by solid-state NMR has been reported by Asakura et al.119 To obtain NMR parameters that can characterize these b-sheet structures, 13C solidstate NMR experiments were performed on two alanine tripeptide samples: one with 100% parallel b-sheet structure and the other with 100% antiparallel b-sheet structure. It was shown that all 13C resonances of the tripeptides could be assigned by a comparison of the methyl 13C resonances of Ala3 with different [3-13C]Ala labelling schemes and also by a series of RFDR (radio frequency driven recoupling) spectra observed by changing mixing times. Differences in the 13C chemical shifts and 13C spin-lattice relaxation times (T1) were observed between the two b-sheet structures. Especially, about 3 times longer T1 values were obtained for parallel b-sheet structure as compared to those of antiparallel b-sheet structure. This very large difference in T1 can be used for differentiating between parallel or antiparallel b-sheet structures. These differences in the NMR parameters found for the tripeptides may be useful for [3-13C]Ala silk protein fibre of a wild silkworm, Samia cynthia ricini. Interactions of two homopolypeptides (polylysine and polyglutamic acid) with a synthetic montmorillonite have been studied by 1H MAS, 1H–27Al HETCOR and 1 H–13C CP MAS NMR experiments.120 Two-dimensional 1H–27Al HETCOR with 1 H spin-diffusion NMR appears to be a powerful probe for the identification of the polypeptide fragments, which interact with the montmorillonite interlayer surfaces. In particular, selective interactions were observed between the polypeptide side chains and the montmorillonite octahedral aluminum atoms. 1H–13C CP MAS NMR experiments were used to assess the dynamics of the two polypeptides through the measurement of the t1/2 characteristic time of selected carbons. Results indicate that the local mobility of the side chains and their interaction with the montmorillonite layers depend on the nature of the adsorbed polypeptides. High-yield expression and purification of a peptide comprising residues 11–26 of the Alzheimer’s b-amyloid protein (Ab11-26), with homoserine lactone replacing serine at residue 26 have been reported.121 Expression in inclusion bodies as a ketosteroid isomerase fusion protein and subsequent purification under denaturing conditions allowed production of milligram quantities of uniformly labelled 13C- and 15 N-labelled peptide, which forms amyloid fibrils suitable for solid-state NMR spectroscopy. Initial structural data obtained by atomic force microscopy, electron microscopy and solid-state NMR measurements of Ab11-26 fibrils are presented. Solid-state NMR studies of PrP89-143(P101L) fibrils probing the conformation of residues in the hydrophobic segment 112–124 with chemical shifts have been reported.122 The conformations of glycine residues were analyzed using doubly 13 CQO labelled peptides by 2D double quantum correlation and double quantum filtered dephasing distance measurements. MQ NMR experiments were carried out Nucl. Magn. Reson., 2007, 36, 196–243 | 217 This journal is

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to probe the relative alignment of the individual peptides in fibrils. These NMR studies indicated that the 112–124 segment adopts an extended b-sheet conformation. Correlation experiments provided useful information in regions with conformational heterogeneity. A new approach has been introduced to characterize conformational ensembles of intrinsically unstructured peptides on the atomic level using 2D solid-state NMR data and their combination with molecular dynamics simulations.123 For neurotensin, a peptide that binds with high affinity to a G-protein coupled receptor, this method permits the investigation of the changes in conformational preferences of a neurotransmitter transferred from a frozen aqueous solution via a lipid model phase to the receptor-bound form. The results speak against a conformational preorganisation of the ligand in detergents in which the receptor has been shown to be functional. It has been shown that further extensions to the study of protein folding are possible. The interaction between synthetic amphipathic peptides and model membranes has been investigated by solid-state NMR and IR spectroscopies.124 Peptides with 14 and 21 amino acids composed of leucines and phenylalanines modified by the addition of crown ethers were synthesized. To shed light on their membrane interaction, 31P and 2H solid-state NMR experiments were performed on both peptides in interaction with DMPC vesicles in the absence and presence of cholesterol, DMPG vesicles and oriented bicelles. 31P NMR experiments on multilamellar vesicles revealed that the dynamics and/or orientation of the polar headgroups are weakly yet markedly affected by the presence of the peptides, whereas 31P NMR experiments on bicelles indicate no significant changes in the morphology and orientation of the bicelles. On the other hand, 2H NMR experiments on vesicles revealed that the acyl chain order is affected differently depending on the membrane lipidic composition and on the peptide hydrophobic length. Finally, IR spectroscopy was used to study the interfacial region of the bilayer. Based on these studies, mechanisms of membrane perturbation are proposed for the 14-mer and 21-mer peptides in interaction with model membranes depending on the bilayer composition and peptide length. Solid-state NMR measurements on the peptide Vpu(1-40), comprising residues 1-40 of the 81-residue integral membrane protein Vpu encoded by the HIV-1 genome have been reported.125 On the basis of a combination of 13C and 15N NMR chemical shifts under MAS, effects of local mobility on NMR signal intensities, site-specific MAS NMR line widths and NMR-detected hydrogen-deuterium exchange, a model has been developed for the structure and dynamics of the Vpu(1-40) monomer in phospholipid bilayer membranes. New information about local variations in the degree of mobility and structural order has been obtained. In addition, the obtained data indicated that the transmembrane a-helix of Vpu(1-40) extends beyond the hydrophobic core of the bilayer. No evidence for heterogeneity in the conformation and intermolecular contacts of the transmembrane a-helix was found, with the exception of two distinct chemical shifts observed for the Ca and Cb atoms of A18 that may reflect distinct modes of helix-helix interaction. The aggregation and packing of a membrane-disruptive b-hairpin antimicrobial peptide, protegrin-1 (PG-1), in the solid-state have been investigated to understand its oligomerisation and hydrogen-bonding propensity.126 Incubation of PG-1 in phosphate buffer saline produced well-ordered nanometer-scale aggregates, as indicated by 13C and 15N NMR line widths, chemical shifts and electron microscopy. Two-dimensional 13C and 1H spin diffusion experiments using C-terminus strand and N-terminus strand labelled peptides indicate that the b-hairpin molecules in these ordered aggregates are oriented parallel to each other with like strands lining the intermolecular interface. In comparison, disordered and lyophilized peptide samples are randomly packed with both parallel and antiparallel alignments. The PG-1 aggregates show significant immobilisation of the Phe ring near the b-turn, further supporting the structural ordering. The intermolecular packing of PG-1 218 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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found in the solid-state is consistent with its oligomerisation in lipid bilayers. It has been suggested that this solid-state aggregation approach may be useful for determining the quaternary structure of peptides in general and for gaining insights into the oligomerisation of antimicrobial peptides in lipid bilayers. In another related paper, the intermolecular packing of PG-1 in lipid bilayers has been determined using solid-state NMR distance measurements.127 Previous spin counting experiments showed that PG-1 associates as dimers in POPC bilayers; however, the detailed dimer structure was unknown. Several intermolecular 13C–19F, 1 H–13C and 15N–13C distances in site-specifically labelled PG-1 were measured using REDOR to constrain the structure of the intermolecular interface. The results indicate that two PG-1 molecules align in a parallel fashion with the C-terminal strand of the hairpin forming the dimer interface. Six hydrogen bonds stabilize this interface and the Phe12 side chain adopts the g conformation in the membrane as in solution. This study demonstrates the utility of the REDOR NMR technique for the elucidation of the oligomeric structure of membrane proteins. A simple solid-state NMR method has been used to study the structure of 13Cand 15N-enriched silk from two Australian orb-web spider species, Nephila edulis and Argiope keyserlingi.128 Spectra from alanine- or glycine-labelled oriented dragline silks were acquired with the fibre axis aligned parallel or perpendicular to the magnetic field. The fraction of oriented component was determined from each amino acid, alanine and glycine, using each nucleus independently and attributed to the ordered crystalline domains in the silk. The relative fraction of ordered alanine was found to be higher than the fraction of ordered glycine. A higher degree of crystallinity was observed in the dragline silk of N. edulis compared with A. keyserlingi, which correlates with the superior mechanical properties of the former. Conformational studies of silk-like peptides modified by the addition of the calcium-binding sequence from the shell nacreous matrix protein MSI60 using 13C CP MAS NMR have been presented.129 The calcium-binding site of the pearl oyster (Pinctada fucata) nacreous layer matrix protein MSI60 was introduced between different Ala-Gly repeating regions derived from the primary sequences of several silk fibroins. Several different organic solvents whose effect on the repetitive domains of silk peptides is well-understood were used to modify the secondary structure of the flanking Ala-Gly repeating regions. The local conformations of the flanking AlaGly repeating regions as well as the calcium-binding motif, MSI60, were determined by 13C CP MAS NMR. The secondary structures of the polyalanine domains were modified by the solvent treatments in a predictable fashion, suggesting that only the solvent treatment and not the conformation of the MSI60 domain affected the conformation of polyalanine regions. Ala-Gly domains behaved differently, taking random coil conformation regardless of the choice of solvent. 6.4 Proteins The solid-state NMR experiment PISEMA is a technique for determining structures of proteins, especially membrane proteins, from oriented samples. One method for determining the structure is to find orientations of local molecular frames (peptide planes) with respect to the unit magnetic field direction, B0. This is done using equations that compute the coordinates of this vector in the frames, which requires an analysis of the PISEMA function and its degeneracies. These equations have been used to derive a formula for the intensity function in the powder pattern.130 With this function and other measures, the effect of small changes in peptide plane orientations depending on the location of the resonances in the powder pattern spectrum has been investigated. It has been shown that dynamic information for uniformly 2H,13C,15N isotopically enriched crystalline proteins can be obtained by solid-state MAS NMR spectroscopy.131 The experiments make use of the deuterium quadrupolar tensor, which is the dominant interaction mechanism. Dynamic properties are accessed by Nucl. Magn. Reson., 2007, 36, 196–243 | 219 This journal is

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measurement of the size of the quadrupolar coupling constant and the value of the asymmetry parameter via evolution of the deuterium chemical shift, as well as by measurement of deuterium T1 relaxation times. Three-dimensional experiments are performed in order to obtain site-specific resolution. It was shown that due to proton dilution, no proton decoupling is required in the carbon evolution periods at MAS rotation frequencies of 10 kHz. Studies of the binding of antifreeze proteins (AFPs) to ice surfaces via 13C spin lattice relaxation solid-state NMR have been reported.132 To find structural evidence for the AFP’s ice-binding side, a variable-temperature dependent 13C spin lattice relaxation solid-state NMR experiment was carried out for two Ala side chains for samples frozen in H2O and D2O, respectively. A model of Ala methyl group rotation/ three-site rotational jump combined with water molecular reorientation was tested to probe the interactions of the methyl groups with the proximate water molecules. This study suggested that the side of the a-helical AFP comprising the i + 4 and i + 8 Ala methyl groups could interact with the ice surface in the ice/water interface. Using the example of a uniformly [13C,15N]-labelled sample of ubiquitin, solidstate NMR methods suitable for the construction of 3D molecular structure have been discussed and the influence of solid phase protein preparation on solid-state NMR spectra has been studied.133 A comparative analysis of 13C, 13Ca and 13Cb resonance frequencies suggests that 13C chemical shift variations are most likely to occur in protein regions that exhibit an enhanced degree of molecular mobility. A combination of solid-state 2H and 19F NMR experiments has been used to provide constraints on amyloid fibril architecture by probing the environment and spatial organisation of aromatic side groups.134 It has been shown that phenylalanine rings within fibrils formed by a decapeptide fragment of the islet amyloid polypeptide, amylin, are highly motionally restrained and are situated within 6.5 A˚ of one another. Taken together with existing structural constraints for this peptide, these results are consistent with a fibril architecture that comprises layers of two or more b-sheets, with the aromatic residues facing into the inter-sheet space and possibly engaged in p–p interactions. The methods presented are expected to be of general utility in exploring the architecture of fibrils of larger, full-length peptides and proteins, including amylin itself. A novel approach using solid-state NMR has been presented that permitted the first site-resolved structural measurement of an intermediate species in fibril formation for a 40-residue Alzheimer’s b-amyloid peptide, Ab (1-40).135 The results provide the initial evidence that a spherical amyloid intermediate of 15–30 nm in diameter exists prior to fibril formation of Ab (1-40) and that the intermediate involves well-ordered b-sheets in the C-terminal and hydrophobic core regions. Verification of the turn at positions 22 and 23 of the b-amyloid fibrils with Italian mutation by solid-state NMR using dipolar-assisted rotational resonance (DARR) has been presented.136 Two sets of chemical shifts for Asp-23 were observed in a ratio of about 2.6:1. The 2D DARR spectra at the mixing time of 500 ms suggested that the side chains of Asp-23 and Val-24 in the major conformer and those of Lys-22 and Asp-23 in the minor conformer could be located on the same side, respectively. De novo site-specific 13C and 15N backbone and sidechain resonance assignments have been presented for uniformly enriched E. coli thioredoxin, established using 2D homo- and heteronuclear solid-state MAS NMR correlation spectroscopy.137 Backbone dihedral angles and secondary structure were derived from the statistical analysis of the secondary chemical shifts and were in good agreement with solution values for the intact full-length thioredoxin. It was found that a large number of cross-peaks observed in the DARR spectra with long mixing times correspond to the pairs of carbon atoms separated by 4–6 A˚, suggesting that DARR could be efficiently employed for observation of medium- and long-range correlations. Note that the 108 amino acid residue E. coli thioredoxin is the largest uniformly enriched protein assigned to this degree of completeness by solid-state NMR spectroscopy to 220 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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date. It is anticipated that with a combination of two-dimensional correlation experiments and high magnetic fields, resonance assignments and secondary structure can be generally derived for other noncrystalline proteins. Site-resolved observation of hydrogen exchange in the micro-crystalline protein Crh has been reported.138 The approach undertaken is based on the use of proton T2 0 -selective 1H–13C–13C correlation spectra for site-specific assignments of carbons nearby labile protein protons. It was shown that in micro-crystalline proteins, solvent accessible hydroxyl and amino protons show comparable exchange rates with water protons as for proteins in solution and that structural constraints, such as hydrogen bonding or solvent accessibility, more significantly reduce exchange rates. Investigations on possible water-protein dipolar transfer mechanisms in the microcrystalline deuterated protein Crh by a set of solid-state NMR techniques have been reported.139 Double quantum filtered and edited heteronuclear correlation experiments were used to follow direct dipolar water-protein magnetisation transfers. Experimental data revealed no evidence for ‘‘solid-like’’ water molecules, indicating that residence times of solvent molecules are shorter than required for DQ creation, typically a few hundred microseconds. An alternative magnetisation pathway, intermolecular cross-relaxation via heteronuclear NOEs, was probed by saturation transfer experiments. The structure and dynamics of a 140-residue protein a-synuclein (AS) have been investigated by high-resolution solid-state NMR spectroscopy.140 Homonuclear and heteronuclear 2D and 3D spectra of fibrils grown from uniformly 13C/15N-labelled AS and AS reverse-labelled for two of the most abundant amino acids, K and V, were analyzed. 13C and 15N signals exhibited line widths of o0.7 ppm. Sequential assignments were obtained for 48 residues in the hydrophobic core region. Two different types of fibrils were identified displaying chemical shift differences of up to 13 ppm in the 15N dimension and up to 5 ppm for backbone and side chain 13C chemical shifts. EM studies suggested that molecular structure is correlated with fibril morphology. Investigation of the secondary structure revealed that most amino acids of the core region belong to b-strands with similar torsion angles in both conformations. Selection of regions with different mobility indicated the existence of monomers in the sample and allowed the identification of mobile segments of the protein within the fibril in the presence of monomeric protein. The expression and purification of a-synuclein, a protein implicated in Parkinson’s disease, from isotopically (13C,15N) labelled bacterial growth media, have been reported as required for solid-state NMR structural studies.141 Highly resolved multidimensional solid-state NMR spectra indicated microscopic order throughout the majority of the AS fibril structure. The number of signals and intensities of wellresolved residue types (Thr, Ser, Ala, Gly, Val and Ile) were consistent with a single conformation. Variations in the fibril growth rates and structural polymorphism exhibited in the solid-state NMR spectra were minimized by careful control of incubation conditions. The application of the 31P NMR spectroscopy to large proteins or protein complexes in solution is sometimes hampered by a relatively low intrinsic sensitivity coupled with large line widths. Therefore, the assignment of the phosphorus signals by 2D NMR methods in solution is often extremely time consuming. In contrast, the quality of solid-state NMR spectra is not dependent on the molecular mass and the solubility of the protein. Solid-state 31P NMR methods have been shown to be more sensitive (by almost one order of magnitude) than liquid-state NMR for the complex of Ras with the GTP-analogue GppCH2p.142 Experiments on Ras GDP complexes showed that the microcrystalline sample can be substituted by a precipitate of the sample and that unexpectedly the two structural states observed earlier in solution were present in crystals as well. The effect of gramicidin A (gA) on bicelle orientation in the absence and presence of Eu3+ has been studied by 31P and 2H NMR at different DMPC/gA ratios.143 Nucl. Magn. Reson., 2007, 36, 196–243 | 221 This journal is

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Solid-state MAS NMR studies of the b1 immunoglobulin binding domain of protein G (GB1) have been presented.144 Chemical shift correlation spectra at 11.7 T were employed to identify signals specific to each amino acid residue type and to establish backbone connectivities. High sensitivity and resolution facilitated the detection and assignment of every 15N and 13C site and side chain resonances from residues exhibiting fast-limit conformational exchange near room temperature. The assigned spectra lend novel insight into the structure and dynamics of microcrystalline GB1. Secondary isotropic chemical shifts were used to compare the conformation in the microcrystalline state with the conformation of single crystals and the protein in solution. High-resolution spectra were observed near room temperature (280 K) and at o180 K, whereas resolution and sensitivity greatly degraded substantially near 210 K. The application of a new technique for constraining protein backbone geometry using a site-resolved 3D dipolar-shift pulse sequence has been presented.145 The dipolar line shapes report on the relative orientations of 1H–15N[i] to 1H–15N[i + 1] dipole vectors, constraining the torsion angles f[i] and c[i]. In addition, from the same 3D data set, several 1H–15N[i] to1H–15N[i + 2] line shapes are extracted to constrain the torsion angles f[i], c[i], f[i + 1] and c[i + 1]. The results for the majority of sites in the 56-residue b1 immunoglobulin binding domain of protein G have been reported using 3D experiments at 600 MHz 1H frequency. Excellent agreement between the solid-state NMR results and a new 1.14 A˚ crystal structure illustrate the general potential of this technique for high-resolution structural refinement of solid proteins. Refinement of the structural model of silk I proposed previously was performed on the basis of a detailed analysis of the 13C solid-state NMR data using 2D spindiffusion NMR and REDOR of stable isotope-labelled (AG)15, coupled with the XRD analysis of the crystalline fraction of B. mori silk fibroin.146 The repeated b-turn type II structure was proposed, with the torsion angles (f,c) = (621, 1251) for Ala residue and (f,c) = (771, 101) for Gly residue of poly(Ala-Gly) chain, which satisfies both solid-state NMR and XRD data quantitatively. The torsion angles determined in this work were slightly different from the previously reported angles, (f,c) = (601, 1301) for Ala residue and (f,c) = (701, 301) for Gly residue. Cocoons produced by different strains of Bombyx mori larvae were investigated by a combination of several high- and low-resolution 1H and 13C solid-state NMR techniques in order to characterize and compare their dynamic behavior at a molecular level.147 A detailed interpretation in terms of molecular motions in these very complex systems was possible thanks to the integrated analysis of different relaxation measurements and high-resolution selective experiments. Untreated cocoons of all strains were found to be mainly constituted by two different types of rigid domains and by a third one, more mobile, due to physisorbed water molecules. Dynamic processes in the MHz and kHz ranges were characterized by means of different 1H and 13C relaxation times. Cocoons arising from different strains exhibited a different content of physisorbed water and also slightly different dynamic behavior, especially in the MHz regime. The transmembrane conformation of the Pseudomonas aeruginosa Pf3 phage coat protein has been investigated using proton-decoupled 15N and 31P solid-state NMR spectroscopy.148 The protein was either biochemically purified and uniformly labelled with 15N or synthesized chemically and labelled at specific sites. The proteins were then reconstituted into oriented phospholipid bilayers and the resulting samples analysed. The data suggested a model in which the protein adopts a tilted helix with an angle of B301 and an N-terminal ‘swinging arm’ at the membrane surface. The effects of Ca2+ binding on the side chain methyl dynamics of calbindin D9k have been characterized by 2H NMR relaxation rate measurements.149 Longitudinal, transverse in-phase, quadrupolar order, transverse anti-phase and double quantum relaxation rates have been reported. The relatively large size of the data set allowed 222 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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for a detailed analysis of the underlying conformational dynamics by spectral density mapping and model-free fitting procedures. The results revealed a correlation between a methyl group’s distance from the Ca2+ binding sites and its conformational dynamics. 51 V solid-state NMR spectroscopy of the 67.5 kDa vanadium chloroperoxidase at 14.1 T has been reported.150 The quadrupolar and chemical shift tensors have been determined by numerical simulations of the spinning sideband envelopes and the line shapes of the individual spinning sidebands corresponding to the central transition. The observed quadrupolar coupling constant of 10.5 1.5 MHz and CSA of 520 13 ppm were found to be sensitive to the geometric and electronic structure of the vanadium centre. DFT calculations of the NMR spectroscopic observables for an extensive series of active site models indicated that the vanadate cofactor is most likely to be anionic with one axial hydroxo group and an equatorial plane consisting of one hydroxo and two oxo groups. 6.5 Bones and apatites Hydrogen-bearing species in the bone mineral environment have been investigated using solid-state NMR spectroscopy of powdered bone, deproteinated bone and B-type carbonated apatite.151 Using MAS and CP techniques three types of structurally-bound water were observed in these materials. Two of these water types were found to occupy vacancies within the apatitic mineral crystal in synthetic carbonated apatite and deproteinated bone and serve to stabilize these defectcontaining crystals. The third water was observed at the mineral surface in unmodified bone but not in deproteinated bone, suggesting a role for this water in mediating mineral-organic matrix interactions. Direct evidence of monohydrogen phosphate in a 1H NMR spectrum of unmodified bone has been presented for the first time. A clear evidence for the presence of hydroxide ion in deproteinated bone by 1H MAS NMR has also been presented. In addition, a 1H–31P heteronuclear correlation experiment provided unambiguous evidence for hydroxide ion in unmodified bone. Hydroxide ion in both unmodified and deproteinated bone mineral was found to participate in hydrogen bonding with neighbouring water molecules and ions. In unmodified bone mineral hydroxide ion was found to be confined to a small portion of the mineral crystal. For many years, octacalcium phosphate (OCP) has been postulated as the precursor phase of biological apatite in bones and teeth. The molecular mechanism of OCP to hydroxyapatite (HAp) transformation in vitro has been studied by several physical techniques, with particular emphasis on solid-state 31P homonuclear DQ NMR spectroscopy.152 The NMR data revealed that OCP crystals transform to HAp topotaxially. It has been suggested that the formation of the central dark line commonly found in biological hard tissues could be explained by the inherent lattice mismatch between OCP and HAp. Furthermore, the data of the 31P{1H} CP NMR suggested that water molecules enter the hydration layers of OCP crystals via the hydrolysis reaction HPO42 + OH = PO43 + H2O, which also accounts for the deprotonation of the HPO42 ions during the transformation. Extracellular matrix proteins regulate hard tissue growth by acting as adhesion sites for cells, by triggering cell signaling pathways and by directly regulating the primary and/or secondary crystallisation of hydroxyapatite, the mineral component of bone and teeth. Despite the key role that these proteins play in the regulation of hard tissue growth in humans, the exact mechanism used by these proteins to recognize mineral surfaces is poorly understood. Interactions between mineral surfaces and proteins very likely involve specific contacts between the lattice and the protein side chains, so elucidation of the nature of interactions between protein side chains and their corresponding inorganic mineral surfaces will provide insight into the recognition and regulation of hard tissue growth. Isotropic chemical shifts, CSAs, NMR line width information, 13C rotating frame relaxation measurements, as Nucl. Magn. Reson., 2007, 36, 196–243 | 223 This journal is

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well as direct detection of correlations between 13C spins on protein side chains and 31 P spins in the crystal surface with REDOR NMR have been used to show that, in the peptide fragment derived from the N-terminal 15 amino acids of salivary statherin (i.e., SN-15), the side chain of the phenylalanine nearest the C-terminus of the peptide (F14) is dynamically constrained and oriented near the surface, whereas the side chain of the phenylalanine located nearest to the peptide’s N-terminus (F7) is more mobile and is oriented away from the hydroxyapatite surface.153 The relative dynamics and proximities of F7 and F14 to the surface together with prior data obtained for the side chain of SN-15’s unique lysine (i.e., K6) were used to construct a new picture for the structure of the surface-bound peptide and its orientation to the crystal surface. Solid-state NMR has been used for a detailed structural analysis of different amorphous calcium phosphate (ACP) and hydroxyapatite (HAp) samples.154 For ACP the NMR data revealed the presence of hydrogenphosphate units in much larger quantities as known previously also showing differences between the samples. Furthermore, phosphate units close to water and a third unknown group were found in the spectra. It has been shown that NMR allows the investigation of the disordered mineral-protein interface and first examples concerning bone and nacre have been presented and discussed. Finally, nanocrystalline hydroxyapatite (HAp) prepared by a precipitation route has been investigated using powder XRD and solid-state NMR.155 A Ca/P ratio of 1.52 was estimated from the NMR data that compares well with the value of 1.51 from chemical analysis. 6.6 Lipids and membranes Isotopic labeling of an unsaturated phospholipids is synthetically very challenging. Therefore as unsaturated hydrocarbon chains predominate in the plasma membrane, novel NMR methods are required to obtain information on these systems. Dipolar recoupling on axis with scaling, and shape preservation (DROSS) is a solid-state NMR technique optimized for measuring 1H–13C dipolar couplings and order parameters in lipid membranes in the fluid phase. It has been used to determine the order profile of DMPC hydrated membranes.156 A preliminary solid-state NMR study of myelin basic protein was carried out and its interaction with model membrane examined. NMR study of MBP interaction with lipid bilayers has been reported.157 Mixtures of dicaproyl- (DC), dimyristoyl- (DM) and 1-tetradecanoyl-2-biphenylbutanoyl-(TBB) phosphatidylcholine (PC) in water produce bicelle membranes that are oriented by magnetic fields. Various mixtures of these lipids were examined by 31 P NMR to determine their orientation. The orientation of hydrophobic helices in membranes, using wide line 15N NMR in combination with circular dichroism, was used to study their orientation in the bicelles.158 A uniformly labeled membrane protein, the 52-residue polypeptide phospholamban, was studied under MAS conditions. Dipolar recoupling experiments were combined with novel throughbond correlation schemes that probe mobile protein segments. When reconstituted in lipid bilayers, the NMR data are consistent with an a-helical trans-membrane segment and a cytoplasmic domain that exhibits a high degree of structural disorder.159 Secondary structure and orientation of dynorphin bound to DMPC bilayer were investigated by solid-state 13C NMR spectroscopy. 13C NMR spectra of the sitespecifically 13C-labeled dynorphin were measured in the membrane-bound state under static, MAS, and slow MAS conditions.160 The polyunsaturated fatty acid docosahexaenoic acid (DHA, 22:6, n-3) is found at a level of about 50% in the phospholipids of neuronal tissue membranes and appears to be crucial to human health. DPPC and the DHA containing 1-stearoyl-2docosahexenoyl phosphatidylserine (SDPS) were used to make DPPC (60%)/SDPS 224 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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(40%) bilayers with and without 10 mol% chlorpromazine (CPZ), a cationic, amphiphilic phenothiazine. It was suggested that CPZ bound to the phosphate of SDPS will slow down and partially inhibit such a DHA acyl chain movement in the DPPC/SDPS bilayer.161 The active site of K+ channels catalyses the transport of K+ ions across the plasma membrane-similar to the catalytic function of the active site of an enzymeand is inhibited by scorpion venom toxins. Using solid-state NMR spectroscopy, it was shown that high-affinity binding of the scorpion toxin kaliotoxin to a chimaeric K+ channel is associated with significant structural rearrangements in both molecules. The approach combined the analysis of chemical shifts and 1H–1H distances and demonstrates that solid-state NMR is a sensitive method for analysing the structure of a membrane protein-inhibitor complex.162 Membrane proteins in highly oriented lipid bilayer samples are useful for membrane protein structure determination. A variety of different methods for this were shown.163 A model membrane system composed of egg sphingomyelin (SM), DOPC, and cholesterol was studied with static and magic angle spinning 31P-NMR spectroscopy. This model membrane system is of significant biological relevance since it is known to form lipid rafts.164 Solid-state NMR experiments on mechanically aligned bilayer and magnetically aligned bicelle samples showed that membrane proteins undergo rapid rotational diffusion about the normal in phospholipid bilayers. Narrow singleline resonances are observed from 15N labeled sites in the trans-membrane helix of the channel-forming domain of the protein Vpu from HIV-1 in phospholipid bilayers.165 A series of histidine-containing peptides (LAH4X6) was designed to investigate the membrane interactions of selected side chains. To this purpose, their pH-dependent transitions from in-plane to transmembrane orientations were investigated by attenuated total reflection FTIR and oriented solid-state NMR spectroscopy.166 Cannabinoid receptors are G-protein-coupled receptors comprised of seven transmembrane helices. It was hypothesized that the extended helix of the receptor interacts differently with POPC bilayers due to the differing distribution of charged amino acid residues. To test this, hCB1(T377-E416) and hCB2(K278-H316) peptides were studied with 31P and 2H solid-state NMR spectroscopy by incorporating them into POPC bilayers. Lipid affinities of the different residue peptides were analyzed on the basis of 31P and 2H spectral line shapes, order parameters, and T1 relaxation measurements of the POPC bilayers.167 Channel-forming colicins are bacterial toxins that spontaneously insert into the inner cell membrane of sensitive bacteria to form voltage-gated ion channels. To understand the dependence of colicin structure and dynamics on the membrane surface potential, solid-state NMR was used to investigate the topology and segmental motion of the closed state of colicin la channel-forming domain in membranes of different anionic lipid contents and ion concentrations.168 To investigate the properties of a pure liquid ordered (Lo) phase in a model membrane system, a series of saturated phosphatidylcholines combined with cholesterol were examined by variable temperature multinuclear (1H, 2H, 13C, 31P) solidstate NMR spectroscopy and X-ray scattering. Compositions with cholesterol concentrations Z 40 mol %, well within the Lo phase region, are shown to exhibit changes in properties as a function of temperature and cholesterol content.169 Membrane topology changes introduced by the association of biologically pertinent molecules with membranes were analyzed utilizing the 1H–13C heteronuclear dipolar solid-state NMR spectroscopy technique (SAMMY) on magnetically aligned bicelles. The phospholipids 1H–13C dipolar coupling profiles lipid motions at the headgroup, glycerol backbone, and the acyl chain region.170 b-sheet antimicrobial peptides and a-helical channel-forming colicins are bactericidal molecules that target the lipid membranes of sensitive cells. Understanding the mechanisms of action of these proteins requires knowledge of their three-dimensional structure in Nucl. Magn. Reson., 2007, 36, 196–243 | 225 This journal is

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the lipid bilayer. Solid-state NMR has been used to determine the conformation, orientation, depth of insertion, oligomerization, mobility, and lipid interaction of these membrane peptides and proteins.171

6.7 Pharmaceutical applications A broad understanding of the binding modes of ligands and inhibitors to cytochrome P450 is vital for the development of new drugs. Ligand binding in a sitespecific fashion on cytochrome P450 BM-3 from Bacillus megaterium, a 119 kDa paramagnetic enzyme, using solid-state MAS NMR was investigated.172 In an interesting combination of techniques, both solid-state NMR and powder XRD were used to study of a novel and stable polymorph of paclitaxel (Taxol) with two molecules per asymmetric unit. The method, employing solid-state NMR constraints, allowed the XRPD Rietveld analysis to establish many of the lattice details that otherwise would be unavailable. NMR structural constraints are provided by isotropic shifts and 3D chemical shift tensors, which are determined by ab initio quantum mechanical calculations.173 To investigate the solvate molecules within estradiol crystal forms, four crystal forms of estradiol were obtained by recrystallization from various organic solvents and their physicochemical properties were characterized using XRD, TGA, DSC and solid-state NMR.174 The study utilizes an oral biocompatible material based on ethylene vinyl acetate copolymer designed to release drugs in vitro at therapeutic levels over several days. The drug stability during film casting process was examined using solid-state NMR techniques.175 13C CP MAS NMR was used to study sildenafil citrate (Viagra) for the identification and quantitation of Viagra in its pharmaceutical formulations.176 13 C MAS NMR spectra of the stable polymorphs of solid bambuterol hydrochloride (BHC) and terbutaline sulfate (TBS) are reported and the resonances assigned with the aid of solution-state spectra.177 The stable polymorphic forms of two drug molecules, indomethacin and nifedipine by 13C CP MAS, 1H relaxation techniques and the resonances have been assigned.178 A detailed analysis of molecular structure in three polymorphic forms of 5-methyl-2-[(2-nitrophenyl)amino]3-thiophenecarbonitrile is made using a combination of multidimensional solid-state NMR experiments and molecular modeling via electronic structure calculations.179 13 C CP MAS has been utilized to extract the molecular structure information of Taxol, which is an anti-tumor therapeutic medicine extracted from the yew bark. The 13C NMR signals have chemical shift values quite consistent with those measured in solution phase.180 Solid-state line widths were measured for various ibuprofen preparations, including crystallization from different solvents, melt-quenching, manual grinding, cryogrinding, compacting, and by blending with various excipients.181 A solid-state NMR MAS probe that can simultaneously acquire up to seven SSNMR spectra is being developed to increase throughput/signal-to-noise ratios.182 Solid-state MAS NMR approaches for the elucidation of structures of the coordinating ligands/drugs and their modes of interactions with the G-protein coupled receptor was examined.183

6.8 Cellulose and related materials The 13C CP MAS NMR line shape of cellulose I has been qualitatively analyzed by direct simulations using the Ornstein-Uhlenbeck stochastic process and the Kubo model. Both approaches describe a hydroglucose C4 carbon as an oscillator with fluctuating Larmor frequency. The simulation results both motivates the use of multiple line shapes when fitting 13C CP MAS NMR spectra recorded on cellulose I 226 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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and gives some insights into why signals from crystalline cellulose I give rise to Lorentzian line shapes.184 The solid-phase nitration and acetylation processes of bacterial cellulose have been investigated mainly by 13C CP MAS NMR spectroscopy to clarify the features of these reactions in relation to the characterization of the disordered component included in the microfibrils.185 Fully bleached softwood kraft pulps were hydrolyzed with cellulase (1,4-(1,3:1,4)beta-D-glucan 4-glucano-hydrolase) from Trichoderma reesei. Structural features of cellulose during enzymatic hydrolysis were examined by using 13C CP MAS NMR spectra in combination with line-fitting analysis.186

6.9 Soils and related materials The environmental impact of forest fire on soil quality is not well understood. This study investigated the composition of organic functional groups as determined by 13 C CP MAS NMR. The 13C CP MAS NMR analyses confirmed that the forest soils exposed to fires had higher potential for humification than unburned control soils.187 Charred organic matter is assumed to contain heavily condensed polycyclic aromatic domains with a considerable proportion of core carbons. To examine their possible underestimation using variable amplitude (VA) 13C CP MAS NMR, the condensation degree of a peat subjected to thermal oxidation and was examined by means of elemental analysis and various NMR techniques.188 Two fractions of dissolved organic matter from a French river, the Gartempe, were obtained using a resin fractionation procedure and were investigated with solidstate 13C CP MAS NMR.189 This study was conducted to investigate the influence of land-use systems and of long-term no-till cropping systems on the composition of organic N forms in a subtropical Acrisol. Soil samples collected were examined by 13C and 15 N CP MAS NMR.190 Elemental composition and spectroscopic properties by FTIR and 13C CP MAS NMR of sedimentary humic substances from aquatic subtropical environments (a lake, an estuary and two marine sites) were investigated.191 Virtually all of the nitrogen detected by 15N CP MAS NMR spectra of four soil clay fractions is amide nitrogen. However, the intensity of this 15N CP NMR signal is 27–57% lower than detected for a wheat protein, gliadin. Two explanations were suggested: the amide N in the soil clay fractions produces proportionately less NMR signal than does the amide N in gliadin, or part of the N in the soil clay fractions produces little or no NMR signal. The CP dynamics of the systems were also investigated.192 Soil destruction was examined by solid-state NMR.193 The variable effect of different types of forest fires on the quantity and quality of soil organic matter was analysed by solid-state 13C NMR spectroscopy.194 Chemically and physically fractionated samples extracted from the surface horizon of a soil developed under a mix of coniferous and deciduous vegetation in southwestern Colorado were studied by 13C MAS NMR.195 Pyrophosphate is the main form of condensed P in the fluid fertilizer ammonium polyphosphate (APP). When APP is applied to soil, pyrophosphate is hydrolyzed to orthophosphate. Changes in P speciation were measured using solid-state 31P NMR spectroscopy.196 Burial of organic carbon in ocean sediments acts as the ultimate long-term sink for both terrestrial and marine carbon, however, the mechanisms controlling the preservation of this carbon are poorly understood. To better understand these mechanisms, solid-state 13C NMR spectroscopy was applied, along with other techniques.197 Nucl. Magn. Reson., 2007, 36, 196–243 | 227 This journal is

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6.10 Coals and carbonaceous materials 13

C MAS NMR was used to study carbon nanotubes grown by catalytic decomposition of acetylene on Fe-silica catalysts. This work analyzed the 13C-NMR signals from CNTs specially prepared using 13C enriched (499%) acetylene as a reactant, several new subspecies were identified.198 Solid-state NMR measurements organoaluminium complexes in coal substance are presented.199 Solid-state 13C CP MAS NMR spectroscopy and ultimate analysis have been applied to a study of samples from the Pleistocene Drama lignite.200

6.11 Polymers The crystalline structure of polyamide-12 (PA12) was studied by solid-state 13 C MAS NMR as well as by synchrotron wide- and small-angle X-ray scattering (WAXS and SAXS).201 Complexes of poly(methacrylic acid) (PMAA) and poly(ethylene oxide) (PEO) with different PEO molecular weight were studied by solidstate 13C NMR spectroscopy. The results of 1H T2 and 13C T1 indicate that the chain mobility of both PEO and PMAA are greatly restricted by inter-molecular hydrogen-bonding interactions.202 Solid-state 13C NMR was employed to characterise polymers made of per-3,6anhydro-a-cyclodextrins with 1,6-diisocyanato-hexane used to bridge the macrocyles.203 A biodegradable diblock copolymer of poly(e-caprolactone) (PCL) and poly (L-lactide) (PLLA) was synthesized and characterized. The inclusion compound of this copolymer with a-cyclodextrin (a-CD) was formed and characterized. Solidstate 13C NMR techniques were used to investigate the morphology and dynamics of both the bulk and a-CD-IC isolated PCL-b-PLLA chains.204 Solid polymer electrolytes based on polyvinyl alcohol (PVA)/ammonium acetate have been prepared for different compositions by solution cast technique. The polymer electrolytes have been characterized by 1H solid-state NMR and other techniques. 1H NMR study has been employed to develop a better understanding of the conduction mechanism.205 Following a previous study on the stereoselective cocrystallization of linear and cyclic dicarboxylic acid residues in copolyamides 12.6/12.1,4-cyclohexanedi carboxylic acid, a series of copolyamides containing trans or cis isomers of 1,4diaminocyclohexane was investigated by solid-state NMR studies and WAXD experiments. These demonstrated that the cis isomer is present in the amorphous regions of the copolyamide, whereas the trans isomer is located in both the crystalline and the amorphous phase.206 This paper deals with the determination of the main characteristics and the assignment of the molecular motions leading to the solid-state transitions observed in amorphous polymers at temperatures lower than the glass-rubber transition. Whereas all the systems considered were investigated by 13C solid-state NMR experiments, some systems were also studied by other techniques such as dielectric relaxation and molecular modelling.207 Two grades of a novel biodegradable copolymer of o-pentadecalactone (PDL) and 2-oxo-12-crown-4 (OC), were characterized with 1D and 2D MAS 1H and 13C NMR spectroscopy. The results indicate that both copolymers are semi-crystalline with PDL divided over the crystalline and amorphous phase, and OC exclusively located in the amorphous phase. 1H T2 and T1 relaxation confirm the existence of small crystalline domains.208 13 C T1 of a conjugated polymer poly[2-methoxy-5-(2 0 -ethyl-hexyloxy)-1,4-phenylene vinylene] in polymer/layered silicate nanocomposites together with the steady state fluorescence emission and transient fluorescence decay measurements have been investigated.209 228 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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Solid-state 1H NMR spectroscopy and other techniques have been performed to evaluate the compatibilising action of random copolymers of polystyrene and polybutadiene and triblock copolymers of poly(styrenebutadiene-styrene) in incompatible polystyrene/polybutadiene (PS/PB) blends. Solid-state 1H NMR experiments were performed on the uncompatibilised and compatibilised blends. The 1H T1, T1r, and T2, were carefully measured for the systems. Significant changes were observed for the systems studied.210 Copolymer networks synthesized from dilactide and diglycolide were characterized by solid-state 13C CP MAS and 1H DQ NMR buildup curves NMR in terms of composition, cross-link density, and rate of cross-linking by UV irradiation.211 In an interesting study, the orientational distribution function for polymer chain segments in plain-strain compressed glassy poly(methyl methacrylate) is evaluated, as a function of two polar angles, from a series of 1D 2H NMR spectra. The experimental data are analyzed using a tailored regulatory approach.212 Peroxide-cross-linked EPM and EPDM rubbers have been investigated with MAS 1 H NMR spectroscopy and static 1H NMR relaxometry.213 The domain-structure of a series of starch/poly (sodium acrylate) grafted samples, in comparison with starch, poly(sodium acrylate) and starch/poly(sodium acrylate) blend, was studied by solid-state 13C NMR spectroscopy at room temperature.214 The motional heterogeneity of a series of poly(ether-block-amide) copolymers was presented and discussed in terms of its NMR fingerprints dependent on a content and length of hard and soft segments and a microphase-separated morphology. Local-field dipolar spectra carry a straightforward signature of microphase-separated morphology endowed with a strong mobility gradient. 1H MAS spectra provides an another fingerprint of phase-separated systems. Other NMR experiments were also carried out.215 13 C solid-state NMR spectroscopy was used to study the structure of amorphous poly(carbonsuboxide) (C3O2)(x). Two different 13C labeling schemes were applied to probe inter- and intramonomeric bonds in the polymer by dipolar solid-state NMR. Four types of carbon environments were distinguished in the NMR spectra. DQ and TQ 2D correlation experiments were used to assign the observed peaks using the through-space and through-bond dipolar coupling. To obtain distance constraints for the intermonomeric bonds, DQ constant-time experiments were performed.216 Polymer blends of polybenzoxazine (PBZ) and poly(e-caprolactone) (PCL) were prepared by solution blending of PCL and benzoxazine monomer. The miscibility and thermal behavior of these PBZ/PCL blends were investigated by solid-state 1H and 13C NMR spectroscopy.217 In a an interesting paper the torsion angles of the OC–CO bonds in crystalline poly(ethylene oxide), PEO, were investigated by solid-state NMR. 2D double quantum (DOQSY) spectra indicate that the OC–CO bonds are all gauche with a narrow torsion-angle distribution. The low-temperature 13C MAS NMR spectrum of unlabeled PEO contains four maxima and several shoulders. Deconvolution of this spectrum, together with 2D 13C INADEQUATE NMR and exchange MAS spectra, suggests a possible assignment of chemical shifts to the 14 carbons in the helical repeat unit.218 Nanoconfined polymer chains, formed when polymers intercalate into layered inorganic materials-show remarkable bulk properties, many of which are connected to dynamical heterogeneity in the polymeric phase. In this work, the slow dynamical modes were examined by 1D and 2D 2H exchange NMR experiments.219 The local dynamics of aromatic cores were analyzed for a series of polyamides in the solid phase incorporating phenyl, biphenyl and naphthyl groups. Preliminary wide-line and spin-relaxation VT 1H NMR measurements revealed the presence of thermally activated molecular motions for each polymer studied. A number of 13C NMR experiments were then implemented to further clarify the nature and extent of such motions. These included 1H–13C 2D separate-local-field measurements, whose Nucl. Magn. Reson., 2007, 36, 196–243 | 229 This journal is

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line shapes revealed that motions involved for all cases a superposition of states.220 The structural changes in unfilled and filled vulcanized deproteinized natural rubber, which is a highly purified natural rubber (NR), were investigated by solid-state 13C NMR spectroscopy. The chemical shifts of new signal were assigned by calculation and compared with those observed by Koenig et al. for conventional vulcanized NR.221 13C NMR spectroscopy was used to analyze the sequence distribution of two diols, 2,2-bis(4-[hydroxyethoxy]phenyl)propane and bis(2 hydroxyethyl)terephthalate, which were incorporated into poly(butylene terephthalate) by solid-state and melt polymerization.222 1 H mobilities in Nafion and sulfonated poly(ether ether ketone) (S-PEEK) have been studied using high-resolution solid-state VT 1H NMR under fast MAS. These studies demonstrated proton exchange between sulfonic acid groups and water within both Nafion and S-PEEK. A rotor-synchronized homonuclear double quantum filter sequence (BABA) was used to disclose the nature of the H-bonding interactions in the two polymers.223 The article examines the characterization of local structures in water-blown flexible polyurethane foams with various amine catalysts. In this study, the authors have applied solid-state NMR relaxation, nuclear spin diffusion techniques.224 The structure and hydrogen bonding of the melt-crystallized atactic poly(vinyl alcohol) (PVA) films, which were carefully prepared without significant thermal degradation, have been charactefized by 13C CP MAS NMR spectroscopy. The 13C T1 relaxation analysis has revealed that there exist three components with different 13 C T1 values, the crystalline, less mobile noncrystalline and mobile noncrystalline components, in good accord with the results for different PVA samples previously reported. Appreciable differences were found between the different preparation methods.225 The structure and dynamics of highly drawn polyethylene samples were studied by solid-state 13C NMR spectroscopy. The analysis of the 13C T1, T2 and CSA patterns were carried out. It was revealed that at least three components with different T1, T2 values, which correspond to the crystalline, less mobile non-crystalline, and rubbery amorphous components. Another new component was found and attributed to the all-trans conformation.226 The quantitative investigation of the radical scavenging properties of polyaniline upon reaction with excess of a stable radical was carried out using 15N and 13C solidstate NMR and ESR spectroscopy.227 The molecular dynamics of poly(L-lactide) (PLLA) biopolymer was characterized through analyses of 1H and 2H NMR line-shapes and T1 relaxation times at different temperatures. At low temperatures, the methyl group rotation is dominant leading to a significant reduction in the proton second moment. In additional to the fast methyl group rotation, hydroxyl groups start to reorient as the temperature increases further, eventually leading to the breakdown of the segments of the biopolymer chains above its glass transition temperature.228 The ternary blends of poly(methyl methacrylate)/poly(vinyl pyrrolidone)/poly(ethylene oxide), PMMA/PVP/PEO, were prepared by melting process, and solidstate NMR was used as a methodology to characterize the molecular mobility of blend components. The NMR results showed that the blends were miscible on a molecular level.229 In cold-drawn, necked high-density polyethylene, solid-state NMR has identified a major fraction of chain segments intermediate to the ordered crystalline and the almost isotropic amorphous phases. This partially mobile and disordered all-trans fraction in the strain-hardened sample contains of all chain segments in the bulk. A series of 1D- and 2D- NMR experiments, several of which make use of an ‘‘inverse 13 C T1 relaxation time filter’’ for selective observation of the intermediate-component signals, show the intermediate component to consist of all-trans chains with disordered packing.230 230 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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6.12 Organometallic and coordination compounds Solid-state MAS 73Ge NMR spectra of some organogermanium compounds were measured. The spectra indicated the symmetry around the Ge nucleus.231 A number of lead(II) O,O 0 -dialkyldithiophosphate complexes were studied by 13C, 31 P, and 207Pb MAS NMR. Simulations of 31P CSA using spinning sideband analysis reveal a linear relationship between the S–P–S bond angle and the principal values d22 and d33 of the 31P CS tensor.232 139 La NMR spectra of static samples of several solid La(III) coordination compounds have been obtained at applied magnetic fields of 11.75 and 17.60 T. The breadth and shape of the 139La NMR spectra of the central transition are dominated by the interaction between the 139La nuclear quadrupole moment and the EFG at that nucleus; however, the influence of chemical-shift anisotropy on the NMR spectra is non-negligible for the majority of the compounds investigated. Detailed analysis of the quadrupolar coupling and the CSA tensor were carried out.233 The quadrupolar Carr-Purcell Meiboom-Gill (QCPMG) and double frequency sweep (DFS)/QCPMG pulse sequences are applied in order to acquire the first solidstate 39K NMR spectra of organometallic complexes, the polymeric main group metallocenes cyclopentadienyl potassium (CpK) and pentamethylcyclopentadienyl potassium (Cp*K). Piecewise QCPMG NMR techniques are used to acquire a high S/N 39K spectrum of the broad central transition of Cp*K, which is ca. 200 kHz in breadth. Analytical and numerical simulations of the quadrupolar coupling constant were carried out together with other 13C MAS NMR experiments.234 A combination of 27Al MAS and MQ MAS, 13C CP MAS, and 13C-{27Al} transfer of population in double-resonance (TRAPDOR) NMR were used for the structural elucidation of the aluminum alkoxides aluminum ethoxide, aluminum isopropoxide, and aluminum tertiarybutoxide. Aluminum alkoxides exist as oligomers with aluminum in different coordinations.235 Two coordination compounds of palladium(II) with N-allylimidazole (L) of the general formula [PdL4]Cl2 3H2O (1) and trans-[PdL2Cl2] (2) have been synthesized. The crystal and molecular structure of complexes 1 and 2 was established by singlecrystal XRD analysis. The X-ray structural data were supplemented by solid-state 13 C NMR measurements.236 Three organosodium complexes, diphenylmethyl sodium, diphenylmethylsodium, and fluorenylsodium, 13C and 23Na solid-state NMR spectra have been measured. They were analysed in terms of CSA and quadrupolar coupling constants.237 The isomeric states and intermolecular packing of tris(8-hydroxyquinoline) aluminum(III) in the alpha-, gamma-, and delta-crystalline forms and in the amorphous state, which are important for understanding the light-emitting and electron-transport properties, have been analyzed by 13C CP MAS NMR.238

6.13 Glasses and amorphous solids The local structural environment and the spatial distribution of the lithium ions in lithium silicate glasses with composition (Li2O)x(SiO2)(1x) (0 o x r 0.40) is studied by NMR and molecular dynamics simulation experiments. Site resolved 29Si{7Li} REDOR studies reveal that the 7Li dipolar fields vary depending upon each site.239 Solid-state NMR has been used to study a complex mixture resulting from the devitrification of an aluminophosphate glass.240 Fluorine containing glasses are important components for glass ionomer cements. Their main advantage is the long-term fluoride release during application. This paper deals with the MAS NMR structural characterization of a series of fluorine containing glasses that could possibly be used for glass ionomer cements and they are based on the following composition: (1.5)SiO2Al2O3(0.5/0.25)P2O5(1-Z-Y) CaO(0.5)CaF2(Z)SrO(Y)Na2O, where X = 0.5, Y = 0.0 or 0.2 and Z = 0.0, 0.8 Nucl. Magn. Reson., 2007, 36, 196–243 | 231 This journal is

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and 1.0. 29Si MAS NMR spectra gave strong evidence for the presence of Q4(4Al) and Q4(3Al) species. 27Al MAS NMR spectra showed the presence of largely Al(IV) and a smaller proportion of Al(VI) particularly in glasses with high phosphorus content. The main species observed by 19F MAS NMR spectra were F–Ca/Srn and Al–F–Ca/Srn.241 Glass and crystalline phases of ceramic waste forms were investigated via powder XRD, scanning electron microscopy, and 29Si, 27Al, 23Na, 7Li, and 35 Cl MAS NMR.242 In an extensive paper, Lee discusses the recent development and advances in solidstate NMR and how its combination, with other techniques has allowed the estimation and quantification of cations and anions in model silicate glasses and melts with varying pressure, temperature and composition. How these microscopic, atomic-scale distributions in the melts from NMR and simulations affect the thermodynamic and transport properties relevant to magmatic processes has been extensively explored recently. Solid-state NMR, particularly 3Q MAS NMR, was found to be most useful.243 The glass-forming reactions between sodium carbonate and silica have been investigated by 23Na, 29Si and 13C MAS NMR. The multinuclear MAS NMR approach identifies and quantifies reaction products and intermediates, both glassy and crystalline.244 Neutron diffraction and isotope-enriched 17O MAS NMR, have been used to characterise the structure of catalytically active (TiO2)x(SiO2)(1x) sol-gel glass as a function of calcination temperature. The results reveal directly two Ti–O distances in a homogeneous sol-gel derived glass. Neutron diffraction using 44 Ca and isotope enriched 17O MAS NMR have also been used to study the detailed nature of the structure of CaO–SiO2 bioactive sol-gel glasses.245 The molecular mechanism of apatite formation on bioactive glass surface is studied using the techniques of solid-state 31P NMR and other techniques. The experimental data support the apatite formation mechanism proposed by Hench concerning the precipitation and crystallization of calcium phosphate.246 An advanced materials characterisation methodology has been used to examine systematically a range of sol-gel glass materials of contemporary biomedical interest. 17O and 31P MAS NMR and a wide range of other techniques have been used to study the local calcium environment in four sol-gel derived bioactive calcium silicate glasses of the general formula (CaO)x(SiO2)(1x).247 Carbon-rich Si–O–C polymer-derived ceramics (PDCs) were investigated by solidstate NMR and other spectroscopic techniques, in order to characterize the evolution of their predominantly amorphous microstructure upon thermal treatment.248 This work reports the structure of two glass ceramics prepared in the calcium phosphate system, MK5B and MT13B, using 31P MAS NMR technique. The results obtained showed that the network connectivity and Q structure of the samples.249 A multinuclear solid-state NMR investigation of the structure of the amorphous alteration products (so called gels) that form during the aqueous alteration of silicate glasses is reported. The studied glass compositions are of increasing complexity, with addition of aluminum, calcium, and zirconium to a sodium borosilicate glass. Two series of gels were obtained, in acidic and in basic solutions, and were analyzed using 1 H, 29Si and 27Al MAS NMR spectroscopy. Advanced NMR techniques have been employed such as 1H–29Si and 1H–27Al CP MAS NMR, 1H DQ MAS NMR and 27 Al MQ MAS NMR. The combination of technique enabled the authors to establish a gelation process for the complex glass systems.250 The suitability of Glass Polyalkenoate Cements (GPCs) for orthopaedic applications is retarded by the presence in the glass phase of aluminium, a neurotoxin. Unfortunately, the aluminium ion plays an integral role in the setting process of GPCs and its absence is likely to hinder cement formation. However, aluminium-free GPCs may be formulated based on calcium-zinc-silicate glasses and these novel materials exhibit significant potential as hard tissue biomaterials. However there is no data available on the structure of these glasses so they were examined by 29Si MAS NMR and other techniques.251 232 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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Al, 23Na and 17O solid-state MAS NMR and 3Q MAS spectra were obtained for sodium tetrasilicate glasses quenched from melts at high pressure up to 8 GPa. The results show clear evidence for the pressure-induced structural changes in the glasses, forming oxygen linking Si-[4] and Si-[5,Si-6] (Si-[4]-O-Si-[5,Si-6]) with increasing pressure.252 The structure and properties of glasses and melts in the CaO–Al2O3–SiO2 (CAS) system play an important role in earth and material sciences. In this paper new results using Raman spectroscopy and 27Al NMR on CAS glasses were obtained by classic and rapid quenching methods. An Al/Si tetrahedral distribution in the glass network in different Qn species was shown.253 The structures of sodium aluminophosphate glasses prepared by both sol-gel as well as melt-cooling routes have been extensively characterized by high-resolution solid-state 23Na, 31P and 27Al single and double-resonance NMR techniques, including quantitative connectivity studies by 27Al–31P and 23Na–31P REDOR methods. Studies along four compositional lines, I: (AlPO4)x-(NaPO3)(1-x), II: (Na2O)(x)-(AlPO4)(1x), III: (NaAlO2)(x)-(NaPO3)(1x), and IV: (Al2O3)(x)(NaPO3)(1x), reveal that the network structures of those glasses that are accessible by either preparation method are essentially identical.254 Strontium is one of the most common substituents in apatite crystals. The presence and behavior of Sr in apatite-group phases are of considerable significance in biology. The present paper investigates the substitution of strontium for calcium in a glass-ceramic of the following composition 4.5SiO23Al2O31.5P2O54CaO1.0CaF2. The glasses were characterized and 19F MAS NMR and other techniques. The all calcium glass crystallized to calcium fluorapatite (Ca5(PO4)3F). Substituting strontium partially for calcium resulted in the formation of a mixed strontium/calcium fluorapatites.255 Sodium ultraphosphate glasses (Na2O)x(P2O5)(1x) show a strongly non-linear dependence of the glass transition temperatures Tg on composition. To explore the structural origins of this behaviour, local and medium range ordering processes have been investigated by 23Na NMR spectroscopies. In particular, 31P–{23Na} and 23Na– {31P} REDOR and 3Q MAS experiments have been analyzed to yield quantitative constraints for the structural description of these glasses.256 6.14 Microporous solids and related materials Several heteronuclear dipolar-coupling based 27Al–31P, 31P-11B, 27Al–11B, 27Al–29Si and 1H–31P double-resonance solid-state NMR techniques to characterize boroaluminophosphate (BAPO)- and silicoaluminophosphate (SAPO)-based mesoporous materials. For the hexagonal BAPO materials, the coordination geometry of the B atoms in the framework was established. For the SAPO-based mesophase, the connectivities between various P and Al sites were found by this study.257 From the solid-state NMR evidence it was shown that Si atoms are not randomly distributed in microporous SAPO-35 materials.258 NMR method that establishes the correlation among three different nuclei was shown. It avoids the difficulty to directly explore the weak coupling between two NMR nuclei, such as 29Si and 27Al. Using this method, it was possible to give an unambiguous assignment to the various peaks in 29Si CP NMR spectrum of MCM-22 zeolite.259 27 Al spin-echo, high-speed MAS (nrot = 30 kHz), and MQ MAS NMR spectroscopy at different magnetic fields were applied for the study of aluminum species at framework and extra-framework positions in non-hydrated zeolites Y.260 A local structure analysis using 27Al MQ MAS and MAS NMR techniques has been performed on porous alumina fabricated by the anodic oxidation of aluminum.261 Species at three stages in the self-assembly of zeolite ZSM-5 have been studied with 1D and 2D MAS 13C, 27Al, 29Si, and 1H NMR spectroscopy and compared with the earlier proposed structures. The effective Si–H and Al–H distances measured with 29Si{1H } and 27Al–{1H} REDOR reflect the interactions between cations and the surrounding aluminosilica.262 Nucl. Magn. Reson., 2007, 36, 196–243 | 233 This journal is

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Al MAS and MQ MAS NMR spectroscopy were used to study the aluminum coordination in dealuminated mordenite. An 27Al MAS NMR signal ascribed to distorted tetrahedrally coordinated Al (DTetrA]) was detected.263 The adsorption of toluene molecules inside zeolite Na–Y by 23Na MAS NMR, static 1H NMR, 1 H–23Na CP and 23Na{1H} REDOR techniques.264 The distributions of Bro¨nsted acidic protons and their acid strengths in zeolite H-MCM-22 have been characterized by density functional theory (DFT) calculations as well as MAS NMR experiments. The DFT theoretical and NMR experimental results enabled a comparison between the different acid sites with other zeolites.265 Dynamics of deuterated p-nitroaniline molecules in the micropores of AlPO4-5 has been investigated by means of solid-state NMR. The 13C MAS and 2H NMR spectra of the guest molecules and 27Al MAS NMR spectra of the host framework were examined.266 VT 29Si MAS NMR spectroscopy has been used to study the thermal behaviour of the aluminosilicate zeolite ferrierite.267 A series of anionic framework aluminophosphates, with different Al/P ratios, have been investigated by 27Al, 31P MAS, 27Al–31P CP, 27Al{31P}REDOR, and 31P{27Al } TRAPDOR. Different Al and P coordinations can be unambiguously determined based on the solid-state NMR spectroscopy.268 The acidity of mesoporous MoOx/ZrO2 and WOx/ZrO2 materials was studied in detail by 1H, 13C and 31P MAS NMR as well as DFT quantum chemical calculations. The multinuclear approach examined different substrates in the mesoprous material.269 Pure aluminophosphate, UT-4, was synthesized using pyridine solvent. 27 Al, 31P MAS, 27Al–31P CP, 1H–31P CP and 27Al–31P HETCOR experiments were employed to investigate the framework of UT-4.270 Mesoporous titanium oxide synthesized using a dodecylamine template was treated with Li- or Na-naphthalene. The composite materials were characterized by solid-state 23Na and 7Li NMR spectroscopy.271 The nature of acid sites in Al-SBA-15 materials with various Si/Al ratios was studied by various NMR techniques including 27Al, 29Si, 1H, 31P MAS, and some double-resonance methods such as 1H -27Al TRAPDOR.272 Dry-gel conversion is a relatively new approach for molecular sieve synthesis. The involvement of 17O-enriched water vapor in crystallization of AlPO4-11 (an aluminophosphate-based molecular sieve) was monitored by 17O solid-state NMR spectroscopy. In addition to 17O MAS technique, several dipolar coupling based double-resonance methods including 17O{27Al}, 17O{31P} REDOR, 17O–31P and 1H–17O CP techniques were used for spectral editing to select different 17O species.273 Catalysts of ZSM-5 type were obtained by synthesis with tetrapropyl-ammoniumbromide (TPABr) as a template and subsequent hydrothermal treatment. 27Al, 29Si, 1 H MAS NMR and 27Al MQ MAS spectroscopy were used to investigate the system.274 It has been demonstrated that 1H MAS NMR compared to 13C MAS NMR spectroscopy can be used as a tool for in situ monitoring the reaction kinetics of 13Clabeled carbon scrambling in alkane molecules adsorbed on zeolite catalysts.275 Solid-state NMR characterization of zeolite catalysts in the hydrated state is often accompanied by an uncontrolled hydrolysis of the framework. In the present work it is demonstrated that the limitations occurring for 27Al, 29Si, MAS NMR spectroscopy of non-hydrated zeolites Y, such as strong decrease of resolution and significant line broadening, can be overcome by loading these materials with ammonia.276 The aluminophosphate framework material AlPO4-14A has a number of unique structural features related to the connectivities in the network of Al and P atoms. A variety of 27Al, 29Si, 31P solid-state NMR experiments have been employed to characterize the AlPO4-14A structure. These together with 27Al 3Q MAS, 1H{27Al} TRAPDOR and 27Al–31P INEPT, 1H–31P CP and 1H–27Al TEDOR experiments show the unique features of this experiment.277 The location of naphthalene in the zeolite ZSM-5 has been determined from solid-state 1H–29Si CP MAS NMR data alone.278 234 | Nucl. Magn. Reson., 2007, 36, 196–243 This journal is

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6.15 Surface science and catalysis Solid-state NMR techniques such as 1H, 31P MAS and 1H–11B, 1H–27Al, 31P-27Al TRAPDOR NMR together with DFT quantum chemical calculations were employed to investigate the detailed structure of acid sites on the BF3/g-Al2O3 alkylation catalyst.279 71 Ga, 27Al, and 29Si MAS NMR and DRIFT spectroscopies were used to characterize the state of gallium in Ga/H-ZSM5 catalysts tested for their ability to catalyse the ammoxidation of propane.280 Solid-state NMR spectroscopy and DFT calculations were employed to study the structure and properties, especially the solid acidity, of MoO3 supported on SnO2. As demonstrated by solid-state NMR experiments, the structure of the active sites was proposed.281 Adsorption of trichloroethylene on alumina-supported palladium catalysts (Pd/Al2O3) was studied in the presence and absence of hydrogen using 13C solidstate NMR. 13C NMR spin-echo amplitude data measured as a function of pulse separation, t, was used to determine the 13C–13C intramolecular dipolar coupling and the carbon–carbon bond length of adsorbed species.282 The interfacial interaction of Mo species with the H-b zeolite was studied by multinuclear 27Al, 29Si and 1H MAS NMR and other techniques. solid-state NMR showed the structural changes in the catalyst.283 The dynamics of interlayer H2O in VOPO4 2H2O have been studied by 1H and 2H NMR measurements. This compound contains two different kinds of water molecules. The interaction of the water was studies as a function of temperature.284 The coordination of OH groups on MgO has been characterized by 1H MAS NMR after appropriate pre-treatment conditions to obtain surfaces free from carbonates and with a controlled degree of hydroxylation.285 The chemically active phosphorus surface sites defined as equivalent to POx, equivalent to POxH, and POxH2, where x = 1, 2, or 3, and the bulk phosphorus groups of PO43 at synthetic carbonate-free fluorapatite (Ca5(PO4)3F) have been studied by means of single-pulse 1H,31P, and 31P CP MAS NMR. The changes in composition and relative amounts of each surface species are evaluated as a function of pH.286 The fate of the persistent organophosphate nerve agent O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) on granular activated carbons that are used for gas filtration was studied by means of 31P MAS NMR spectroscopy.287

6.16 Inorganic and other related solids Solid-state 87Rb NMR characterization for rubidium cations bound to G-quartet structures formed by self-association of guanosine 5 0 -monophosphate and 5 0 -tertbutyl-dimethylsilyl-2 0 , 3 0 -O-isopropylidene guanosine was reported.288 The high sensitivity of the ST MAS NMR technique was exploited to obtain highresolution 17O MAS NMR spectra of the three polymorphs of Mg2SiO4: forsterite (a-Mg2SiO4) wadsleyite (b-Mg2SiO4), and ringwoodite (g-Mg2SiO4). High NMR sensitivity was important in this application because 17O-enriched, Fe-free materials are required for 17O NMR and high-pressure syntheses of the dense beta and gamma polymorphs result in only a few milligrams of these solids.289 This paper gives results from NMR experiments measuring the dynamics of proton motion in various ice samples. Specifically,17O T1 were measured for pure ice, and for HCl and KOH-doped ices.290 The mechanism of the reaction between a silica sample coming from acid treatment of sepiolite and an organosilane, namely bis(triethoxysilylpropyl)tetrasulfane, has been evaluated by solid-state NMR spectroscopy, and compared with the silanization reaction of a commercial silica.291 Polycrystalline tetra-nuclear Cu4[S2P(O-i-C3H7)2]4, hexa-nuclear Cu6[S2P(OC2H5)2]6, and octa-nuclear Cu8[S2P(O-i-C4H9)2]6 complexes were synthesized and analyzed by means of solid-state 31P CP MAS and 65Cu static NMR spectroscopy.292 Nucl. Magn. Reson., 2007, 36, 196–243 | 235 This journal is

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Apatite-type silicates have been attracting considerable interest as a new class of oxide ion conductor, whose conduction is mediated by interstitial oxide ions. 29Si solid-state NMR studies of these materials was carried of thirteen compositions. The results indicate a correlation between the silicon environment and the observed conductivity.293 The mono-starmides of the alkali metals were investigated by 119Sn NMR spectroscopy and full-potential local-orbital method calculations of the electronic structure and calculations of the electron localization function.294 T1, T1r and T2 for the 1H and 2H nuclei in (NH4)3H(SO4)2 and (ND4)3D(SO4)2 single crystals grown using the slow evaporation method were measured for phases I, II, III, IV and V. The 1H and 2H NMR relaxation data was measured for each phase and different trend determined.295 Previous XRD and NMR studies on Ti-doped NaAlH4 revealed the reaction products of two heavily doped samples. On heavily doped solvent-mixed samples, 27Al MAS NMR 27Al MQ MAS indicates the presence of an oxide layer of Al2O3 on the surfaces of potentially bulk nanocrystalline Ti, nanocrystalline TiAl3, and/or metallic aluminum. The 1H MAS NMR and T1 data also indicate the possible coordination of aluminum with oxygen atoms in the THF molecules and the presence of TiH2.296 59Co and 15N NMR spectra of the nitritopentamminecobalt(III) chloride, [(NH3)5CoONO]Cl2, and nitropentamminecobalt(III) chloride, [(NH3)5CoNO2]Cl2.297 Defect-pyrochlores based on the formulation CsM0.5W1.5O6 (M = Ti, Ti/Zr, Zr and Hf) have been studied using neutron diffraction and MAS NMR.298 A Cu(I)/ Cu(II)/Zn(II) mixed-valent [Cu(en)2][Zn(NC)4(CuCN)2] polymer, which has a 2-D layer structure with six structurally inequivalent cyanides in four distinct bonding modes, has been prepared; structurally informative 13C and 15N MAS NMR spectra of this paramagnetic system are readily observable.299 The relation between structure and ion dynamics in the three polymorphs of Ag5Te2Cl has been investigated using 109Ag, 125Te, and 35Cl NMR spectroscopies.300 71 Ga MAS NMR experimental results for polycrystalline GaN samples made by different synthetic approaches, with both unintentional as well as intentional (Ge) dopants have been reported.301 CeRu4Sn6 is a tetragonal ternary compound which develops strong correlations at low temperatures. NMR T1 and Knight shifts investigations on the 119Sn nuclei are reported for the first time.302 VT 17O NMR and T1 measurements, covering a temperature range from room temperature to 973 K, were conducted on various samples from 17O enriched yttriastabilized zirconia for the first time.303

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Multiple pulse NMR Daniel Nietlispach DOI: 10.1039/b618339p

1. Introduction This report is a continuation of the review from last year and surveys literature on multiple resonance methods published in the period June 2005 to May 2006. The current review period featured a remarkable number of contributions that accelerate the recording of multidimensional data. New acquisition schemes emerged that exploit the benefits of faster magnetization recovery and allow faster pulsing thus increasing sensitivity per unit time. Further improvements were described using limited sampling and processing methods which can lead to time-savings of one order of magnitude compared to conventional sampling schemes. These novel acquisition and processing techniques can be combined to bring even larger savings in time. Accordingly a wealth of new or modified triple-resonance assignment experiments has emerged. Further, an amino acid selective position-specific protonation approach has been introduced for efficient and improved structure determination. Protonless methods have been improved for the study of paramagnetic proteins. Additional developments were reported in the areas of side chain and backbone relaxation measurements in particular with applications to off-resonance spinlock and/or relaxation dispersion experiments to measure exchange contributions or in the use of MQ relaxation to monitor correlated protein motions. Continuing improvements were reported for scalar coupling and RDC measurements.

2. General methods and theoretical developments RF pulse and pulse sequence analysis Pulse optimization and maximization of coherence transfer are some of the more recent applications of numerical computer simulations. NMR experiments commonly employ composite and shaped pulses of varying flip angles. Universal rotation (UR) pulses that achieve an effective rotation for any arbitrary initial magnetization vector position are e.g. used for refocusing and mixing. The design of UR pulses is typically considerably more difficult than the development of point-topoint rotation pulses (PP) that achieve a transformation from a given initial position to a defined final direction. A simple recipe was presented by Luy et al.1 that allows the construction of any UR pulse from a PP pulse of half the flip angle through combination of a time- and phase-reversed PP pulse followed by the PP pulse itself. Following this e.g. a refocusing pulse can be constructed from a given excitation pulse by applying the phase-reversed excitation pulse followed by the time-reversed excitation pulse. A wide range of available PP pulses can thus be accessed to construct broadband and selective UR pulses. By taking advantage of recently developed excitation pulses this allows the design of short refocusing pulses. In an attempt to find possible links between pulse sequences and to understand how certain experiments might be related to each other Sorensen2 explored the derivative response of two pulse sequences. Pulse sequence derivative linking might be a promising tool for the development of new experiments in the future. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, UK CB2 1GA. E-mail: [email protected]


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Solvent suppression Suppression of the water signal is a standard requirement for the study of biological samples and a multitude of methods that achieve this are known. A presaturation method utilizing relaxation gradients and echoes (PURGE) was described by Simpson and Brown3 as a method to achieve high levels of water suppression without the introduction of baseline and phase distortions. The occurence of radiation damping on probes with a high quality factor and at high magnetic fields makes selective irradiation based methods of water suppression increasingly difficult. Wu and Otting4 improved the established WET solvent suppression scheme for high Q applications by using bipolar pulsed-field gradient interleaved DANTE pulses (SWET) instead of the original water-selective pulses. They showed that under conditions where water suppression was primarily due to the inhomogeneity of the B1 field the shorter and lower field strength saturation with the modified SWET method compared advantageous to selective presaturation techniques. Pulse calibration A single scan 1H pulse length calibration method based on nutation spectroscopy was introduced by Wu and Otting.5 The method works equally well on aqueous and organic samples and is easily amenable for automation. As reduced power levels are normally used to avoid sample heating or limitations due to hardware, the amplifier power response has to be linear in order to allow the calculation of hard 901 pulses. Hardware The effect of dielectric properties of solvents on the quality factor for cryogenic probes beyond 900 MHz was studied by Horiuchi et al.6 on a 930 MHz cryoprobe model, complementing earlier studies on the effects of ionic conductivity. They found that at 930 MHz in salt-free aqueous solutions the maximal achievable sensitivity was less than 34% due to sample resistance effects related to the dielectric conductivity of water. The conventions with regard to pulse phases vary with spectrometer manufacturer and disagree from the nutation axis phases of spin-dynamics commonly used in NMR theory. This is particularly problematic for spin-state selective experiments where correct multiplet selection relies on an intricate interplay of pulse phases and for a given spectrometer frequently has to be done by trial and error setting of pulse and receiver phases. Roehrl et al.7 suggested a simple experiment to manifest these phase differences on a spectrometer and presented a table to unravel interdependencies between theoretical values and phase settings in commercially available spectrometers. Software MathNMR, a Mathematica package was introduced by Jerschow8 that allows spatial tensor manipulations and symbolic multi spin calculations to describe NMR experiments. Basis changes, commutator calculations, decompositions of operators and Redfield matrix elements can be calculated. Calculations can be performed for any spin system containing spins 1/2 and quadrupolar spins. Veshtort and Griffin9 introduced SPINEVOLUTION, a powerful tool for the comprehensive description of complex solid-state and liquids experiments performed on multi-spin systems. Both programs are obtainable over the web or on request from the authors.

3. Fast multidimensional methods Over the past year a multitude of acquisition and processing methods that aim at the reduction of experiment time were further developed. In the past such methods were Nucl. Magn. Reson., 2007, 36, 244–261 | 245 This journal is

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predominantly applied to small and medium sized proteins where sensitivity is not limiting and spectral dispersion is quite good but they are now also increasingly used on larger proteins. Traditionally data between interacting spins is encoded through sampling of several time-domains, requiring independent successive time incrementation. Being determined by the sampling, the experiment time becomes excessively long making it impossible to record e.g. 4D experiments at high resolution. Here reduced dimensionality experiments are able to provide high digital resolution within a shorter amount of measurement time by sampling the frequencies of several nuclei together along a single dimension. Depending on the processing method employed and ignoring smaller experimental differences such spectra are then either used to generate shift lists (GFT, APSY, HIFI) or to completely reconstruct a higher dimensionality spectrum from different plane projections (PR). In addition, nonuniform sampling of timespace has been used together with non-linear processing methods to improve digital resolution. This allows to increase the signal-to-noise ratio by spending more time on signal averaging. Very limited time-domain sampling can be processed with the filter-diagonalization method. Time reduction is brought to an extreme in an alternative approach which achieves monitoring of spin interactions through spatial encoding. With the help of pulsed field gradients this is achieved in a single scan. Filter-diagonalization-method The FDM method allows to reconstruct high-resolution nD spectra from data that was sparsely sampled in the indirect dimensions, incuring dramatic savings in experiment time. In comparison to traditional processing methods such as FT and LP where the resolution of a particular dimension is limited by the number of points, in FDM the resolution power is determined by the product of data points in all dimensions. So far calculations are very demanding in computer time but Armstrong and Bendiak10 introduce the single basis FDM which leads to a reduction of processing time by several orders of magnitude. Single basis FDM can be used for parameter optimization for the final FDM iteration or e.g. ‘on-the-fly’ inspection of spectra while data acquisition is still in progress. Ultrafast NMR Usage of spatial encoding in order to observe indirect spin-evolution instead of the traditional time-domain incrementation is the basis for single-scan ultrafast 2D NMR acquisition methods. Two strategies have previously been presented to achieve this spatial encoding: discrete excitation yielding phase-modulation and continuous spatial encoding that results in amplitude-modulated signal. Tal et al.11 presented a hybrid of both methods where on hardware much less demanding continuous spatial encoding was applied to obtain a phase-modulated signal, allowing the recording of 2D homonuclear experiments such as COSY and SE-TOCSY. A double-frequency sweep modification described by Shapira et al.12 was applied to the amplitude-modulated ultrafast methods and results in improved lineshape and increased sensitivity. Spatial encoding is achieved in a symmetrical way sweeping from both ends of the sample towards the center and for a required resolution achieves a two-fold saving in time. Sensitivity permitting, ultrafast TOCSY and 15N HSQC methods were used by Gal et al.13 to study H/D exchange and to track the formation of a transient complex, following rapid mixing. Individual spectra were recorded in 2–4 seconds. Non-uniform sampling and maximum entropy Non-uniform sampling schemes allow to concentrate time-domain data recording in regions where the signal is more intense e.g for decaying data to use a exponentially 246 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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weighted sampling distribution which is biased towards the beginning of the time domain. When combined with appropriate processing methods this has the advantage that less sampled data points achieve a required resolution. In other words, for a given digital resolution this results in higher sensitivity per unit time, allowing faster data recording or to collect more scans per increment for improved experimental sensitivity. Approaches for 3D and 4D based backbone, and NOE assignment that make use of non-uniform sampling (NUS) in combination with maximum entropy processing were described in several contributions.14–18 Data sampling relied on an incomplete linear scheme and a more detailed description of these NMR experiments can be found in chapter 8.3. Non-linear FT A fast Fourier transform method to record sparse, non-linearly sampled data was presented by Marion19 using a parabolic sampling scheme where the spacing between the digitized sampling points varies continuously. Lagrange interpolation is used to restore a regularly sampled FID. As the amount of interpolation can be chosen freely and is not related to the number of sampled points this allows for a free adjustment of the spectral-width through processing. Compared to other non-linear processing methods no user defined parameter optimizations are required. A twodimensional transform for pairs of frequencies instead of the sequential 1D transformations was presented by Kazimierczuk et al.20 based on a 2D Quaternion FT algorithm. The method is unlike the inverse Radon transform or reduced dimensionality approaches not limited to a radial sampling scheme and it can equally be extended to higher dimensionality. The method maintains the advantage that a full nD spectrum can be visualized. The authors showed that spiral sampling leads to a significant reduction of spectral artifacts. Multiway decomposition Three-way decomposition has been used recently as a versatile analysis tool for several kinds of NMR data. Luan et al.21 tested the influence of signal-to-noise and peak overlap on the analysis of NOESY and relaxation data using three-way decomposition (TWD) and concluded that the method is robust and conservative, not leading to any false positives. Malmodin and Billeter22 showed that multiway decomposition is suited for spectra with coupled evolution periods by application to a (5,2)D HACACONNH-GFT experiment. Emerging peak lists can be used for automatic assignment. The use of sparse-sampling in combination with multiway decomposition was tested by Luan et al.23 on 4D HCCH NOESY data that was recorded on a protonated protein. Their study revealed that very similar resolution and amplitudes as in the reference spectrum could be obtained with only 30% of the full dataset. Despite the large dynamic range of the signals the linewidths were accurately reproduced and no false peaks were introduced. The loss of some peaks was in agreement with the increased noise level due to the shortened measurement time. GFT An entirely GFT based approach was used by Shen et al.24 to solve the structure of a 14 kDa protein. The protocol relied on the use of 5 through-bond 4D and 5D GFT experiments together with a NOESY that used a combination of simultaneous and GFT acquisition techniques. The (4,3)D GFT NOESY resulted in two subspectra which revealed 15N/15N, 13Cali/15N and 13Cali/13Cali resolved NOE information, with the GFT axis encoding peaks at oH oX (X = 15N, 13Cali). Center peaks, which provide the unmodulated 1H shift information were obtained from a simultaneous 3D 15N/13Cali/13Caro NOESY. Data recording took 16.9 h for the through-bond Nucl. Magn. Reson., 2007, 36, 244–261 | 247 This journal is

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experiments and 39 h for the two NOESY sets (30 h for the (4,3)D and 9 h for the central peak 3D) on a 600 MHz spectrometer equiped with a cryoprobe. The impact of GFT sampling on quality and abundance of NOE data and initial structure was further assessed. Malmodin and Billeter25 described a general approach, EVOCOUP, for the calculation of chemical shifts from spectra with coupled evolution periods. The approach is based on systematic searches and does not rely on e.g. the occurence of doublet symmetry relation patterns. Tests on a 128 residue protein gave no false positives and missed only three cases which could be resolved through recording of additional projections. Projection reconstruction, tilted plane reduced dimensionality Venters et al.26 showed the applicability of projection-reconstruction methodology to larger proteins using a (4,2)D approach for the backbone assignment of HCA II (29 kDa) and Calbindin (30 kDa). A combination of 4D backbone triple-resonance experiments (TROSY versions of HNCACB, HN(CO)CACB, intra-HNCACB, HNCACO, HNCOCA, HNCOi1CAi and HACANH, HACA(CO)NH) optimized for projection reconstruction and a hybrid backprojection/lower-value algorithm for the reconstruction of the data was applied. The 4D reconstruction was obtained from 8 data sets for each of the (4,2)D experiments: 3 orthogonal planes and 5 planes at tilt angles with 64 increments per projection. This translated into much higher digital resolution than obtainable through real 4D sampling and a ca. 10-fold saving in time. The total recording time for the 8 (4,2)D experiments was 12.8 days (800 MHz, cold probe). An average spectrum maintained 60% of the S/N ratio of the full 4D recorded over the same time. The lower-value algorithm is suited for data with few dispersed signals and high signal-to-noise as the cross-peak height is determined by the intensity in the weakest projection plane and therefore leads to the loss of less intense signals. A new hybrid backprojection/lower-value (HBLV) algorithm was suggested which showed to increase sensitivity without the introduction of major artifacts. Signal accumulation is achieved by first applying a backprojection of a determined number of planes in all possible combinations followed by the lower-value approach. This leads to signal accummulation according to the number of planes used for the backprojection and further leads to flat baselines by removing the ridge artifacts characteristic of the backprojection method making this particularly useful for less sensitive data. The number of planes used for the backprojection need to be balanced according to levels of artifact suppression, signal intensity and line broadening (which increases with higher number of projection planes used). A modified filtered backprojection reconstruction algorithm was introduced by Coggins et al.27 for the reconstruction of 4D NOESY data. The method originally developed for radioastronomy requires a large number of projections. All projections contribute towards the final signal intensity and the algorithm performs well in the presence of large numbers of peaks that have a sizeable dynamic range. The complete 4D CH3-NH NOESY spectrum of HCA II (29 kDa) was reconstructed from 100 (4,2)D projection experiments providing a dataset with much higher resolution than obtainable through conventional sampling. The measurement time has to be long enough to observe weaker NOEs (88 h for 100 planes). Reardon and Spicer28 reported the backbone assignment of GB1 in its bacterial cell environment using rapid 3D projection reconstruction methods. HNCA projection planes were recorded within 2 h, compatible with the limited lifetime of the cells. Coggins and Zhou29 introduced PR-CALC, a program for the reconstruction of spectra from lower dimensionality projection data. PR-CALC allows the use of several currently described reconstruction alogrithms such as lower-value, backprojection, hybrid backprojection/lower-value and filtered backprojection algorithms and can reconstruct full spectra or just a subset of the entire spectrum of 248 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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any dimensionality from projections. Projections with different dimensionalities and number of points can be used together. Several schemes for projection reconstruction e.g. deterministic backprojection and the lower-value algorithm and statistical search methods such as least-squares fitting, maximum entropy, Bayesian analysis based model-fitting with the reversiblejump Markov chain Monte Carlo procedure were studied by Yoon et al.30 and compared in terms of reliability, artifacts and signal-to-noise. Of the newly proposed statistical methods, the reversible-jump Markov chain Monte Carlo algorithm seems very promising. An approach to generate peak lists from 2D reduced dimensionality spectra was presented by Eghbalnia et al.31 as general strategy for the rapid collection of multidimensional data. The so called HIFI-NMR (for high-resolution iterative frequency identification) approach relies on the recording of tilted reduced dimensionality data which is used to determine the chemical shift frequencies rather than to reconstruct a full spectrum. While frequency knowledge can be sufficient for assignment purposes this obviously avoids all the problems related to spectrum reconstruction but also lacks the visual benefits of PR. In HIFI the advantages of high digital resolution 2D spectra are combined with the power of tilted-plane projection spectra to separate overlapped peaks (provided shift differences occur in at least one orthogonal dimension). To minimize total experiment time a routine is used which predicts the tilt angle of the next plane to be recorded so that additional signal identification is at a maximum. The HIFI approach was demonstrated for (3,2)D triple-resonance experiments on several proteins up to 20 kDa in size and was able to create nearly complete shift lists when compared to an independently handpicked full 3D dataset. Time savings on the order of 10-fold were achieved with the number of tilted planes and angles strongly depending on the experiment type. A similar automated peak list based approach called automated projection spectroscopy (APSY) was described by Hiller et al.32 Using (4,2)D HNCOCA or (5,2)D HACACONH projection data this resulted in the fully automatic generation of close to complete peak lists for a 63 and a 116 residue protein. Resonance frequencies were obtained from 2D projections via an algorithm which based on geometrical considerations recognizes peaks originating from the same resonance without any need for manual intervention. Fiorito et al.33 used a reduced dimensionality (6,2)D HNCOCANH sequential experiment as input data set for the successful automated peak list generation through APSY. All assignment approaches that rely on direct correlations between nuclei are clearly limited by the number of coherence transfer steps, relaxation and the dimensionality of the experiments. Kupce and Freeman34 showed in an alternative approach how connectivities that are experimentally not directly observed can be reconstructed from directly observed ones obtained through a combination of different experiments. Following this they reconstructed a hypothetical 10D experiment from 3D projection-reconstruction data, correlating all backbone atoms of two sequential amino acids without the requirement to ever record the high-dimensionality data.

4. Spin relaxation methods 4.1 Auto-relaxation Measuring off-resonance 1H relaxation rates at an angle of y = 35.51 results in the mutual cancellation of the transverse and longitudinal cross-relaxation rates so that the observed magnetization decays with a effective rate similar to a selective proton R1. Such a rate shows a monotonous increase with growing rotational correlation time and therefore allows to recognize higher MW species or the onset of oligomerization. Exploiting this a off-resonance 1H R1r 2D TOCSY experiment was Nucl. Magn. Reson., 2007, 36, 244–261 | 249 This journal is

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demonstrated by Esposito et al.35 to allow the characterization of the residues in a peptide involved in oligomer formation through noncovalent self-recognition. Several new 2H relaxation experiments for the dynamics study of methyl-containing residues in large proteins (B100 kDa) were introduced by Tugarinov et al.36 and tested on Ile-d1 positions of the 723 residue malate synthase G. The HSQC based pulse sequences measure rates in 13CH2D and 13CHD2 isotopomers and are optimized for sensitivity and resolution, imperative when studying such large systems. Most investigations use the 13CH2D isotopomer since the presence of a single deuteron makes analysis and the design of experiments for the measurement of a given relaxation term easier than for 13CHD2. But for very large proteins the INEPT based experiments on the 13CHD2 isotopomer have superior sensitivity and so make the measurement of transverse relaxation in this isotopomer attractive. Order parameters for methyl groups obtained for both isotopomers were shown to be in good agreement. Dynamics studies rely on the high-quality measurement of several relaxation rates, most of which are obtained from a relaxation series where a time parameter i.e. the relaxation delay is varied. For a given temperature this results in changes in the duty cycle leading to differential heating within a given relaxation series. This is particularly dramatic in experiments which use short interpulse delays such as CPMG or spin-lock measurements. A duty cycle compensation module using prescan saturation was described by Yip and Zuiderweg37 improving temperature control and stability during a measurement series. The scheme is applicable to all types of relaxation experiments and increases the accuracy of measured relaxation parameters. While pulse sequence associated experiment-specific errors have been continuously reduced, system-specific errors in relaxation measurements have obtained much less attention. Pawley et al.38 provided an analysis and suggested a series of control experiments that are recorded together with the relaxation measurements to detect and quantify such errors, to identify their source and if possible to correct for systematic changes in order to obtain more accurate relaxation parameters. Their analysis showed that relaxation dispersion measurements at lower fields where smaller exchange contributions lead to a shallow dispersion curve can be particularly prone to systematic errors and that extracted rates might depend strongly on the way the data was recorded. 4.2 Cross-correlated relaxation experiments Methyl group relaxation is a popular tool to probe dynamics which is typically studied via the measurent of 2H rates in 13CH2D isotopomers. A specifically labelled sample has to be prepared often for the sole purpose of these dynamics studies. Zhang et al.39 introduced a new method that allows the study of methyl dynamics on protonated methyl groups without any requirement for deuteration, based on the measurement of dipole–dipole cross-correlated relaxation in combination with the methyl 13C longitudinal relaxation rate. The cross-correlation rate is obtained from a sensitive 2D CT HSQC-based experiment with a variable 1J(C,H) evolution period. Determination of the overall rotational correlation time is important for dynamics studies but also simply to obtain information about the quality of a sample and to optimize parameters in NMR experiments. A modified 1D TROSY sequence that measures the decay of the TROSY and anti-TROSY lines was presented by Lee et al.40 to estimate tc of the 1H–15N vectors from the ratio of the two decaying coherences via the cross-correlation rate. Effects from dipole–dipole relaxation from neighbouring protons and contributions from exchange broadening are eliminated, increasing the robustness of this method. Conformational exchange on a timescale slower than tc manifests itself in a way similar to cross-correlated relaxation in zero and double-quantum coherences leading to differences in measured ZQ/DQ relaxation rates. Lundstro¨m et al.41 used 250 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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differential relaxation effects in 13Ca(i-1)/13Ca(i) multiple quantum spin-pairs to probe the existence of correlated motions in a mutant of the C-terminal domain of calmodulin. By using highly deuterated protein the correlated modulation of chemical shifts dominates the differential MQ relaxation rate so that a measurement of e.g. 2IxSx vs. 2IySy allows to determine the cross-correlation rate constant. Similarly, Del Rio et al.42 introduced a experiment to measure chemical shift modulated cross-correlation in multiple quantum coherence between a 13Cmethyl nucleus and the preceding neighbouring 13C position. Contributions to the crosscorrelation rate that come from ps-ns processes had to be estimated to obtain the interference contribution due to conformational exchange. 4.3 Relaxation dispersion. Measurement of chemical exchange contributions The study of slow internal motions and conformational changes on ms to ms time scales are particularly important from a biological point of view and have further attained large attention including also reports about correlated dynamics in proteins and applications to exchange processes involving multiple sites. Analytical expressions for the rotating-frame relaxation rate constant R1r were obtained by Miloushev and Palmer43 for two-site chemical exchange. The obtained formula is simpler than existing equations and in many cases more accurate and will help the analysis of R1r relaxation dispersion experiments for systems in slow-to-intermediate exchange. Two off-resonance rotating-frame amide proton R1r experiments were introduced by Lundstro¨m and Akke44 and Eichmu¨ller and Skrynnikov,45 respectively, which allow the characterization of exchange parameters for processes that are considerably faster than what can be probed with 13C or 15N relaxation. In the earlier case the pulse sequence consisted of a 15N HSQC followed by a 1H off-resonance spinlock element. Deuterated protein was used in both studies to suppress crossrelaxation and cross-correlation effects and to improve the overall sensitivity and relative extent of the chemical exchange contribution. Alternatively in the first study a selective 1801 pulse centered in the middle of the spin-lock period was introduced to suppress off-diagonal relaxation pathways when using protonated samples. In the latter study to this effect the decay of two-spin order was monitored and the tilt angle was maintained at y = 351 for cancellation of longitudinal and transverse crossrelaxation contributions. A modified SQ/MQ spin-echo pulse element (CEESY) was described by Van Ingen et al.46 which allows from a 2D spectrum to determine the sign of the frequency difference between exchanging states in the fast-to-intermediate regime. The method exploits the differences in exchange induced shifts of MQ and SQ coherence resulting in a small net evolution of the coherence during the spin-echo element and was demonstrated for 1H and 15N nuclei. The analysis of exchange parameters from CPMG relaxation dispersion data typically assumes that the exchange-free relaxation rates of the different sites are identical. Ishima and Torchia47 analyzed for a two-site exchange process the magnitude of errors introduced by this assumption and found that the general 0b assumption of R0a 2 = R2 leads to errors in the relative population pa and exchange lifetime tex, while the difference in chemical shift of the two sites Do is not affected. The interdependence of the fitting parameters pa, kex and Do in equations describing conformational exchange detected in CPMG relaxation dispersion experiments was studied by Kovrigin et al.48 which found, that frequently multiple equivalent solutions can equally satisfy the experimental data. The strong interdependence of the fitting parameters can be readily overcome by repeating the measurements at different static magnetic fields, allowing the accurate assessment of the exchange behaviour. A biosynthetic protein expression method based on using [1-13C]-glucose in E.coli leads to the incorporation of isolated 13C–1H two-spin pairs into the d-position of Phe/Tyr, the d2/e1-position in His and the d1/e2/e3-position in Trp as described by Nucl. Magn. Reson., 2007, 36, 244–261 | 251 This journal is

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Teilum et al.49 This dramatically simplifies the recording and analysis of relaxation data in aromatic residues and is suited for CPMG and spin-lock dispersion measurements. As aromatic residues are frequently in hydrophobic pockets or involved in ligand binding this will complement the information obtained through methyl relaxation. The measurement of off-resonance 13C relaxation in methyl groups of universally 13 C labelled, partially random deuterated protein was introduced by Brath et al.50 to characterize fast ms exchange dynamics in the 13CHD2 isotopomer. The intrinsically slow exchange-free relaxation rate assures the method to be highly sensitive even towards small exchange contributions. The removal of cross-correlation effects allows the simple analysis of the data while homonuclear Hartmann-Hahn effects are shown to be negligible for the majority of the residues except the Leu-d methyl groups. With the majority of exchange studies relying on a simpler two-state model, extraction of kinetic parameters describing multi-site exchanges remains much more challenging, particularly if the kinetics of each exchange process are not too dissimilar. Three-site exchange folding can be studied by recording six CPMG-based relaxation dispersion experiments which measure exchange contributions to backbone 15N and 1H SQ, ZQ, DQ and MQ coherences. Korzhnev et al.51 showed that through the combined use of such six measurements all parameters describing the multi-site exchange process could be extracted at a single temperature, with one of the intermediate states being populated even below 1%. Assumptions about temperature dependence of rates and shift changes typically required in studies using only SQ data become unnecessary. The combined use of ZQ and DQ dispersion profiles allowed the calculation of the relative signs of DoH and DoN, which together with information on the sign of DoN obtained from a generalized two-state exchange allowed to reconstruct the 1H, 15N correlation spectra for both minor, invisible states. The same authors52 further assessed the availability of different relaxation rates on the extraction of parameters describing the multi-site exchange process and concluded that the availability of SQ data or even temperature dependent SQ data was insufficient and led to larger errors, justifying the measurement of additional ZQ, DQ and MQ rates.

5. Diffusion experiments A method to measure slow diffusion was proposed by Cavadini et al.53 which exploits the increased lifetimes of singlet spin states when comparing to longitudinal relaxation times. The method is particularly interesting to measure diffusion coefficients of very large molecular assemblies as singlet spin state lifetimes are easily an order of magnitude longer than typical longitudinal relaxation times. The required singlet states can be generated from a scalar-coupled 2-spin system. Momot and Kuchel54 introduced a convection-compensated gradient-selected homonuclear double-quantum filtered experiment for measuring diffusion coefficients of small- or medium-sized molecules in non-deuterated solvents or in crowded spectra. The pulse sequence consists of two 1/2J periods that surround the longitudinal diffusion period and based on the DQ-filter provides excellent water suppression. Extraction of diffusion coefficients from overlapped spectra for species with similar exponential decays is difficult to achieve. Here heteronuclear methods can provide additional resolution but this leads to a significant increase in measurement time. A hadamard-encoded 1H heteronuclear diffusion measurement method was introduced by Steinbeck and Chmelka55 leading to time-savings of one order of magnitude when compared to the corresponding HSQC-based correlation experiments. Non-uniformity in pulse field gradient profiles and RF fields across the sample lead to errors in the determination of diffusion coefficients. To reduce such errors 252 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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and to measure diffusion coefficients in a quantitative way Zhang56 used a offsetindependent adiabatic inversion pulse to achieve volume selection for a central region of the sample where the RF field is uniform and the PFG strength changes in a linear way. The author used a standard diffusion sequence following the volume selection pulse/gradient element by a stimulated echo with a longitudinal diffusion period. Overlap in 2D-DOSY spectroscopy requires frequently the introduction of a second frequency dimension leading to 3D-DOSY spectra. Nilsson and Morris57 addressed the problem of convection in 3D diffusion-ordered spectroscopy. Convection compensated versions of COSY-IDOSY and 2DJ-IDOSY were presented and compared with non-compensated versions. Compensation is efficient and can be implemented at a minimal loss in sensitivity.

6. Coupling constant measurement 6.1 Scalar couplings Nolis and Parella58 presented two modified 2D HSQC-TOCSY pulse schemes that lead to selective spin-state cross peak pattern correlation spectra without the requirement to extend the length of the original H/X correlation sequence. The n J(X,H) and J(H,H) coupling constants can be extracted from E.COSY type patterns in fully coupled H/X correlation spectra or in the case of substantial overlap from spin-state edited sub-spectra by using an additional double-TROSY transfer, in both cases taking advantage of the excellent chemical shift dispersion of the X nucleus. The experiments are limited to IS spin-systems and are of interest for molecules with a substantial number of NH and CH at natural abundance e.g. carbohydrates and peptides. Starting from HN or Ha in a peptide allows the measurement of 2J(N,Ha), 3 J(N,Hb), 2J(Ca,HN), 2J(Ca,Hb), 3J(Ca,Hg), 3J(HN,Ha) and 3J(Ha,Hb). The essential features of the pulse sequence consist of a modified planar mixing or corresponding TROSY/anti-TROSY backtransfer after X nucleus shift labelling allowing for spin-state selection, followed by a isotropic mixing transfer onto nuclei coupled via J(H,H). A double-J-modulated DJM-INEPT-INADEQUATE experiment was introduced by Pham et al.59 which provides simultaneously one-bond and long-range C,C connectivities along with information about the size of J(C,C) couplings. In comparison to the original INEPT-INADEQUATE the sensitivity is lower due to the two-fold signal reduction in each of the J-modulated time periods but this is partly compensated since there is no loss from 1J or nJ mis-match due to the absence of fixed carbon-coupling evolution intervals. A further benefit is that one-bond and longrange couplings are obtainable from only one spectrum. The coupling constant values were obtained through deconvolution of the time domain signals and the experiment seems particularly suited for carbohydrates. The angular dependence of 3J(N,Cg) for Asp and Asn residues as a function of the w1 N–Ca–Cb–Cg angle was investigated by Juranic et al.60 Experimental 3J(N,Cg) values for the Karplus expression were obtained from Asp residues where the orientation was fixed either through hydrogen bonding or coordination to a calcium atom. A slightly modified version of a previously described quantitative J(N,N) constant-time spin-echo (CTSE) difference experiment was used by Dingley et al.61 to measure h2J(N7,N2) trans-H-bond scalar coupling constants for different cationbound forms of a Oxy-1.5 DNA guanine quadruplex. Due to the reduced length of the transfer periods the suggested experiment is more sensitive than a previously employed h2J(N2,N7)-COSY experiment. Variations in the size of the coupling constant were shown to correlate with the length of the N2–H2 N7 H-bond in the according structure. Analysis of couplings at different temperatures revealed that the Nucl. Magn. Reson., 2007, 36, 244–261 | 253 This journal is

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5 0 strand end was the most thermolabile region of the DNA quadruplex, regardless of the kind of cation bound. De Alba and Tjandra62 investigated the effects of cross-correlated relaxation on quantitative J-methods which lead to errors in the measurement of 1J(C,H) scalar and dipolar couplings and return different values for 1J(C,H) in methine and methylene groups depending on whether proton or carbon magnetization is monitored. The effect of cross-correlation can be understood as a mechanism of magnetization transfer between operators that interferes with the trigonometric dependency of the coupling evolution. The size of the error depends on the crosscorrelation rate therefore increasing with the correlation time and varies with the J values of interacting spins and the time during which J-evolution and crosscorrelation effects occur. For methylene groups the error can be several Hz. Observed errors were in agreement with the theoretical description of the crosscorrelation effects. As the errors vary with anisotropy, RDC measurements are equally affected and this is particularly noticeable for RDC measurements in methylene groups. The use of selective pulses is suggested to refocus such crosscorrelation pathways.

6.2 Residual dipolar couplings Variable-angle sample spinning (VASS) methods were used by Lancelot et al.63 on a sample of ubiquitin in a 32% w/v bicelle system to measure 1D(N,H) RDCs and 15N shift changes due to CSA. All measurements were obtained on a single sample as slight variations of the rotor angle provide different scaling of the anisotropic interactions and isotropic values are obtained from the magic angle spectrum. The measured RDC and CSA values correlated well with previously published values obtained on a 5% w/v DMPC/DHPC bicelle sample. Under magic angle conditions the quality of the 15N spectra was similar to high resolution conditions indicating that the presence of bicelles had little effect on the correlation time of the protein, while under VASS conditions the change in ordering of the bicelle system seemed to slightly increase the correlation time of the protein. As long as the correlation time is not affected by the presence of high concentrations of bicelle the residual dipolar interactions will be the main source of spectral broadening allowing therefore also the study of other proteins. More anisotropic proteins could be studied at lower bicelle concentrations. In order to be used as structural restraints RDCs need to be measured in multiple alignment media to overcome their orientational ambiguity. Unfortunately this is often hampered by incompatibilities of a protein with certain alignment media or the difficulty to predict that a new medium will provide novel information. Ruan and Tolman64 have investigated into the possibility to obtain multiple alignments from one type of alignment medium. To this purpose they changed the morphological characteristics of a composite medium consisting of stretched polyacrylamide gel with ordered bacteriophage Pf1 particles embedded in the gel. Different orientations of the Pf1 particles relative to the long axis of the gel in the NMR tube could be obtained by allowing gel polymerization to occur at variable angles in a magnetic field. Data recorded on ubiquitin showed that the gels prepared at different angles allowed to collect independent sets of RDCs. An alternative strategy to accelerate the measurement of multiple dipolar coupling constants was suggested by Vijayan and Zweckstetter.65 Previously this was achieved by a multitude of experiments which allowed simultaneous evolution of multiple couplings. Possible setbacks of such strategies are the increase in overlap and a reduced sensitivity due to multiple splittings. In contrast the new approach only measures one coupling per experiment but uses a common reference experiment for all measured couplings reducing the experiment time without any increase in overlap. Two modified experiments allow the measurement of 1D(N,H), 1D(C 0 ,N) 254 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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from 3D TROSY-HNCO and 1D(Ca,Ha), 1D(Cb,Hb) and 1D(Ca,C 0 ) from a CBCA(CO)NH for small to medium sized proteins and unfolded proteins. Four experiments to measure 1J(Ca,Ha) and 1D(Ca,Ha) coupling constants from peak separations were suggested by Ball et al.66 The 2D (HNCO)-(J-CA)NH and 3D (HN)CO-(J-CA)NH use Ca for evolution of 1J(Ca,Ha) while in the 2D (J-HACACO)NH and 3D J-HA(CACO)NH coupling evolution occurs with Ha in the transverse. The 2D experiments use evolution of 1J(Ca,Ha) during the 15N chemical shift labelling period leading to a doublet pattern. The two multiplet components can be separated through an IPAP approach while in the 3D experiments the resolution may be enough not to require any further multiplet editing. Increased resolution in the Ca evolution experiment was achieved through the use of selective Ca pulses allowing to extend the maximal evolution time. Tang et al.67 used an isotope labelling scheme where in a 15N,13C labelled and otherwise at non-exchangeable positions fully deuterated protein, all the methyl groups and methine positions of Val and Leu were protonated to allow the determination of the conformation of these residues. A combination of HN-Hg and Hg(i)-HN(i + 1) NOEs combined with RDCs for Val Cb–Hb and Leu Cg–Hg allowed to orient the side chain. Methine 1J couplings were determined from a series of intensity J-modulated 3D CT-HCCH-COSY experiments where the 1 J(Cb,Hb)/1J(Cg,Hg) refocusing period was varied. The experiment was modified to optimize coherence transfer from the Cb/Cg positions to the methyl groups allowing to increase the methyl refocusing period to be set to 1/2J(C,C). Additional dipolar relaxation contributions to methyl groups originating from the protonated methine positions were found to be small making this approach sensitive enough to be used on larger proteins. A novel interpretation of RDCs was presented by Bernado´ et al.68 that simultaneously analyses local conformational sampling and longrange structural order and can lead to improved understanding of the conformational behaviour of an unfolded protein in solution. It was used to describe structure and dynamics of a-Synuclein. To this purpose a statistical ensemble of coil conformations was generated to allow the calculation of averaged RDCs which were then compared with the experimental data. The measured data could be reproduced provided longrange contacts between regions that were distant in the primary sequence and local fluctuations in the F/C space were included in the description of the behaviour of a-Synuclein in solution. A program for the analysis of RDCs was introduced by Wei and Werner.69 Program functionalities include amongst others estimation of the alignment tensor from a RDC occurrence histogram and order tensor analysis by singular value decomposition (SVD) doable on an entire family of structures.

7. Homonuclear spectroscopy 13

C detection and protonless experiments

Dramatic improvements in probehead technology permit to obtain 13C observed experiments with acceptable sensitivity, allowing amongst other benefits to take advantage of the good 13C signal dispersion. The use of a 13C observed 3D HCCTOCSY was suggested by Hu et al.70 for protonated and partially deuterated proteins. This leads to higher sensitivity and reduced peak overlap in a previously introduced 2D 13C/13C TOCSY type experiment. A MQ H/C transfer scheme combined with 13C CT shift encoding was used to reduce relaxation effects when compared to a SQ implementation. A net sensitivity improvement came from the faster repetition rate and the larger 1H polarization, making this experiment competitive with the 13C/13C experiment even at increased levels of B85% deuteration. Directly 13C detected experiments offer particular advantages in the study of proteins with a paramagnetic relaxation center. Bertini et al.71 compared the Nucl. Magn. Reson., 2007, 36, 244–261 | 255 This journal is

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sensitivity of 2D experiments containing different CO/Caliphatic transfer schemes to characterize resonances that are in immediate proximity to the metal center (o9 A˚) and found that due to the very fast transverse relaxation a Caliphatic to CO transfer was superior to the MQ or SQ out-and-back COCaliCO style experiments. A suite of new 2D and 3D protonless 13C direct detected experiments was proposed by Bermel et al.72 to allow the extension of a carbon nucleus based assignment strategy for a complete backbone and aliphatic residue assignment of paramagnetic and/or large proteins. The success of the carbonyl observed experiments relies on the suppression of the large 1J(Ca,CO) splitting in the acquisition dimension using IPAP or S3E techniques, on the use of a third dimension in the CCCO experiment and on the introduction of 15N evolution in a indirect dimension in CBCACON, CCCON and CANCO experiments to provide the required resolution. Experiment times for a 1.5 mM sample varied between 4–6 days. Bermel et al.73 suggested further a novel 3D COCON-IPAP experiment for the sequence-specific backbone assignment in unfolded proteins. The sequential connectivity was obtained through TOCSY transfer via the small 3J(CO,CO) coupling. Small molecules Double-quantum spectroscopy e.g. 2D INADEQUATE can have advantages over the corresponding single-quantum correlation e.g. excellent suppression of unwanted signals or the better separation of signal over less multiplet components. Nevertheless the analysis of such spectra is more difficult than for the SQ experiment. Zhang et al.74 used covariance spectroscopy to convert a 2D 13C–13C doublequantum spectrum into a symmetrical 2D single-quantum spectrum. The use of the covariance scheme does not require any modifications to the pulse sequence. The appearance of strong coupling artifacts is a major problem for many homonuclear experiments. A method was presented by Thrippleton et al.75 to suppress signals that follow such transfer pathways. It can be applied to experiments which contain a J-resolved or constant-time domain.

8. Inverse proton detected correlation spectroscopy 8.1 Double-resonance experiments Spin-state selection. Spin-state-selective (S3) experiments can result in higher sensitivity and/or sharper lines and their use is well established in high molecular weight studies and for the measurement of coupling constants. Such experiments normally only work for IS spin-systems while Nolis et al.76 presented a way to achieve spin-state selection in the acquisition dimension of HSQC spectra that is independent of the multiplicity of the S nucleus. Multiplet editing is achieved through the combination of sub-spectra from experiments that employ a sensitivity-enhanced COS scheme with varying pulse phases. The experiment should be useful for the measurement of sign and magnitude of coupling constants in all InS spin systems. Methyl deuteration. Selective methyl labelling strategies are a powerful approach to enable studies of dynamics and high molecular weight structural work. The performance of the methyl isotopomers CH3, CH2D and CHD2 in 2D 13C correlation experiments were compared by Ollerenshaw et al.77 Taking into account the subtle relaxation differences they presented for each isotopomer relaxation optimized sequences, namely improved heteronuclear zero-quantum 13CH3 HZQC, 13 CH2D TROSY and 13CHD2 HZQC experiments. According to their findings all three methyl labelling patterns led to similar resolution whereas sensitivity benefits at least larger than 2.4-fold were observed when using the 13CH3 labelling approach. Their study emphasizes the use of 13CH3 selective protonation as the method of 256 | Nucl. Magn. Reson., 2007, 36, 244–261 This journal is

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choice for structural studies while the two other isotopomers are attractive for 2H dynamics investigations. Polarization recovery. TROSY type experiments only convert half the amount of the starting polarization into observable signal while the magnetization corresponding to the unwanted spin-state normally is discarded. In terms of sensitivity this is unsatisfying and Diercks and Orekhov78 introduced a scheme to partially alleviate this situation. Two sequential acquisitions are recorded per scan, with the second part of the experiment being executed during the relaxation delay of the first half (qTROSY, for queued TROSY). The first part of the sequence records the TROSY spectrum. The second half of the experiment operates with the anti-TROSY polarization left from the first half of the experiment and converts it into the corresponding TROSY correlation which is then observed during the second acquisition period. Therefore this allows for a partial polarization recovery of the otherwise unused anti-TROSY magnetization component. Superposition of the two sequential acquisitions increases the sensitivity. Crucial for the successful implementation of this experiment is the use of a orthogonal spin-state separation before t1 which prepares the transverse TROSY component while storing the anti-TROSY contribution along the z-axis. Fast pulsing methods. The majority of heteronuclear experiments that start with the excitation of protons suffer from the slow non-selective recovery of all 1H nuclei, requiring a long interscan-delay and therefore slow repetition rates. It has been shown previously e.g. in L-TROSY that the recovery of polarization from wanted pathways can be accelerated by returning unused magnetization to the z-axis, leading to improved sensitivity per unit time. A modified sensitivity enhanced 15N HSQC was suggested by Deschamps and Campbell79 which achieves the return of non-used magnetization to the z-axis through a combination of a selective pulse and pulse phase adjustments. Improvements around 20% were observed at typical repetition delays of one second and the faster recovery allowed to increase the pulse repetition rate. Schanda and Brutscher80 described a 15N HMQC based approach that uses selective amide proton excitation and refocusing pulses and combines the advantages of fast selective T1 polarization recovery together with optimal Ernstangle excitation (SOFAST-HMQC) to reduce the total experiment time of 2D correlation experiments to just a few seconds. Applications to fast H/D exchange measurements in proteins were shown in an example where the reaction was completed within a few minutes. Under very fast repetition rate conditions (B100 ms recycle time) the sensitivity of the SOFAST approach is increased by a factor of 3–6 times over standard techniques allowing rapid completion of 2D experiments within seconds. Importantly it was also shown that with the typically used relaxation delays (e.g. 1 second) the absolute sensitivity of SOFAST experiments is also higher than with conventional experiments. The authors adapted the methodology further to be better suited for the current generation of cryo probes, to measure 1J coupling constants and to observe 2D methyl 13C correlations.81 Saturation-transfer mapping. Reduced sensitivity due to increased levels of solvent D2O and lower saturation-transfer efficiency with the positioning of backbone amide atoms mostly away from the binding interface are severe limitations for 1H/15N directed cross-saturation experiments. Takahashi et al.82 demonstrated a modified approach where they used CH3 groups as the reporter resonances in an otherwise highly deuterated protein. A band-selective irradiation of the aliphatic to amide region, excluding the methyl region preceded a 1H, 13C correlation experiment. Because of the favourable methyl proton relaxation properties the approach suffers less from spin-diffusion effects, needs no high levels of D2O and is much more sensitive than the amide based method. Nucl. Magn. Reson., 2007, 36, 244–261 | 257 This journal is

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8.2 Heteronuclear triple resonance experiments Rapid magnetization recovery. Extending the idea of a reduced proton spin lattice temperature into triple-resonance experiments, Diercks et al.83 presented several versions of HN detected HSQC-based out-and-back type experiments. These included extended flip-back schemes to return magnetization of 13C attached protons to the z-axis with the aim to accelerate the recovery of HN polarization such as to enable faster pulsing. Several implementations using band-selective flipback pulses or J-coupling evolution were tested experimentally and compared with theoretical simulations. Relative signal improvements of up to 40% per unit time at faster repetition rates were obtained with 1H polarisation recoveries reaching a maximum of 60%. Most square 1801 proton pulses were substituted by pairwise broadband inversion BIP pulses and a XY16 CPMG-scheme was used for 1H decoupling. CPMG interpulse delays were adjusted to reduce the duty cycle while keeping relaxation losses low. Isotope labelling. A method relying on the incorporation of chemically synthesized stereo- and regio-specifically labelled amino acids through cell-free expression was proposed by Kainosho et al.84 The approach, called stereo-array isotope labelling (SAIL) aims at the reduction of the number of observed NMR signals and the reduction of transverse relaxation and spin-diffusion pathways in order to increase the sensitivity of experiments and to improve the quality of NOE information for high throughput protein structure determination without a loss of structural quality. To this purpose universally 13C, 15N labelled amino acids were prepared where the number of protons per aliphatic carbon atom was reduced to one, deuterating the remaining proton positions. Aromatic positions were labelled with alternating 13 C–1H and 12C–2H pairs. Spectral improvements were demonstrated through a comparison with universally labelled proteins. With only one third of the number of protons the sensitivity of methyl groups with all protons was maintained while for methylene positions the sensitivity was increased by a factor of 3–7 fold. While the number of NOEs was reduced by 40–50% the quality of the remaining restraints was dramatically improved as was shown by solving the structures of calmodulin and maltose binding protein (MPB). In the case of the latter a correct orientation of N- and C-terminal domains based solely on NOE data was possible. 1 H directed backbone assignment. Ambiguities in backbone assignment often arise due to the degeneracy of 13C resonances. To circumvent this problem two modified higher sensitivity, high-resolution versions of the existing 3D HNcocaNH experiment were suggested by Sun et al.14 to facilitate purely 1H, 15N based sequential connectivity in protonated proteins. The feasibility of this approach relies on high digital resolution in all sampled dimensions. To this purpose 1H and 15N dimensions were incremented in semi-CT fashion and non-uniform sampling (NUS) was used to increase the sensitivity by sampling more densely at short evolution times. Sensitivity of the experiment was increased through simultaneous evolution of both J(N,Ca) couplings while on 13Ca rather than on 13CO, leading to a more efficient coherence transfer. For the same resolution the NUS sampling scheme brings approximately a 10-fold saving in time as shown with the small protein GB1. According to a chemical shift survey of BMRB deposited data, spectral crowding effects should only fail to assign B10% of the residues in a larger 150–200 AA protein. Consequences of lower experimental sensitivity were not considered which would further decrease the rate of success. Although the sequence can be adapted for 2H labelled proteins using this approach should be particularly attractive for proteins up to 100 amino acids in size. A better suited experiment for larger proteins to obtain sequential assignment without 13C shift matching is the 3D TROSY hNcaNH that was described by Frueh et al.15 Here resolution and sensitivity improvements were achieved through the use of TROSY for both semi-CT evolution periods in combination with non-uniform


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sampling. In contrast to the previously mentioned experiment there is no carbonyl transfer step involved making the experiment more suited for high magnetic fields. Experimental implementations with bidirectional and simplified unidirectional transfer were presented and used on a 2H, 13C, 15N labeled 37 kDa protein. An alternative backbone assignment strategy for small proteins was described by Frueh et al.16 which relies on a time-shared 3D experiment where the pathways following (HA)CANH and (H)NCAHA transfers to HN and Ha are simultaneously observed. The spectrum was recorded with gradient coherence order selection to provide sufficient levels of water suppression to allow analysis of the Ha part of the acquired dimension. Every indirect dimension records either 15N or 13C and after a initial 901 rotation of the Ha-detected part during processing every spectrum plane contains at a particular 15N or 13Ca peak position two Ha and HN peaks, of which one intra- and one interresidue. Assignments can be established by using both the Ha or HN route. Making sequential connectivities follows a simplified ‘stairway’ pattern. H directed side chain assignment. Jiang et al.85 described a novel intra-HC(C)NH experiment that correlates aliphatic H/C positions with the amide backbone pair while suppressing the sequential pathway. The sensitivity of the experiment is determined by 13CO and 13Ca relaxation during the extensive transverse periods required for the filter element. While this experiment is well suited for smaller proteins fractional deuteration combined with 2H decoupling can help in the case of intermediate size proteins around 15 kDa. Intra-HC(C)NH and HC(CCO)NH experiments were recorded as (4,3)D reduced dimensionality experiments and 4D spectra were reconstructed from 10 projections using the lower-value algorithm. The reduced number of signals per residue in the intra-HC(C)NH version helped to keep the number of required projections low. The large quantity of NOEs in bigger proteins makes their assignment a difficult task. On the other hand if selective labelling strategies are employed to keep the number of NOEs down then this sparse set of information needs to be assigned as completely as possible. The total assignment of all NOEs in ILV 13C-methylprotonated, 15N labelled samples based on two time-shared 3D and 4D NOE experiments was described by Frueh et al.17 A 3D NOESY 15N-TROSY/13C-SEHSQC was used featuring simultaneous evolution of methyl-13C and 15N as reported previously. The 4D 1H,13C/15N-HSQC NOESY 15N-TROSY/13C-SE-HSQC features simultaneous recording of 13C and 15N frequencies in both heteronuclear dimensions. Two datasets with inverted phases were recorded interleaved to generate 4 types of separated NOE connectivities: HN to HN, HN to HC, HC to HN and HC to HC. The total experiment time was 10 days. 1

Aromatic side chain assignment. Lo¨hr et al.86 described a novel two-step approach for the sequence-specific J-coupling based total assignment of aromatic residues of histidine and tryptophan residues in small to medium sized proteins. A initial assignment of d-protons and d-carbons to the backbone amide of the consecutive residue using 3D H(CDCGCBCACO)NH or (H)CD(CGCBCACO)NH is followed by the establishment of the connectivities between 1Hd/13Cd and the remaining 1 H/13C spin positions of the He/Ne indole through (H)C(NC)HHis or HC(C)NHTOCSYTrp. All signals from other amino acids are efficiently suppressed. RNA experiments. Low sensitivity and increasing 15N shift overlap with larger (430 nucleotides) doubly labeled RNA makes the use of HCN based experiments to provide intranucleotide sugar-base connectivity inefficient. Frequently nucleotidespecific labeling would be required to increase spectral resolution. Two new TROSY optimized 3D CT-HCN(C) experiments were presented by van Melckebeke et al.87 which lead to high resolution in 13C and 15N dimensions and employed a base-type Nucl. Magn. Reson., 2007, 36, 244–261 | 259 This journal is

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editing step to increase spectral resolution allowing identification of the base-type without the requirement of selective isotope labeling. Instead of the usually used 13C CT periods to remove the effects of carbon–carbon couplings Dayie88 applied adiabatic band-selective decoupling to increase resolution and sensitivity in several 3D RNA experiments. According modifications were described to decouple C5 and C6 pyrimidine positions in a (H)C-TOCSY-(C)NH and the C1 0 from the C2 0 atom in C1 0 -selected NOESY, (H)CCH-TOCSY and H1C1C2 ribose experiments. The modified sequences were used to resolve ambiguities in the assignment of a 36 nucleotide hairpin RNA.

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NMR of proteins and nucleic acids S. J. Matthews DOI: 10.1039/b618334b

1. Introduction This report highlights key papers, published this year, that describe advances in the development and application of NMR techniques to the study of proteins and nucleic acids. Many of the sections presented below reflect evolving trends in recent methodology developments, such as in automated NMR, membrane protein NMR and paramagnetic relaxation enhancement methods. Automated NMR methods are not only well-established in labs focusing on high-throughput structural studies but are also becoming more widely used in mainstream groups. Despite difficulties in protein production and technical limitations, solid and liquid state NMR studies on membrane-associated proteins have been growing at an increasing rate. Rejuvenation in the use of spin-labelling and paramagnetic relaxation enhancement (PRE) in structural and dynamic studies of large macromolecular complexes is also particularly notable. One novel paper describes detection of low population transient intermediates in the intra and intermolecular DNA search processes of a sequence-specific transcription factor.1 Furthermore, I draw the reader’s attention to studies reporting new insight into structure, dynamics and folding of biological macromolecules. Line narrowing methods such as TROSY, CRIPT and CRINEPT offer much promise but have yet to address truly important biological questions. Expansion in this area is taking place and this year has witnessed some key examples: Conformation changes and dynamics have been monitored in a 91 kDa oligomer trp RNA-binding attenuation protein (TRAP),2 the 75 kDa intrinsically unstructured p21-KID bound to its biological target,3 substrate protein human dihydrofolate reductase (hDHFR) while bound to the 900 kDa molecular chaperone GroEL,4 the 500 kDa complex between p47 and the AAA + ATPase p97/VCP5 and the interactions of the 300-kDa cylindrical protease ClpP.6

2. New methodology 2.1 Automated analysis New developments have been reviewed in the automated and high-throughput analysis of protein NMR spectra and structure determinatiom.7 An essential step in NMR studies is determining the backbone resonance assignment, which maps backbone atoms from individual residues to resonance frequencies. Automated procedures have yet to gain complete acceptance due to assignment errors because significant ambiguity often exists in both connectivity and amino acid type. Referencing is an important prerequisite for accurate automated spectral analysis. Wang et al. have statistically analysed differences between the secondary shifts of the alpha- and beta-carbons and provided the means to reference errors.8 Moreover, new algorithms have been proposed this year that address these issues. BaileyKellogg et al. have developed a novel random-graph theoretical framework and algorithm for connectivity-driven NMR sequential assignment.9 The random graph model captures the structure of chemical shift degeneracy, a key source of Department of Biological Sciences, Imperial College London, Exhibition Road, South Kensington, London, UK SW7 2AY


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connectivity ambiguity and provides the basis for a randomized algorithm for finding optimal assignments as sets of connected fragments in NMR graphs. The approach is able to overcome significant noise and local ambiguity in identifying fragments of sequential assignments. Vitek et al. have presented a complete branchcontract-and-bound search algorithm. The algorithm controls the search space by scoring partial assignments and employing statistically sound pruning criteria. It considers all solutions consistent with the data, and uniformly treats all combinations of extra and missing data. They successfully demonstrate the approach on experimental data from five proteins ranging in size from 70 to 154 residues.10 Lin et al. have presented a new method called GANA that uses a genetic algorithm to automatically perform backbone resonance assignment. GANA takes spin systems as input data and uses two data structures, candidate lists and adjacency lists, to assign the spin systems to each amino acid of a target protein. Using GANA, almost all spin systems can be mapped correctly onto a target protein, even with significant noise.11 An iterative relaxation algorithm, called RIBRA, has been described by Wu et al.12 To deal with noisy NMR data, RIBRA is executed in an iterative fashion based on the quality of spectral peaks. The average accuracy of RIBRA on perfect datasets is 495%. Eghbalnia et al. have developed a novel strategy (PISTACHIO) for the probabilistic assignment of both backbone and side-chain chemical shifts in proteins. The algorithm uses peak lists derived from various NMR experiments as input and provides as output ranked lists of assignments for all signals recognized in the input data as constituting spin systems. The performance of PISTACHIO showed no direct dependence on protein size, but correlated instead with data quality.13 Northeast Structural Genomics Consortium has summarized progress in standardizing NMR data collection and building an integrated platform for automated analysis. The platform encompasses the following steps: standardised NMR data and processing, automated peak picking and peak list editing, automated analysis of resonance assignments and nuclear Overhauser effect spectroscopy (NOESY) data together with 3D structure determination, and methods for protein structure validation.14 A more detailed article focuses on the NOESY interpretation problem and describes the use of graph theory in a novel, bottom-up, topologyconstrained distance network analysis algorithm. AutoStructure implements this and iteratively generates structures using structure calculation programs XPLOR/ CNS or DYANA.15 Eiso et al. have presented a new method that significantly enhances the robustness of automated NMR structure determination by allowing the NOE data corresponding to unassigned NMR resonances to be used directly.16 The unassigned resonances are represented by ‘‘proxy’’ residues that enable distance restraints to be assigned. If sufficient NOE information is available, the restraints should place the ‘‘proxy’’ residues at positions close to the correct atoms for the unassigned resonance, which can then facilitate assignment. A similar ‘contact-based’ assignment approach is demonstrated by Kamisetty et al.17 Spectral data are represented in a graph with vertices for putative residues and edges for hypothesized NOESY interactions. An assignment is derived by identifying consistent patterns of edges (e.g. for alphahelices and beta-sheets) within a graph and by mapping the vertices to the primary sequence. Fossi et al. have investigated systematically the effects of chemical shift tolerances on automated structure calculations.18 Large tolerance windows, and the correspondingly high levels of ambiguity, are acceptable when slower cooling was used in the simulated annealing protocol. In cases where a high percentage of wellconverged structures are not achieved, it is more productive to calculate fewer structures whilst applying slow cooling. Etezady-Esfarjani et al. have successful demonstrated an automated NMR structure determination on data recorded in a crude cell-extract for the first time.19 New approaches for speeding up the acquisition of multidimensional NMR spectra are attracting growing attention. Freeman and Kupce have reviewed two such methods.20 The first uses sparse radial sampling of the time-domain data Nucl. Magn. Reson., 2007, 36, 262–284 | 263 This journal is

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instead of the systematic recording of all the elements of the multidimensional array. Fourier transformation of skew sections through the time-domain signal generates plane projections of the frequency-domain spectrum. From a small number of such projections the full multidimensional spectrum can be reconstructed. The second technique economises measurement time by restricting the excitation to selected frequencies, using prior information from a conventional spectrum. This involves an encoding and decoding scheme based on Hadamard matrices. For isotopicallyenriched samples, this Hadamard method can be exploited to highlight the important sites, as if the molecule has been specifically enriched at the chosen locations.20 Projection-reconstruction NMR (PR-NMR) involves measuring lower-dimensional projections of a higher-dimensional spectrum, which are then used for the mathematical reconstruction of the full spectrum. Reconstruction of an image from a set of projections is well-established in X-ray tomography, electron microscopy and magnetic resonance imaging. In order to tackle this for NMR in a user friendly fashion, new algorithms have been developed. Coggins and Zhou have described the program PR-CALC which performs this task.21 Malmodin and Billeter have presented EVO-COUP, a tool for the analysis of reduced dimensionality spectra.22 Yoon et al. have explored several practical reconstruction schemes, including deterministic methods such as additive back-projection and lowest-value algorithms and statistical search methods including iterative least-squares fitting, maximum entropy, and model-fitting schemes based on Bayesian analysis.23 Hiller et al. have presented an automated projection spectroscopy (APSY) method for recording projections from multidimensional NMR experiments at operator-selected projection angles and identifying correlation cross peaks.24 The result from APSY is the fully automated generation of the complete peak list. Unambiguous calculation of the peak positions in the N-dimension can be achieved for all cross peaks that are not overlapped in at least one dimension. Building upon this Fiorito et al. have proposed a 6-dimensional (6D) APSY-seq-HNCOCANH NMR experiment that correlates two sequentially neighbouring amide moieties in proteins via the C 0 and Ca nuclei.25 The automatic analysis of 2D projections with GAPRO and the sequential assignment with GARANT are also described. Eghbalnia et al. have described a novel approach to the rapid collection and processing of multidimensional NMR data.26 The HIFI-NMR algorithm incorporates several innovative features. Two orthogonal 2D planes are collected and then, tilted planes are selected by analyzing spectral space rigorously to derive the optimal angle for the next plane. Peak lists are then assembled with associated probabilities without total reconstruction of the 3D spectrum and are ready for use in automated assignment or structure determination. Jiang et al. have demonstrated the application PR-NMR to (4,3)D HC(CCO)NH and intra-HC(C)NH experiments to achieve rapid data collection and unambiguous assignment of aliphatic side chain nuclei at high resolution.27 2.2 Dipolar couplings Residual dipolar couplings (RDCs) offer highly precise structural information and are now accepted as a valuable complement to NOEs in structure determination. New experiments have been developed to measure RDCs with ever more accuracy. Ball et al. have reported new 2D and 3D experiments for the measurement of CHa residual dipolar coupling constants in 13C and 15N labelled proteins. Two experiments, 2D (HNCO)-(J-CA)NH and 3D (HN)CO-(J-CA)NH, sample the CHa splitting by means of Ca magnetization, while 2D (J-HACACO)NH and 3D J-HA(CACO)NH use Ha magnetization to achieve a similar result.28 Similarly, Cicero et al. have presented a revised version of the HACACO experiment that is both sensitive and an accurate method to measure CHa RDCs.29 Pervushin et al. have proposed a general method for constructing optimised sequences that are capable of transferring a spin operator encoding the chemical 264 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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shift of heteronuclear spins to another spin operator suitable for signal detection.30 This method is illustrated on the application of optimized coherence-transfer pulsesequence elements for measuring 1H–1H and 1H–13C RDCs in a 17 kDa protein aligned in Pfl phage. Vijayan and Zweckstetter have developed a novel NMR strategy to measure a large number of RDCs simultaneously without increasing resonance overlap and subsequent error.31 In order to reduce the experimental time a single reference experiment is used for the extraction of more than one type of coupling. The coupling-dependent parameter is varied according to the quantitative J-correlation method or via accordion spectroscopy. The ever-increasing precision with which RDCs can now be measured under weakly aligned conditions is starting to reveal the subtle effects of internal protein dynamics. RDCs are sensitive to the direction and amplitude of motions taking place on a timescale slower than rotational diffusion.32 Clore and Schwieters have demonstrated that backbone residual dipolar coupling data in five independent alignment media, generalized order parameters from 15N relaxation data, and Bfactors from crystal structures are entirely consistent with each other. The analysis of the parameters reveals the same low-amplitude anisotropic motions arising from fluctuations in backbone f/c torsion angles on the picosecond to nanosecond timescale in both solution and crystalline environments.33 Bouvignies et al. have applied geometric motional models in combination with high-resolution structures to fit experimental RDCs and extract local dynamics. They compared the behaviour of three dynamic modes: the Gaussian axial fluctuation model (1D-GAF), the twosite jump model’’ and a model supposing axially symmetric motion about a mean orientation.34 Prestegard and Yi have presented a method to analyze the dynamics of carbohydrates by combining RDCs and molecular dynamics simulations. Molecular dynamic simulations of methyl-3,6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranoside suggest that the dynamics of the two types of glycosidic linkages, 1–3 and 1–6, are quite different. Although the correct populations of the three conformers cannot be obtained from molecular dynamics, they are obtained for all three states from RDC data.35 Wu et al. used a database of RDC-refined DNA and RNA structures to demonstrate that the electrostatic alignment tensor could be predicted reliably and accurately. The approach is based on the Debye-Huckel approximation for the electrostatic interaction potential, which is satisfied when the charge of alignment medium and solute are of equal sign, as for nucleic acids in a Pf1-phage medium. It is proposed that this ability can facilitate improved structure determination of nucleic acids and a better assessment of dynamics.36 Zweckstetter et al. have extended their approach for predicting alignment tensors of a biological macromolecule dissolved in filamentous phage at neutral pH to low pH.37 Furthermore, they also show that RDCs induced in the protein ubiquitin by the presence of cetylpyridinium bromide/ hexanol/sodium bromide can be predicted accurately by a simple electrostatic alignment model. In summary, electrostatic interactions dominate weak alignment of biomolecules for a wide range of pH values both in filamentous phage and in surfactant liquid crystalline phases. Secondary structure orientations and detailed peptide plane orientations, extracted from RDCs contain both global and local conformation information because they are referenced to a global alignment tensor. Walsh et al. have presented a novel and direct structure determination method for helical proteins that uses RDCs from a single alignment medium in combination with dipolar waves and the RDC-PP correlation.38 They demonstrated its application in the determination of the backbone structure of domain 1 of the receptor-associated protein (RAP) using 40 Ca–Cb and 52 of each N–HN, Ca–C 0 , and C 0 –N couplings. A structure was derived with backbone accuracy of 1.0 A˚ together with a minimal number of NOE distance restraints using a new Xplor-NIH module. In a similar study Wu et al. determined the solution structure of murine gamma S-crystallin using restraints derived from two sets of dipolar couplings, recorded in different alignment media, and Nucl. Magn. Reson., 2007, 36, 262–284 | 265 This journal is

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supplemented by a small number of NOE distance restraints.39 Their method relies on the recently introduced molecular fragment replacement method, which capitalizes on the large database of protein structures previously solved by X-ray crystallography and NMR. RDCs are orientational in nature and are therefore highly complementary to NOEs and the study of the protein complexes. However, NMR studies of protein complexes are time-consuming even if the free protein structures are known. As a result, there is increasing interest in the ability to model the structure of a complex using the structure of the free proteins and a few easily-obtained NMR parameters; such as chemical shift perturbation (CSP) data and orientational restraints from RDCs. A combined method is proposed in which RDCs are first introduced as intervector projection angle restraints and at a later stage as direct restraints, which is shown to give the most accurate results.40 Mettu et al. have introduced the solution to geometric optimization problem for identifying the interface region of a protein complex from unassigned NMR data. They presented results on NMR data for seven proteins from five protein complexes.41 Nuclear vector replacement (NVR) has been proposed as a method for rapidly assigning NMR data given prior structural information. Yan et al. have presented a novel method to establish the accuracy of the estimated Saupe alignment tensors.42 Furthermore, they have proposed that this method could also be used in X-ray crystallography or molecular docking to quantify the accuracy of calculated rotations of proteins, protein domains, nucleic acids, or small molecules. Zhuang et al. have presented a novel strategy for the enhancement of RDCs from bound states. The protein is modified by addition of a hydrophobic alkyl tail that anchors it to the bicelles, which are a part of the ordering medium needed for RDC measurement.43 2.3 TROSY-based techniques Recent advances in instrumentation and isotope labelling techniques allow proteins up to 100 kDa in size to be studied in detail using NMR spectroscopy.44 Methyl protonation in a perdeuterated background not only improves the relaxation properties of larger proteins but offers a route to the assignment of sufficient NOE restraints for structure determination. Jorden et al. have demonstrated the usefulness of the 13C-detected CH3-TOCSY experiment for complete methyl group assignment of a 45 kDa bimolecular protein complex (p21-KID/Cdk2) at low concentration and high ionic strength.45 New pulse sequences embracing line narrowing techniques have been developed that provide further improvements in the sensitivity of assignment experiments. Frueh et al. have developed new hNcaNH experiment that incorporates TROSYbased elements resulting in remarkable sensitivity and resolution enhancements. Non-uniform sampling in both indirect dimensions combined with Maximum Entropy (MaxEnt) reconstruction enables dramatic resolution enhancement while maintaining short measuring times. The method was applied to a 0.3 mM sample of a 37 kDa fragment of the E. coli enterobactin synthetase module EntF.46 TROSYtype HNCOCA and HNCACO experiments are limited to low field spectrometers by the rapid 13C 0 transverse relaxation, due to the large 13C 0 chemical shift anisotropy (CSA). Lee et al. have proposed a sensitivity enhanced, time-optimised experiment called COCAINE to correlate chemical shifts of 13C 0 and 13Ca spins, which is applicable to the sequential backbone assignments of deuterated proteins. Compared to the standard HSQC, the COCAINE experiment delivers a 2.7-fold gain in sensitivity.47 Due to the spin-state selection employed, the COCAINE experiment can also be used for efficient measurements of one-bond couplings (e.g. scalar and residual dipolar couplings) in any two-spin system. Frueh and co-workers have described two time-shared experiments that enable the characterisation of all NOEs in 1H–13C-ILV methyl-labelled proteins that are otherwise uniformly deuterated and 15 N enriched.48 A 3D experiment simultaneously provides the spectra of a 3D 266 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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NOESY-HN-TROSY and of a 3D NOESY-HC-PEP-HSQC, and allows for the unambiguous determination of all NOEs involving amide and methyl protons. Lee et al. have also reported a highly-efficient, TROSY-based NMR pulse scheme, 15 N–1H TRACT, that permits the determination of effective rotational correlation times, without interference from dipole–dipole coupling of the amide proton with remote protons.49 This experiment would be useful for the rapid estimation of NMR relaxation rates and the subsequent identification of aggregation. Hamel and Dahlquist have described a new method to map the residues at a protein–protein interface for macromolecular complexes of molecular weights greater than 100 kD.50 The method exploits 13C methyl TROSY methodology for large molecule but the reduction in dipolar interactions is lost if a given methyl group comes in contact with protons from interaction partner. They compared the 13CH3 resonances of the protein of interest in the presence of a protonated versus deuterated interaction partner, revealing interfacial methyls. This year has also seen a rise in the application of narrowing techniques to address real biological questions. Uniform 15N/2H labelling combined with the TROSY pulse sequence enables protein up to 100 KDa to be readily studied. A number of studies have exploited this technology to great effect: Eletsky et al. have used TROSY methods to complete the assignment the 44 kDa trimeric enzyme.51 They also mapped chemical shift perturbations and changes in intramolecular mobility caused by the ligand binding. Significant structural consolidation of the protein was found in the presence of a bound ligand, particularly a highly flexible region at the C-terminus. These data suggest direct contact between this section and the bound ligand, thus suggesting that the C-terminus serves as a lid for the active site, limiting diffusion into and out of the pocket and imposing conformational control over bound substrate. To overcome the challenges associated with the high molecular weight (75 kDa) and low solubility of the ternary complex (0.2 mM), Wang et al. used perdeuteration, TROSY, and high-sensitivity cryogenic NMR probes at high magnetic-field strengths to characterize an intrinsically unstructured protein, p21-KID, bound to its biological target.3 Binary sub-complexes facilitated resonance assignment and opens an avenue for the study of other large, intrinsically unstructured proteins. McElroy et al. have qualitatively assessed residue-specific broadening in TROSY NMR spectra of the 91 kDa oligomer, trp RNA-binding attenuation protein (TRAP).2 Implications for the mechanism of ligand-mediated TRAP activation through a shift in a pre-existing conformational equilibrium and an induced-fit conformational change were discussed. Hastings et al. have used TROSY NMR spectroscopy to probe the changes in 1H–15N chemical shifts of the dimeric 29 kDa replication terminator protein (RTP) mutant upon binding a 21 base pair symmetrical DNA binding site.52 Data correlated more closely to protein structural changes upon complex formation rather than to interactions at the protein-DNA interface. Chen et al. have analyzed the Ca2+-binding properties of the neuronal SNARE complex formed by synaptobrevin, syntaxin and SNAP-25 using TROSY NMR methods.53 Several Ca2+-binding sites are found on the surface of the SNARE complex, but most of them are not specific for Ca2+ and all have very low affinity. They also illustrate that the E170A/Q177A SNAP-25 mutation does not alter interactions between the SNARES and the Ca2+ sensor synaptotagmin 1, but impairs SNARE complex assembly. The results suggest that the SNAREs do not act directly as Ca2+ receptors but SNARE complex assembly is coupled tightly to Ca2+-sensing during neurotransmitter release. Carrick et al. have used TROSY NMR to monitor chemical shifts movements of IGF binding protein-2 (IGFBP-2) upon interaction with IGF-I and -II.54 Their results confirm that the C-domain of IGFBP-2 plays a key role in binding regions of IGF-I and -II. Cross-correlated relaxation-induced polarization transfer (CRIPT), and crosscorrelated relaxation-enhanced polarization transfer (CRINEPT) extend further the application of 1H–15N correlation NMR spectra to complexes of several 100s kDa. Horst et al. have illustrated this on the substrate protein human dihydrofolate Nucl. Magn. Reson., 2007, 36, 262–284 | 267 This journal is

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reductase (hDHFR) while bound to the molecular chaperone GroEL or to a singlering analogue, SR1.4 Using a specifically labelled protein, they confirmed that the NMR-observable parts of hDHFR do not adopt a defined 3D structure and have high internal mobility. Measurements of the build-up rates of the magnetization transfer mechanisms enabled the dynamic properties of the bound substrate to be characterised and suggest that the bound state includes random coil conformations devoid of stable native-like tertiary contacts and that bound hDHFR is described as a dynamic ensemble of randomly structured conformers. The AAA + ATPase p97/VCP, helped by adaptor proteins, exerts its essential role in cellular events such as endoplasmic reticulum-associated protein degradation or the reassembly of Golgi, ER and the nuclear envelope after mitosis. Beuron et al. combined EM with NMR data to study the interaction between p47, and the various nucleotide states of the AAA + ATPase p97/VCP.5 TROSY and CRIPTTROSY NMR spectra of 15N, 2H labelled p47 in complex with unlabelled p97 enabled a structural model to be presented. Characteristic chemical shifts perturbation identified key interaction sites and the presence of a trimeric central SEP domain. A very promising new approach to the study of very large macromolecular complexes (4100 kDa) is the methyl TROSY effect. HMQC spectra of protonated methyl groups in high molecular weight, highly deuterated proteins have large enhancements in sensitivity and resolution, which derive from a TROSY effect in which complete cancellation of intra-methyl 1H–1H and 1H–13C dipolar interactions occurs for 50% of the signals. This method provides alternative probes to 1H–15N spectra for the structural and dynamic studies of high molecular weight systems. Sprangers et al. have used the methyl TROSY effect to study the interaction of the 300-kDa cylindrical protease ClpP, an important component of the cellular protein quality machinery.6 ClpP consists of 14 subunits arranged into two heptameric rings that enclose a large chamber containing the protease active sites. ClpP also associates with ClpX and ClpA ATPases that unfold and translocate substrates into the chamber. Methyl TRIOSY spectra and relaxation dispersion experiments identified that the interface between the heptameric rings exchanges between two structurally distinct conformations. Using site-directed mutagenesis to introduce rigidifying disulphide bonds, the authors provide evidence to suggest that these motions play an important role in product release. Furthermore, using a combination of site-directed spin labelled peptides in conjunction with methyl-TROSY spectra, Kreishman-Deitrick et al. were able to characterise the interface of a 300 kDa protein complex.55 2.4 Paramagnetic relaxation enhancement (PRE) TROSY-based methods have extended the size limitations for NMR study of biological macromolecules in solution. Furthermore, the novel application of new NMR parameters such as RDCs provides greater accuracy and further promise for large molecules. The use of spin labelling and the measurement of paramagnetic enhancement of relaxation are being revisited as a means to provide new distance information. A nitroxide spin-label attached to a cysteine in a region of a protein, and in its oxidized (paramagnetic) state, will enhance the relaxation of NMR signals for nuclei within 20–25 A˚. Ensembles of structures can then be calculated by restraining simulations using such PRE-derived distance thresholds. An attractive feature of such experiments is that only partial spectral assignment is required, thus opening new avenues to study large protein complexes. A major challenge for the structure determination of large proteins and integral membrane proteins is the limited number of NOE restraints as extensive deuteration is often necessary. Paramagnetic relaxation enhancement (PRE) by means of nitroxide spin-labels can provide valuable long-range distance information. Liang et al. used the integral membrane protein OmpA as a model system and 268 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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demonstrated that distances up to 24 A˚ can be readily determined.56 The protein was labelled at 11 water-exposed and lipid-covered sites, and 320 PRE distance restraints were measured and structures of reasonable quality were obtained with these restraints. Using a combination of site-directed spin labelled peptides in conjunction with methyl-TROSY spectra, Kreishman-Deitrick et al. were able to characterise the interface of a 300 kDa protein complex, thereby demonstrating the utility of NMR for studying ligand binding events in large, asymmetric, macromolecular assemblies.55 Proteins in the Wiskott-Aldrich syndrome protein (WASP) family activate the Arp2/3 complex through a conserved C-terminal element termed the VCA domain. The VCA domain of the neuronal Wiskott-Aldrich syndrome protein (NWASP) is a potent activator of the Arp2/3 complex, a 240 kDa heteroheptameric actin-nucleating assembly. Intensities of the ARPC3 methyl signals in 1H, 13C methyl group labelled, perdeuterated ARPC3-loaded Arp2/3 complex were monitored in the presence various spin-labelled CA peptides. The data suggest that CA binds to Arp3, Arp2, ARPC1, and ARPC3, with the C-terminus of the C region and the C-terminus of the A region proximal to ARPC3. The N-terminus of the C region appears to be distal to ARPC3 and may interact with an actin monomer and/or other cross-linking subunits of the Arp2/3 complex. In idiopathic Parkinson’s disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein a-synuclein (aS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, aS to neurotoxic forms are largely unknown. Using PRE and RDCs, Bertoncini et al. have showed that monomeric aS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerisation and aggregation.57 15N-relaxation time measurements and PRE from three different cysteine-containing mutants (A18C, A90C and A140C) allowed the detection of native-like contacts and hydrophobic clusters. These conformations fluctuate in the range of nanoseconds to microseconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and temperature increases release this inherent tertiary structure, leading to a completely unfolded conformation that aggregates readily. In a similar study, Dedmon et al. created several cysteine mutations aS to facilitate the attachment of a site specific spin-labels.58 PRE and molecular dynamics simulations revealed the presence of long-range contacts that are B200 times more probable than in a random coil. This approach has also been used to measure distances in the denatured state of ACBP and simulate conformational ensembles representing.59 A detailed comparison of the residual structure within the denatured state of ACBP has enabled us to infer that regions in the N and C-terminal parts of the protein sequence have a high tendency to interact in the unfolded state under physiological conditions. By comparing the structural features in the denatured states with those in the transition state for folding, the authors also provided new insights into the mechanism of native state formation. A growing number of modules including FYVE domains target key signalling proteins to membranes through specific recognition of lipid head groups and hydrophobic insertion into bilayers. Brunecky et al. incorporated 5- and 14-doxylphosphatidylcholine spin-labels into dodecylphosphocholine (DPC) micelles and measured the PRE in the early endosome antigen 1 (EEAI) FYVE domain.60 They were able to determine the geometry of micelle penetration by the FYVE domain, which revealed an elongation of the membrane insertion loop (MIL) whereby the hydrophobic residues of the loop tend to move deeper into the nonpolar core of micelles. The micelle insertion mechanism of the FYVE domain is consistent with mutagenesis data and chemical shift perturbations. Herbig et al. used PRE and the spin label 5-doxylstearate to probe the association of human calcitonin (hCT)derived cell-penetrating peptide with DPC micelles. Data reveal the helix engaged in parallel orientation to the micelle surface.61 These demonstrate the usefulness of Nucl. Magn. Reson., 2007, 36, 262–284 | 269 This journal is

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using the spin-label NMR approach for investigating the binding geometry by peripheral membrane proteins. In a seminal piece of work, Iwahara and Clore were able to detect directly the poorly populated transient intermediates in the DNA search processes of the homeodomain from HOXD9, a sequence-specific transcription factor.1 The PRE data in the fast exchange regime and it reveals the presence of transient intermediates formed in a stochastic manner at non-cognate sites whose structure is similar to that of the specific complex. Two distinct search processes involving intra- as well as intermolecular translocations were delineated. The intermolecular PRE method can be readily applied to investigations of transient intermediates in other macromolecular binding processes.

3. Macromolecular structures In this Section I have chosen not to describe solution structures of free proteins, as such publications have increasingly modest impact. Structures of macromolecular complexes are considerably more informative from a biological perspective and this year has seen further impressive studies. 3.1 Membrane proteins Growth in the characterization of membrane proteins by both solution and solid state NMR has continued, with much promise for the future. Structural information about the interactions between membrane proteins and their ligands provides insights into membrane protein function. A variety of surfactants have been used for successful structural analyses of membrane proteins, however, the use of surfactants frequently increases the conformational instability and distorts normal function. Yokogawa et al. have proposed a new strategy of membrane protein reconstitution into lipid bilayers on affinity beads, which maintains the native conformation and function of the protein for NMR studies.62 The first steps in any structural study is to purify the protein and acquire an simple 1D or 2D NMR spectrum, the quality of which can then be used to assess the feasibility of the project. Few integral membrane proteins (IMPs) have been subjected to this. Tian et al. have outlined some NMR feasibility testing methods that are tailored for histagged IMPs produced in E. coli.63 Generally applicable protocols are presented for expression testing, purification, and NMR sample preparation. A 2D TROSY pulse sequence that has been optimized for use with IMPs is also presented. Lipid choice is very important and determines whether protein-containing micelles, bicelles, or bilayers, are obtained. Solution NMR methods are applied to weakly aligned micelle and small bicelle samples. Solid-state NMR methods can be used with mechanically aligned bilayer and magnetically aligned bicelle samples.64 Recent studies have demonstrated that it is viable to use micro-crystalline preparations of water-soluble proteins in solid-state NMR experiments. Lorch et al. have extended this approach to studying membrane proteins.65 They have prepared small crystals of the alphahelical membrane-protein diacylglycerol kinase (DGK) and proteoliposomes. It was found that crystalline samples produce better-resolved spectra than proteoliposomes. Gor’kov et al. have describe a new 600 MHz 15N–1H solid-state NMR probe with a large RF coil for high-power, multi-pulse sequence experiments, such as polarization inversion spin exchange at the magic angle (PISEMA).66 Solid-state NMR application to membrane proteins has developed to the extent that observing drugs and ligands at their site of action is possible. Even large, functionally active complexes can be studied, revealing structural and dynamic details at high resolution.67 One of the highlights of the year is Lange and coworkers’ characterisation of a potassium channel-toxin interaction.68 The active site of potassium (K+) channels catalyses the transport of K+ ions across the plasma 270 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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membrane and is inhibited by toxins from scorpion venom. It was shown using high-resolution solid-state NMR spectroscopy, that high-affinity binding of the scorpion toxin kaliotoxin (KTX) to a chimeric K+ channel (KcsA-Kv1.3) is associated with significant structural rearrangements in both molecules. A comparison to two-dimensional >13C,13C] correlations from spin-diffusion spectra observed for free and unbound, KTX revealed significant 13C chemical shift changes for several residues. A secondary chemical shift analysis indicated that bound and free KTX had a comparable backbone fold and further analysis yielded a structural model of KTX. This work demonstrates that solid-state NMR is a sensitive method for analysing the structure of a membrane protein-inhibitor complex. The latest methodological progress towards constructing 3D structures from solid-state NMR data obtained under magic-angle-spinning conditions has been reviewed.69 Using uniformly 13C/15N-labeled sample of ubiquitin, Seidel et al. have illustrated the solid-state NMR methods tailored to the construction of 3D molecular structure.70 They supplement this with a systematic study of the influence of solid phase protein preparation on NMR spectra. Andronesi et al. have demonstrated dipolar recoupling experiments and novel through-bond correlation schemes on a uniformly 13C/15N labelled variant of the 52-residue polypeptide phospholamban.71 When reconstituted in lipid bilayers, the NMR data are consistent with an alpha-helical trans-membrane segment and a cytoplasmic domain that exhibits a high degree of structural disorder. Sinha et al. have reviewed the role of peptides in the development of solid-state NMR spectroscopy of aligned samples.72 Recent developments of pulse sequences and NMR probes for triple-resonance NMR of aligned samples are presented. The solid-state NMR experiment PISEMA, is a technique for determining structures of proteins, especially membrane proteins, from oriented samples. Degeneracy in the PISEMA function enables peptide planes orientations to be determined with respect to the magnetic field direction. Quine et al. have derived a formula for the intensity function in the powder pattern.73 They also use it to determine the effect of small changes in peptide plane orientations depending on the location of a resonance in the powder pattern spectrum. Jones and Opella have applied maximum Entropy reconstruction to PISEMA spectra of stationary samples of proteins in magnetically aligned virus particles and membrane bilayers.74 Improvements in signal-to-noise were observed with minimal distortion of the spectra leading to substantial reductions in experimental time. Park et al. have performed solid-state 15 N NMR experiments on mechanically aligned bilayer and magnetically aligned bicelle samples and demonstrated that membrane proteins undergo rapid rotational diffusion about the normal in phospholipid bilayers.75 Narrow single-line resonances were observed from 15N labelled sites in the trans-membrane helix of Vpu from HIV-1 in phospholipid bilayers with their normals at angles of 0, 20, 40, and 90 degrees, and bicelles with their normals at angles of 0 and 90 degrees with respect to the direction of the applied magnetic field. This can only be explained if the entire polypeptide undergoes rotational diffusion about the bilayer normal. The same group has also investigated the compensation mechanism of a trans-membrane helix in response to hydrophobic mismatch.76 Tilt and rotation angles of the trans-membrane helix of Vpu aligned in lipid bilayers of various thicknesses were determined using orientation-dependent frequencies obtained from solid-state NMR experiments. A tilt angle of 18 degrees was observed in 18:1-O-PC/DOPG (9:1) lipid bilayers, which have a hydrophobic thickness that approximately matches the hydrophobic length of the trans-membrane helix of Vpu. Upon decreasing the hydrophobic thickness of lipid bilayers, no significant change in rotation angle was observed. However, the tilt angle increased systematically with increasing positive mismatch. Protein structure determination by solid-state NMR of aligned samples relies on the fundamental characteristics of the anisotropic nuclear spin interactions. Significant progress has been made in the implementation of these orientational restraints into new algorithms that calculate protein structures. The use of chemical Nucl. Magn. Reson., 2007, 36, 262–284 | 271 This journal is

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shift and heteronuclear dipolar coupling interactions has been described using both simulated and experimental data.77 Luo and Hong have now provided an analysis of the mixing-time-dependent centerband-only detection of exchange (CODEX) intensities using spin diffusion theory to obtain quantitative distances for structure determination.78 The exchange curve is fit to a rate equation, where the rate constants are proportional to the square of the dipolar coupling and the spectral overlap integral between the exchanging spins. Applying the 19F CODEX experiment and analysis, they studied the transmembrane peptide of the M2 protein (M2TMP) of influenza A virus bound to 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine bilayers. It was determined that M2TMP associates as tetramers in lipid bilayers, similar to its oligomeric state in detergent micelles and the interhelical F-F distance supports the structural model derived from previous solid-state NMR 15N orientational data. The same group has proposed a sensitivity-enhanced 1D 1H spin diffusion experiment, CHH, for determining membrane protein topology.79 By transferring the 13C magnetization from the labelled protein to lipid and water protons, the CHH experiment reduces the time of the original 2D 13C-detected experiment by two orders of magnitude. The sensitivity enhancement results from 1 H detection and the elimination of the 13C dimension. The technique, demonstrated on colicin la channel domain, confirms the presence of a transmembrane domain and the predominance of surface-bound helices. Channel-forming colicins are bacterial toxins that spontaneously insert into the inner cell membrane of bacteria to form voltage-gated ion channels. Studies were extended to include characterisation of the membrane insertion properties of the bacterial toxin, colicin la.80 Conformational changes were monitored during the transfer from a polar to the hydrophobic environment. Proton-driven 13C-spin diffusion spectra of selectively 13C-labeled protein show unequivocal attenuation of cross-peaks after membrane binding, which can be assigned to distance increases and not reduction of the diffusion coefficient. The observed cross-peak reduction correlates well with an abundance of short interhelical contacts in the soluble protein and not when it is membrane bound, suggesting that colicin la channel domain becomes open and extended upon membrane binding. This can be thought of as a ‘‘molten globule’’, in which the helical secondary structure is retained while the tertiary structure is unfolded. Yao et al. have investigated segmental motion of the closed state of colicin la channelforming domain in membranes of different anionic lipid contents and ion concentrations.81 Proton spin diffusion experiments indicate that the protein contains a small domain that inserts into the hydrophobic centre of anionic membranes, similar to when it binds to the less anionic membranes. Measurements of dipolar couplings indicate that the protein exhibits the least mobility under the high-salt and lowanionic lipid condition, which has the most physiological membrane surface potential. These results suggest that optimal channel activity requires the protein to have sufficient segmental rigidity so that entire helices can undergo the cooperative conformational motions required for translocating the channel-forming helices across the lipid bilayer. Solution-state nuclear magnetic resonance (NMR) studies of large membraneassociated proteins are limited by the difficulties in preparation of stable proteindetergent mixed micelles, by excessive line broadening and the paucity of distance information available from the highly deuterated proteins. Cierpicki et al. have demonstrated that significant improvement in the structure accuracy of the membrane protein OmpA can be achieved by refinement with RDCs.82 Chill et al. have used the 68-kDa homotetrameric KcsA, a thermostable N-terminal deletion mutant of a bacterial potassium channel from Streptomyces lividans, as a model system for applying NMR methods to membrane proteins.83 Backbone assignments of KcsA in SDS micelles were successfully completed and the secondary structure closely agreed with the KcsA crystal structure. The C-terminal cytoplasmic domain, absent in the original structure, contains a 14-residue helix that could participate in tetramerisation via interhelix interactions. 272 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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Zamoon et al. have mapped the interaction surface of an integral membrane protein for its regulatory target, an integral membrane enzyme. Phospholamban (PLN) regulates cardiac contractility via its modulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity.84 Differential perturbations in NMR line widths and chemical shifts, measured as a function of position in the PLN sequence, provide insight into the extensive SERCA contacts in both cytoplasmic and transmembrane domains of PLN. A dynamic equilibrium between two conformational states in the cytoplasmic domain of PLN is also identified. Buffy et al. have used solution NMR to map the structural changes occurring within the integral membrane protein Sarcolipin upon its interaction with the regulatory target, SERCA.85 Excellent 1H–15N correlation spectra were obtained after reconstituting Sarcolipin or both proteins in DPC detergent micelles. Analysis of the structural dynamics of SLN in DPC micelles reveals the presence of four subdomains: a short unstructured N terminus (residues 1–6), a short dynamic helix (residues 7–14), a more rigid helix (residues 15–26), and an unstructured C terminus (residues 27–31). Upon addition of SERCA, monitoring of both peak intensities and chemical shifts revealed the existence of three different states: free, bound, and an unbound intermediate. In the same way as PLN,84 the various dynamic regions of Sarcolipin show differential behaviour upon interaction with SERCA, as revealed by the changes in 1H chemical shifts, and is correlated with changes in hydrogen bond interactions or secondary structures upon interaction. Ulmer et al. have reported the structure and dynamics of micelle-bound protein alpha-synuclein (aS), which associates with presynaptic vesicles and has been implicated in the molecular chain of events leading to Parkinson‘s disease.86 V3V37 and K45-T92 form curved alpha-helices, connected by a well ordered, extended linker in an anti-parallel arrangement, followed by another short extended region (G93-K97), and a highly mobile tail (D98-A140). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the glycine-rich segments of the helices, which may serve to mitigate the effect of aS binding on membrane fluidity. Buck-Koehntop et al. have reported the 3D structure and dynamics of Stannin (SNN), an 88-residue mitochondrial membrane protein identified as the specific marker for neuronal cell apoptosis induced by Trimethyltin intoxication.87 The highresolution structure in detergent micelles and its topological orientation in lipid bilayers were determined by a combination of solution and solid-state NMR methods. SNN is a monotopic membrane protein composed of three domains: a single transmembrane helix (residues 10–33) that transverses the lipid bilayer at approximately a 20 degrees angle with respect to the membrane normal, a 28 residue unstructured linker, which includes a conserved CXC metal-binding motif and a putative 14-3-3 binding domain; and a distorted cytoplasmic helix (residues 61–79) that is partially absorbed into the plane of the lipid bilayer with a tilt angle of approximately 80 degrees from the membrane normal. 3.2 Macromolecular complexes NMR continues to provide key structural and dynamic insights into biological function. This section focuses on some of the notable achievements in solution-based structural studies of protein–protein, protein–inhibitor, protein–lipid and protein– nucleic acid complexes. Weak protein–protein interactions are important in many biological processes. However, in contrast to the large number of well-characterized, strongly interacting protein complexes, weak interactions are notoriously difficult to study. Despite NMR being particularly useful in studying such systems, only a few 3D structures exist. Vaynberg et al. have reported the NMR structure of an extremely weak focal adhesion complex (Kd B 3 mM) between Nck-2 SH3 domain Nucl. Magn. Reson., 2007, 36, 262–284 | 273 This journal is

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and PINCH-1 LIM4 domain. Although in a 1:1 mixture of LIM4 and SH3-3 only 21% would be in complex, 15N/13C filtered, 3D NOESY experiments successfully detected 14 intermolecular NOEs. The structure exhibits a remarkably small and polar interface with distinct binding modes for both SH3 and LIM domains. Such an interface suggests a transient Nck-2/PINCH-1 association process that may trigger rapid focal adhesion turnover during integrin signalling.88 Suh et al. have solved the solution structure of the weak, post-transition state complex between the isolated cytoplasmic A (IIA(Mtl)) and phosphorylated B (phospho-IIBMtl) domains of the mannitol transporter of the E. coli phosphotransferase system.89 The active site His554 of IIA(Mtl) was mutated to glutamine to block phosphoryl transfer activity, and the active site Cys-384 of IIBMtl was substituted by serine to permit the formation of a stable phosphorylated form of IIBMtl. Electrostatic interactions between the two proteins are limited, which accounts for the low affinity of the complex (Kd B 3.7 mM). The release of neurotransmitters is controlled by complex protein machinery that control exquisite temporal and spatial regulation that characterizes synaptic exocytosis. It comprises two large multidomain proteins, Munc13s and a-RIMs, which control priming of synaptic vesicles to a readily releasable state, and interact with each other via their N-terminal sequences. Using NMR spectroscopy Dulubova et al. have elucidated the 3D structure of alpha-RIM zinc-finger domain, which facilitated the design of a double point mutation that abolishes the alpha-RIM/ Munc13 binding.90 Selective disruption of this interaction in the calyx of Held synapse decreased the size of the readily releasable vesicle pool. The alpha-RIM N-terminal sequence also binds to Rab3s (small synaptic vesicle GTPases), an interaction that regulates presynaptic plasticity. It was also demonstrated using NMR that alphaRIMs contain adjacent but separate Munc13- and Rab3-binding sites, allowing formation of a tripartite Rab3/RIM/ Munc13 complex. Combined data suggested that the ternary Rab3/RIM/Munc13 interaction facilitates recruitment of synaptic vesicles to the priming machinery, thereby providing a substrate for presynaptic plasticity. The modular architecture of alpha-RIMs, with nested binding sites for Rab3 and other targets, may be a general feature of Rab effectors that share homology with the alpha-RIM N-terminal sequence. Small GTPases of the Ras family are central regulators of cellular signal transduction processes leading to cell proliferation, cell differentiation, and apoptosis. The novel Ras effector mNore1, capable of inducing apoptosis, is a multidomain protein. It comprises a C1 domain homologous to PKC and an RA domain similar to the Ras effectors AF-6 and RalGDS. Harjes et al. have resolved the structure of the C1 domain of mNore1 and investigated its interactions with the RA domain and Ras using chemical shifts, relaxation rates and isothermal titration calorimetry (ITC).91 No direct binding of C1 to Ras was found, but an intramolecular complex of the C1 and RA domains of Nore1 was formed. Titration of Ras disrupts this intramolecular complex, allowing the C1 domain to tumble freely in solution and to bind other interaction partners. Pleckstrin homology (PH) domains play diverse roles in cytoskeletal dynamics and signal transduction. Split PH domains represent a unique subclass of PH domains that have been implicated in interactions with complementary split PH domains ‘hidden’ in other proteins. Whether partial PH domains exist as independent structural units alone and whether two halves of a split PH domain can fold together to form an intact PH domain are not known. Yan et al. have solved the solution structure of the PHN-PDZ-PHC tandem of alpha()syntrophin.92 The split PH domain of alpha-syntrophin adopts a canonical PH domain fold. The isolated partial PH domains of alpha-syntrophin, although completely unfolded, remain soluble in solution. Mixing of the two isolated domains induces folding and yields a stable PH domain. It was also demonstrated that two complementary partial PH domains are capable of binding to each other to form an intact PH domain. Furthermore, a tandem construct of PHN-PDZ-PHC forms a functionally distinct 274 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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supramodule, in which the split PH domain and the PDZ domain function synergistically in binding to inositol phospholipids. p53 is a potent transcriptional activator that induces expression of many target genes whose products mediate cell-growth arrest and apoptosis, thus suppressing cell transformation and tumor formation. The transcriptional activation function of p53 is associated with its highly acidic amino-terminal TAD and a key target is the transcription factor II H (TFIIH). The interaction between the amino-terminal transactivation domain (TAD) of p53 and TFIIH is directly correlated with the ability of p53 to activate both transcription initiation and elongation. Di Lello et al. have identified a region within the p53 TAD that specifically interacts with the PH domain of the p62 and Tfb1 subunits TFIIH.93 In addition to characterizing the thermodynamics of this interaction, they solved the 3D structure of the complex between the p53 TAD and the PH domain of Tfb1 by NMR spectroscopy. The structure reveals that p53 forms a nine residue amphipathic alpha helix upon binding to Tfb1. Results suggest that a phosphorylation cascade involving Ser46 and Thr55 of p53 could play an important role in the regulation of select p53 target genes. The human ERCC1/XPF complex is a structure-specific endonuclease with defined polarity and participates in multiple DNA repair pathways. Tripsianes et al. were able to co-express the heterodimer and refold, which enabled the full repertoire of hybrid labelled NMR samples to be produced and filtering experiments to be recorded.94 The heterodimeric solution structure of the C-terminal domains of both proteins responsible for ERCC1/XPF complex formation was determined and exhibits two double helix-hairpin-helix motifs that are related by a pseudo-2-fold symmetry axis. In the XPF domain, the hairpin of the second motif is replaced by a short turn. NMR titration data show that only the ERCC1 domain of the ERCC1/ XPF complex is involved in DNA binding. Spinocerebellar ataxia type 3 is a human neurodegenerative disease resulting from polyglutamine tract expansion. The affected protein, ataxin-3, which contains an Nterminal Josephin domain followed by tandem ubiquitin (Ub)-interacting motifs (UIMs) and a polyglutamine stretch, has been implicated in the function of the Ub proteasome system. Two groups have completed an NMR-based structural analysis and revealed that the Josephin domain belongs to the family of papain-like cysteine proteases, sharing the highest degree of structural similarity with bacterial staphopain.95,96 A unique structural feature of Josephin is a flexible helical hairpin formed by a 32-residue insertion, which could determine substrate specificity. The papainlike fold binds protease inhibitors and Ub in a manner reminiscent of other deubiquitinases. Mutation of the catalytic Cys enhances the stability of a complex between ataxin-3 and polyubiquitinated proteins. This effect depends on the integrity of the UIM region, suggesting that the UIMs are bound to the substrate polyubiquitin during catalysis. Human Wilson protein (WLNP) is a copper-transporting P-type ATPase located in the secretory pathway and plays a crucial role in copper transport and homeostasis. Mutations in WLNP are associated with changes in human copper metabolism leading to the neurological disorder, Wilson’s disease. Copper accumulates in the liver, brain and kidneys, causing DNA damage, inactivation of certain enzymes, and lipid peroxidation. Achila et al. have reported the solution structure of apoWLN5-6 and reveal two ferredoxin folds that behave as a single unit in solution.97 Various titration experiments with copper, adjacent copper-binding domains and the associated copper chaperone reveal new insight into the mechanism of the copper transport. Copper binding produces chemical shift changes limited to the two copper-binding regions and does not affect the overall structure. An NMR titration of apoWLN5-6 with the metallochaperone Cu(I)HAH1 reveals no complex formation and no copper exchange between the two proteins, whereas titration of Cu(I)HAH1 with WLN4 shows the adduct formation that is in fast exchange on the NMR timescale. An NMR titration of apoWLN5-6 with Cu(I)WLN4 shows copper transfer, first to WLN6 then to WLN5, without the formation of an adduct. Nucl. Magn. Reson., 2007, 36, 262–284 | 275 This journal is

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Therefore, we suggest that WLN4 and WLN2 are two acceptors of Cu(I) from HAH1, which then somehow route copper to WLN5-6, before the ATP-driven transport of copper across the vesicular membrane. Bacterial cytokinesis requires spatiotemporal coordination of the assembly of a complex of cell division proteins, collectively known as the divisome, at the incipient division site. DivIB/FtsQ is a conserved component of the divisome in bacteria with cell walls, suggesting that it plays a role in synthesis and remodelling of septal peptidoglycan. Robson et al. have demonstrated that the extracytoplasmic region of DivIB comprises three discrete domains and determined the solution structure of the central domain.98 It has a unique 3D fold, with no similarity with any eukaryotic counterpart, and experiences interconversion between two discrete conformations via cis-trans isomerisation of a Tyr-Pro peptide bond. It is proposed that this isomerisation modulates protein–protein interactions of the flanking domains. Interactions between the WW domains of Drosophila Nedd4 (dNedd4) and Commissureless (Comm) PY motifs promote axon crossing at the CNS midline and muscle synaptogenesis. Kanelis et al. have reported the solution structure of the dNedd4 WW3 domain complexed to the second PY Motif ((227 0 )TGLPSYDEALH(237)) of Comm.99 Unexpectedly, there are interactions between WW3 and ligand residues both N- and C-terminal to the PY motif. Residues Y232-L236 form a helical turn, following the PPII helical PY motif. Similarly, Chong et al. have presented the solution structure of the complex between the Smad7 PY motif region (ELESPPPPYSRYPMD) and the WW3 domain from Smurf2, an E3 ubiquitin ligase that drives degradation of the transforming growth factor-beta receptors and other targets.100 The structure reveals that, in addition to binding the PY motif, the WW3 domain binds six residues C-terminal to the PY motif (PY-tail). Dematin is an actin binding protein from the junctional complex of the erythrocyte cytoskeleton. The protein has two actin binding sites and bundles actin filaments in vitro. This actin bundling activity is reversibly regulated by phosphorylation in the carboxyl terminal ‘‘headpiece’’ domain (DHP). DHP is a typical villintype headpiece actin binding motif and contains a flexible N-terminal loop and an alpha-helical C-terminal subdomain that is phosphorylated at Ser74. Jiang and McKnight have described the solution structure of a phosphorylated variant of DHP using a standard triple resonance NMR approach.101 The Ser74 was mutated to Glu (DHPs74e) to mimic the effects of phosphorylation. The negative charge at Ser74 does not alter the conformation of the C-terminal subdomain, but attracts the Nterminal loop toward the C terminus, changing the orientation of the N-terminal subdomain. NMR relaxation studies also indicate reduced mobility in the affected N-terminal loop in DHPs74e. Phosphorylation serves as a switch controlling the conformational state of DHP and the actin bundling activity of dematin. Further structural highlights of protein–protein and protein complexes include the following: Song et al. have solved the solution structure of SUMO-1 in complex with a peptide containing the SUMO binding motif derived from the protein PIASX (KVDVIDLTIESSSDEEEDPPAKR). Surprisingly, the structure reveals that the bound orientation of the SBM can reverse depending on the sequence context.102 Ogura et al. have determined the solution structure of the p47(phox) tandem SH3 domains complexed with the proline-rich peptide of p22(phox), which induces the NADPH oxidase to translocate flavocytochrome b558.103 Abdulaev et al. have determined the solution structure of the C-terminal 147 residues of the yeast nucleoporin, Nup116p, which plays an important role in mRNA export and protein transport.104 Petrosky et al. have solved the solution structure of the heterodimer composed of the L27 domains from LIN-2 and LIN-7, key domains involved in directing specific assembly of supramolecular signalling complexes at synapses and other polarized cell-cell junctions.105 Kang et al. have reported the three-dimensional structure of human RPB8 (hRPB8), a subunit present in all three types of eukaryotic RNA polymerases, at high resolution and studied its interaction with DNA.106 Haupt et al. have presented the solution structure of the AMP-PNP-bound 276 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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nucleotide binding domain KdpBN of the E. coli Kdp-ATPase at high resolution.107 Cliff et al. have described the solution structure of a complex of the TPR domain of Ppp5 with the C-terminal pentapeptide of Hsp90.108 Lorenzen et al. have presented the solution structure of the IL-15R alpha sushi domain and a model of its complex with IL-15.109 Park et al. have elucidated the solution structure of yeast Ufd1 N domain and shown that it exhibits striking similarities to the double-psi barrel motif of p97 and has two distinct binding sites for mono- and polyubiquitin.110 Macao et al. have used NMR to show that the SEA domain from the human MUC1 transmembrane mucin undergoes a novel type of autoproteolysis, which is catalyzed by conformational stress and the conserved serine hydroxyl.111 Although structural studies of RNA-protein complexes and their components are particular challenging, NMR has made a foremost contribution to this field. The polypyrimidine tract binding protein (PTB) is a 58 kDa protein involved in many aspects of RNA metabolism. Vitali et al. have determined the structure of the two C-terminal RNA recognition motifs (RRM3 and RRM4) of PTB and its interaction with RNA.112 They determined the structure of the same fragment in complex with RNA and found that the two RRMs interact extensively. Using an improved segmental isotopic labelling protocol they were able to produce intact PTB34 and unambiguously characterize the interdomain interface. One hundred and thirty interdomain NOEs between the two RRMs were identified, which facilitated the calculation of a very precise structure. On a similar theme this group also reported the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU, which is involved in regulating alternative splicing of tissue-specific exons.113 Although the last three nucleotides, UGU, are recognized in a canonical way by the four-stranded beta-sheet of the RBD, the first four nucleotides, UGCA, are bound by two loops of the protein in a novel mode. This novel RNA binding site is independent from the beta-sheet binding interface. This study demonstrates the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element. Riboswitches are highly structured RNA elements that control the expression of many bacterial genes by binding directly to small metabolite molecules with high specificity and affinity. Noeske et al. have used NMR spectroscopy to identify intermolecular base triples between both purine ligands and their respective riboswitch RNAs by NMR spectroscopy.114 Results revealed that specificity is mediated by the formation of a Watson-Crick base pair between the guanine ligand and a C residue or the adenine ligand and a U residue of the cognate riboswitch RNA, respectively. The heterogeneous nuclear ribonucleoprotein (hnRNP) K is implicated in multiple functions in the regulation of gene expression and acts as a hub at the intersection of signalling pathways and processes involving nucleic acids. Central to its function is its ability to bind both ssDNA and ssRNA via its KH (hnRNP K homology) domains. A combined crystallographic and NMR approach was used to reveal the structures of hnRNP K KH3 domain and it binding mode for several ssRNA ligands and CTC4 ssDNA.115 Adenosine deaminases that act on RNA (ADARs) site selectively modify adenosines to inosines within RNA transcripts, thereby recoding genomic information. Stefl et al. have reported the NMR solution structures of the two double-stranded RNA binding motifs (dsRBMs) of rat ADAR2 and a chemical shift perturbation study of the interaction with a 71 nucleotide RNA encoding the R/G site of the GluR-B.116 The protein and the RNA interface surfaces were identified and an NMR-based model of the complex was proposed revealing RNA structure-dependent recognition. dsRBM1 recognizes a conserved pentaloop, whereas dsRBM2 recognizes two bulged bases adjacent to the editing site. Natively unfolded proteins play key roles in normal and pathological biochemical processes. However they are difficult to study because of the inherent flexibility and conformation heterogeneity. Veprintsev et al. have stabilised the tumor suppressor p53, which consists of four 393-residue chains that possess two natively unfolded Nucl. Magn. Reson., 2007, 36, 262–284 | 277 This journal is

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and two folded domains, to make it more suitable for NMR study.117 The NMR spectra of full-length p53 revealed changes in chemical shifts suggesting interactions between the core domains. The NMR data was used as constraints in docking algorithms, which found a self-complementary surface for the association of core domains into dimers within the tetrameric complex. Binding to DNA requires about a 70 degrees rotation to break these subunit interactions to form the p53-DNA complex, which was verified by the effects of mutation on DNA binding.

4. Protein folding Protein folding involves the coordination of numerous weak interactions that stabilize the eventual folded three-dimensional structure. Small proteins are often thought to fold in an all-or-none process. Widely used approaches such as equilibrium protein stability and folding kinetics experiments are unable to address this directly. Sadqi et al. have illustrated the novel use of chemical shift data on the thermal unfolding.118 One hundred and fifty eight backbone and side-chain protons out of a total of 204 provide were tracked through the thermal denaturation of BBL from E. coli, thereby providing a detailed view of the structural events during folding. Proton chemical shifts were measured as a function of temperature and display varied pattern of behaviours, with two-thirds being sigmoidal and the rest showing two apparent transitions. The average atomic unfolding behaviour obtained by singular value decomposition of the chemical shift versus temperature matrix produces a smooth sigmoidal curve. At the midpoint atoms experience environments ranging from all native to all unfolded in a smooth distribution. Data confirms that BBL unfolds in an atom by atom fashion starting from a defined 3D structure, which confirms the statistical nature of folding, and exposes the interplay between hydrogen bonding, hydrophobic forces, backbone conformation and sidechain entropy. An interaction network map was derived, which reveals the source of folding cooperativity. In a similar study Tunnicliffe et al. have measured NMR spectra at various temperatures using a range of concentrations of denaturant and revealed that many residues have curved amide proton temperature dependence, indicating that they significantly populate alternative, locally unfolded conformations. The results, therefore, provide a view of the locations of low-lying, locally unfolded conformations.119 Recent NMR relaxation methodology has enabled investigations into molecular dynamics that are important for protein function and folding. 15N relaxation dispersion NMR spectroscopy has emerged as a useful tool to study exchange dynamics in folding process. Transverse relaxation methods allow a quantitative measurement of the cooperativity in folding reactions on a residue by residue basis. Choy et al. have analysed such relaxation data on two mutants of Rd-apocyt b(562), a redesigned four-helix-bundle protein, over a range of temperatures establishes.120 They ascertain that exchange is best modelled as a two-state process and that it derives from the folding/unfolding transition. Their results agree with predictions based on the folding reaction coordinate determined from native-state hydrogen exchange data. Teilum et al. have studied the folding kinetics of bovine acyl-CoA binding protein by 15N relaxation dispersion experiments.121 Relaxation dispersion profiles were measured at several concentrations of guanidine hydrochloride. Individually, the stopped-flow and NMR relaxation data fit two-state models for folding. However, a combined analysis of all data does not comply with a two-state model but indicates that an unfolding intermediate exists on the native side of the transition state. Furthermore, the temperature dependence of the chemical shifts identifies regions of the protein that are selectively destabilized in the intermediate. These results illustrate the power of combining stopped-flow kinetics and NMR spectroscopy to analyze protein folding. Similarly, Zeeb and Balbach have observed 278 | Nucl. Magn. Reson., 2007, 36, 262–284 This journal is

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chemical exchange contributions to the transverse relaxation rate for every residue of cold shock protein CspB.122 By comparing the dependence of the apparent folding rate on the denaturant concentration using stopped-flow fluorescence with relaxation dispersion experiments, the homogeneity of the folding reaction was probed. Korzhnev et al. have used the pressure dependence of 15N NMR relaxation dispersion rates to study the changes in volumetric parameters that accompany the folding reaction of this protein.123 The results suggest a transition state ensemble that is collapsed but loosely packed relative to the folded state and significantly hydrated, suggesting that the release of water occurs after the rate-limiting step in protein folding. Tollinger et al. have used NMR to acquire folding kinetic data for the marginally stable N-terminal SH3 domain of the Drosophila protein drk as a function of pH. The slow exchange between folded and unfolded forms gives rise to separate NMR resonances for both folded and unfolded states and therefore kinetic data can be derived from the magnetization transfer between these two states without the need for denaturants. pKa’s of D8 were measured in the transition state for the wild-type protein and for a H7A mutant. The data are consistent with the partial formation in the transition state ensemble of an Asp8 side chain carboxylate-K21 backbone amide interaction that represents a highly conserved contact in folded SH3 domains.124 Hirota et al. have presented a new method to investigate the initial protein folding events by combining a pulsed laser light triggering method and a unique transient grating method.125 The side chain of the cysteine residue of apoplastocyanin (apoPC) was site-specifically modified with a 4,5-dimethoxy-2-nitrobenzyl derivative, such that the modified protein was unfolded. The substituent was cleaved by photoirradiation in B400 nanos, and subsequent CD and NMR spectra showed the recovery of native beta-sheet structure. Protein folding dynamics were monitored in the time domain and revealed that observed volume decrease of apoPC in time scale of 270 ms is attributed to the initial hydrophobic collapse. The increase in the diffusion coefficient (23 ms) is considered to indicate a change from an intermolecular to an intramolecular hydrogen bonding network. Photochemically induced dynamic nuclear polarization NMR pulse-labelling techniques enable detailed information about side-chain surface accessibilities in the partially folded state to be determined. Pulse labelling involves generating nuclear polarization in the partially folded state, rapidly refolding the protein within the NMR sample tube, then detecting the polarization in the well dispersed nativestate. Mok et al. revealed differences in the solvent accessibility of specific side chains in the various molten globule states of alpha-lactalbumin.126 Results indicate that the hydrophobic clusters involved in stabilizing the alpha-lactalbumin fold can be formed from interactions between different hydrophobic residues. The multiple subsets of hydrophobic clusters are likely to result from the existence of distinct but closely related local minima on the free-energy landscape of the protein. Water-soluble proteins encapsulated within reverse micelles may be studied under a variety of unusual conditions, including extreme low temperatures. Direct highresolution detection of information relating to protein folding intermediates and pathways can be monitored by low-temperature solution NMR. Van Horn et al. have monitored ubiquitin resonances at varying temperatures and salt concentrations and show that structure of the encapsulated protein experiences significant reverse micelle-protein interactions and low-temperature effects.127 Removal of micelle-protein interactions in high salt allowed the phenomenon of cold denaturation to be explored. Nishimura et al. have used site-directed mutagenesis to probe stabilising interactions within equilibrium and burst phase kinetic intermediates formed by apomyoglobin.128 Results reveal that the burst phase intermediate observed during kinetic refolding of apomyoglobin consists of an ensemble of compact, kinetically trapped states in which the topology appears to be correct, but with some non-native interactions that must be resolved before folding can continue. Nucl. Magn. Reson., 2007, 36, 262–284 | 279 This journal is

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Many neurodegenerative diseases are characterized by the accumulation of amyloid fibres in the brain, which can occur when a protein misfolds into an extended beta-sheet conformation. The mechanism of assembly of amyloid fibrils is largely unknown. Jahn et al. have identified a specific folding intermediate, containing a non-native trans-proline isomer, that is the direct precursor of fibril elongation.129 Structural analysis using NMR shows that this species is highly native-like but contains perturbation of the edge strands that normally protect beta-sandwich proteins from self-association. The results demonstrate that aggregation pathways can involve self-assembly of highly native-like folding intermediates. Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease consists of the amyloid peptide A beta bearing abnormal zinc ion content. Zirah et al. have determined the solution structure of the A beta-(1-16)Zn2+ complex. Aging experiments on A beta-(1–16) led to the formation of truncated and isomerised species.130

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NMR of carbohydrates, lipids and membranes Elizabeth Hounsell DOI: 10.1039/b601690c

1. Introduction As in previous reviews of this series (the last being1), the present report is responding to a broad remit, but one that due to space constrictions, has to offer a personal view. My interest in glycosylation of proteins involved in pathology comes to the fore and thus Section 2 relates to recent work on the two major glycoproteins that lead to folding disorders, prions and the transmembrane amyloid b glycoprotein. Studies of b2 microglobulin (b2M), causing dialysis-related amyloidosis, is also discussed here, although this protein is not N-glycosylated but does become glycated giving advanced glycation end products (AGEs) which are highly important in pathology (as in diabetes for example) and should be viewed similarly as affecting protein conformational change. For enzyme-catalysed N- and O-glycosylations there are more data on how these affect protein conformation and vice versa and several NMR studies on glycoproteins and glycosylphosphatidyinositol (GPI) anchors. Such glycosylation also has its own function in intermolecular interactions for which it is important to review oligosaccharide conformation and recognition (Section 4). The larger parts of the literature, as this review reflects, are concerned with membranes, bacterial polysaccharides and glycoside phytotherapeutics (Sections 3, 6 and 7, respectively). The largest Section 3, as previously, is taken over by the solution and solid-state NMR of proteins, peptides and lipids by which we are beginning to understand cells, metabolites and cell membranes. Such studies are also extended to modern hyphenated techniques and metabonomic approaches (Section 5) which have a place here although only the tip of the iceberg of applications can be reviewed. In addition to phytotherapeutics and metabonomic studies other natural products with pharmaceutical, biological, nutriceutical and materials science applications are reviewed in Sections 8 and 9. 2.

Glycosylated protein conformation and folding

This Section deals with domains of glycosylated proteins that interact with the cell membrane in particular those of viruses (second half of the Section) or are involved with (glyco)protein folding disorders including prions and the glycoprotein involved in Alzheimer’s disease (AD). The majority of the studies were carried out on the nonglycosylated proteins or peptides, but the structures serve as a scaffold on which to append N-glycosylation and, in the case of prions, GPI anchors. Selective precipitation of the infectious isoform of the prion protein (PrPSc) over the normal cellular protein (PrPC) by polyoxometalate complexes was followed by NMR and IR spectroscopy.2 The dynamic evolution of the PrPC from its NMRderived conformer to a b-sheet rich, aggregation-prone conformation was studied through all atom explicit solvent molecular dynamics (MD).3 Hosszu et al.4 examined the unfolding transitions of human recombinant isotope-labelled PrPC in guanidinium hydrochloride in studies to identify transitions to PrPSc, and showed a gradual shift of NMR signals in the regions between aa 125–146 and 186–196 (presumably unglycosylated). Nazabal et al.5 compared 1H NMR and CID-MS for hydrogen/deuterium (H/D) exchange experiments of the HET-s218-295 prion protein leading to evidence of highly protected regions along the peptide sequence. The doppel prion homologue determined by NMR for mouse Dp1(1-30) in DHPC/ School of Biological and Chemical Sciences, Birkbeck, University of London, Malet Street, London, UK WC1E 7HX


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CMPC bicelles6 gave a possible channel formation mechanism for toxicity. A NMR survey of potential replacement (non-paramagnetic) metal ions for Cu++ binding to the octapeptide repeat of prion N-terminus was published.7 In studies fine tuning the structure of the Cu++ complex with the chicken prion protein repeat by proline isomerisation, the single hexa-repeat unit ChPrP(54-59) was investigated by NMR and different coordination modes for the trans/trans and cis/trans isomers found.8 From prions comes a renewed interest in the conjugates of metal ions with proteins in general. In studies of an unrelated peptide PKKKRKF, but with Cu++ and Zn++, NMR supported metal coordination to the N,N-bis(2-picolyl)amine (bpa) ligand in the bioconjugates suggesting9 these as artificial metalochaperones with potential to deliver metal ions to specific compartments in the cell as determined by the peptide moieties. For the amyloid b-peptide, Ab(1-42), in AD disruption of lipid membranes and the effect of metal ions (Cu++ and Zn++) on model membranes was studied using 31 P and 2H SS NMR, fluorescence and Langmuir Blodgett monolayer methods.10 Lazo et al.11 studied using solution state NMR the earliest step in Ab(1-40) assembly, i.e. the creation of a folding nucleus from which oligomeric and fibrillar assemblies emanate. They showed that in the protease resistant fragment Ab(21-30), turn formation within the Val24–Lys28 region nucleates the intramolecular folding, thus suggesting this as a target for drug therapy and providing a mechanistic basis for the pathological effects of amino acid substitutions at Glu22 and Asp23 that are linked to familial forms of AD or cerebral amyloid angiopathy. Results on the structural preferences and temperature-induced transitions of the segments in the monomeric form of Ab, for example by analyzing temperature-dependent 3JHNHa couplings and hydrodynamic radii obtained by NMR of Ab(1-9) and Ab(1-12), suggested that these transitions may be related to the processes leading to the aggregation and formation of fibrils in the Alzheimer plaques.12 Ferrao-Ganzales et al.13 describe the stabilisation of small oligomers of Ab by the use of sulfonated, hydrophobic (naphthalene-containing) molecules such as AMNS, ANS and bis-ANS. The 1H-TOCSY spectra of Ab(13-23) in the presence of AMNS displayed chemical shift dispersion similar to that in SDS suggesting a conserved conformation. Structural models for amyloid fibrils have been built using information from X-ray diffraction, electron microscopy, SS NMR and EPR.14 The 3D structure of the fibrils comprising Ab(1-42) modelled15 using H-bonding constraints from quenched H/D exchange NMR and SS NMR, showed side chain packing constraints for pair-wise mutagenesis studies with in-register b-sheet arrangement leading to partially unpaired b-strands at the fibrillar ends which explained the sequence selectivity, the cooperativity and the apparent unidirectionality of the amyloid fibrils.15 Based on data from NMR measurements and MD simulations of short amyloid fibrils, Buchete et al.16 constructed a structural model of long fibrils including the b-sheet arrangement where Asp23 and Lys28 formed buried salt bridges resulting in alternating negative and positive charges along the fibril axis. Olofsson et al.17 investigated the H/D exchange of Ab(1-42) under physiological conditions by solution NMR to look at solvent accessible and solvent protected residues that may be important in fibril formation. Transferred residual dipolar couplings (tr RDC) were measured and trNOE data collected in solution state NMR for peptide ligands binding weakly to amyloid fibrils to characterise18 two inhibitor peptides, LPFFD and DPFFL, bound to fibrillar Ab(14-23) and Ab(1-40). AGEs were studied using a model helical peptide system containing a di-Lys motif from human serum albumin and they were shown to alter its properties including charge, helicity and tendency to aggregate.19 Glycation caused distortion of the ahelix forcing the region of the helix around the preferential site of glycation of one of the Lys residues to adopt a 310 helical structure implying biological significance. Radford et al.20 review the current knowledge on the structure of b2M fibrils and identify the regions thought to be important in fibril formation in dialysis-related amyloidosis and Armen and Daggett21 looked at two partially unfolded 286 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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intermediates suggesting that the formation of the previously known a-sheet structure facilitates self-assembly into partially unfolded prefibrillar amyloidogenic intermediates. The various physicochemical methods used to characterise the structure and stability of b2M including H/D exchange NMR and isothermal calorimetry22 was reviewed and additional biophysical measurements of b2M using NMR identified the b-strand arrangements that support the formation of amyloid fibrils.23 Other studies include comparison of the solution NMR of b2M with the crystal structures for type I major histocompatibility complex MHC.21 Fusion of viral glycoproteins with the cell membrane is an essential infectious process. MD simulations of the fusion peptide of influenza virus haemagglutinin in micelles and bilayers25 and of two Glu-rich fusion peptide analogues26 were investigated and the NMR structure and MD of the in-plane a-helical membrane anchor of the protein 5A from bovine viral diarrhoea virus.27 Cyanovirin-N that blocks HIV virus-to-cell fusion through high mannose-mediated interactions, studied using a-Man-(1-2)-Man functionalised PAMAM dendrimers, was characterised by NMR.28 One of the strongest inhibitors of HIV fusion is a 36-residue peptide named T-20 and composing residues 638–673 of gp41. This water soluble derivative was shown to have a helical region of residues 659–671 using heteronuclear 2D and 3D methods of uniformly labelled and expressed protein to determine its structure.29 The dynamics of HIV-1 Vpu transmembrane domain was revealed by SS NMR with MAS. Experiments included new information about local variations in the degree of mobility and structural order by 13C and 15N chemical shifts, NMR signal intensities, site-specific MAS NMR line widths and NMR-detected H/D exchange.30 The tilt and rotation angles of the trans-membrane helix of Vpu aligned in lipid bilayers of various thickness was determined31 using orientation-dependent frequencies obtained from SS NMR of aligned samples and the tilt angle shown to increase systematically with increasing positive lipid mismatch (PC/DMPG, to PC/DLPG, to PC/PG). The 30 N-terminal residues of HIV-1 gp41in SDS, DPC, mixed SDS/DPC and LPPG micelles was studied by NMR of 15N, 13C and 2H-labelled peptides.32 The authors showed that the ensemble NMR structures revealed an uninterrupted ahelix for the least mobile residues (Ile4 to Met9), with transient helical character extending up to Ala22. The correct folding of myristoylated Nef of HIV was shown by NMR in studies of its conformation and function.33

3. Studies of proteins and small molecules in membranes Nielsen et al.34 review techniques and applications of NMR to membrane proteins. Progress In NMR Spectroscopy reviews the structural and dynamical investigations of membrane-associated peptides by MAS SS NMR techniques.35 An Introduction to SS NMR Spectroscopy36 is provided by Blackwell (Oxford) author M.J. Duer ISBN 1-40-519014-9. According to Schwalbe et al.,37 in July 2005, more than 400 structures of proteins, protein-nucleic acid complexes, nucleic acids and carbohydrates that had been solved by NMR were deposited in the Protein data bank (http:// www.rcsb.org/pdb/holdings.html). Membrane proteins made up a tiny proportion of the elucidated structures (approx. 0.5%; for an updated list see http:// www.mpibp-frankfurt.mpg.de/michel/public/memprotstruct.html). At that time, of the 148 available high-resolution structures of multitopic membrane proteins only three had been elucidated by NMR and five by electron diffraction, the rest being derived from X-ray crystallographic studies. New methods to overcome this block are published each year. Watts38 reviews SS NMR in drug design and discovery for membrane embedded targets including two previously reported strategies using a novel 2H approach,39 17O SS NMR as a probe40 and studies of multiply-labelled membrane proteins by 15N MAS NMR.41 For small membrane polypeptides either in oriented or MAS samples the magnetization rates crucial for the design of polarization transfer experiments were characterised in a systematic study of the Nucl. Magn. Reson., 2007, 36, 285–308 | 287 This journal is

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spin–lattice relaxation in the rotating frame for several nuclei (1H, 13C and 15N).42 Solution NMR methodologies to characterise protein–protein interactions, and for ligand binding studies and drug discovery are reviewed by Pellecchia.43 A large number of the published studies are on bacterial membranes for example, as follows. 3.1.

Bacterial proteins and anti-microbial peptides

Glaubitz44 reviews the applications of SS NMR to membrane proteins using isotopelabelled ligands with bacteriorhodopsin and diacyl glycerol kinase as examples. Further studies on bacteriorhodopsin include: site directed SS 13C NMR of [13C]Valor [13C]Pro-labeled protein and its single and double mutants recorded at various pH values to look at local dynamics of the B and C a-helices;45 structural and orientational constraints of bacteriorhodopsin in purple membranes determined by oriented-sample SS NMR.46 Soubias and Gawrisch47 studied the interaction of mono- and poly-unsaturated PCs with rhodopsin by 1H NMR and saturation transfer difference spectroscopy with magic angle spinning (STD-MAS NMR) to show a strong preference for interaction of rhodopsin with the polyunsaturated docosahexaenoic acid. Triba et al.48 describe a protocol for the reconstitution of the largest transmembrane protein into lipid membranes so far characterised, the 171-residue transmembrane domain of the outer MPA from Escherichia coli, i.e. the tOmpA b-barrel protein domain, and suggest that alignment in the magnetic field may be facilitated if the protein is folded as a b-barrel. As the detergents used in membrane protein structural studies have a destabilising effect, Zoonens et al.49 explored the use of short amphipathic polymers (amphipols of Apols) for studies of tOmpA. Uniformly 13 C, 15N-labeled outer membrane protein G (OmpG) of E.coli was reconstituted in lipid bilayers and analysed by MAS NMR.50 The structure and mode of action of the membrane permeabilising anti-microbial 26-mer peptide pheromone plantaricin was determined in dodecylphosphocholine (DDPC) micelles. Initially a non-chiral interaction occurs with the target cell membrane involving the amphiphilic a-helical region stretching from residues 12 to 21, followed by a chiral interaction of the N-terminus, explaining its dual pheromonal and anti-microbial activities.51 Marvyn et al.52 provide a comparison of models from X-ray fibre diffraction and SS NMR studies of bacteriophage assembly at the bacterial membrane. At the peptide level, two synthetic cationic antimicrobial peptides with alternating a- and b-residues were shown53 by 31P NMR and X-ray diffraction to have different effects on the morphology of liposomes composed of PPE and PPG. The findings were consistent with the different relative toxicities of the a/b peptides for different bacteria as reflected in the lipid composition of the bacterial membranes (more or less anionic character cf. PPE and PPG). The peptide KWGAKIKIGAKIKIGAKI with strong antimicrobial activity designed to form amphiphilic b-sheet structures when bound to lipid bilayers was studied in POPC and POPG/POPC by static powder spectra 31P and 2H SS NMR with sn-1 chain perdeuterated POPC and POPG as the isotopic labels.54 The membrane interactions and solution conformation of the b-hairpin antimicrobial peptide, protegrin-1 (PG-1) were investigated by 31 P SS NMR of uniaxially aligned membranes and the 31P line shapes shown to correlate with the structural components of antimicrobial potency.55 The structure of novisirin G-10 (an 18-residue designed cationic peptide derived from the Nterminal part of an antimicrobial peptide from sheep, but having more bacterial specificity) was solved in SDS and the cationic detergent LTAC by NMR.56 AFM studies of membrane thinning due to antimicrobial peptide MSI-78 was consistent with concentration dependent 31P and 2H NMR in DMPC bilayers.57 Antimicrobial peptide cyclo(RRWWRF) in DMPC was characterised at different lipid:peptide ratios to show that the membrane is not an efficient hydrophobic 288 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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barrier in the presence of peptides.58 Antimicrobial peptides isolated from the dorsal glands of Australian tree frogs59 called aurein (13 amino acids), citropin (16 amino acids) and maculatin (21 amino acid residues) were shown to adopt amphipathic ahelical structures in the presence of lipid and vesicles as revealed by 2H and 31P SS NMR of 15N labeled peptides. SS NMR methods are reviewed for b-sheet antimicrobial peptides and a-helical channel forming colicins that are bacteriocidal molecules that target the lipid membranes of sensitive cells.60 Long timescale simulations of the 18-residue helical anti-microbial peptide ovispirin-1 in SDS micelles gave favourable comparison with NMR-based predictions about structure/function in host cell toxicity.61 The peptide [LSSLLSL]3, previously shown to exhibit well defined and discrete ionic conductances investigated by single channel measurements, has been further studied by 15N SS NMR. The data provided experimental evidence for an equilibrium between in-plane and transmembraneoriented helix configurations in slow exchange.62 3.2.

Mammalian proteins

A variety of NMR methods applied to different surfactant aggregates are reviewed63 including the use of NMR line shapes, spin relaxation and self-diffusion experiments and specialised techniques such as rheo and electrophoretic NMR. To get round the problem of destabilisation in surfactants, a new strategy of membrane constitution into lipid bilayers on affinity beads was proposed64 which maintains the native conformation and function of the protein for NMR studies. The methods were successfully applied to the interaction of a iron channel, KcsA, and a pore blocker, agitoxin 2 (AgTx2). SS NMR methods have been used65 to investigate the dynamics of the inhibitory association between phospholamban (PLB/PLN which regulates calcium transport across the sarcoplasmic reticulum of cardiac cells to control contraction and relaxation of the heart) and Ca++-ATP-ase. The enzyme and 13C labelled PLB were incorporated into PPC membranes studied by 13C CP-MAS and measurement of dipolar couplings. Solution NMR has been used to study the atomic resolution of an unphosphorylated PLB pentamer in DDPC micelles showing an unusual bellflower-like assembly held together by Leu/Ile zipper motifs along the membrane spanning helixes where the dynamic N-terminal amphipathic helixes point away from the membrane perhaps facilitating recognition and inhibition of the calcium pump.66 Colicin Ia channel domain reconstituted into membranes with different POPG and KCL concentrations was studied by measurement of C–H and N–H dipolar coupling67 and the interactions of cytochrome cyt c3 in cardiolipin (CL) and PC/CL membranes by 31P and 2H SS NMR.68 CD and SS NMR of the anti-angiogenic peptide anginex showed that it forms a b-sheet and adopts a unique and highly ordered conformation upon binding to lipid membranes, accounting for its pathogenicity.69 Localisation of coenzyme Q10 in the centre of a deuterated lipid membrane by neutron diffraction of perdeuterated DMPC/DMPS was used to show that ubiquinone, in addition to its free radical scavenging and its well known role in oxidative phosphorylation as a carrier of electrons and protons, might also act as an inhibitor of transmembrane proton leaks.70 Human calcitonin-derived cell penetrating peptide (HCT9-32), which translocates the plasma membrane in mammalian cells and has been suggested as a cellular carrier in biomedical studies, was studied in DDPC micelles.71 13C NMR of site-specifically 13C-labelled dynorphin, measured in the membrane DMPC bound state under static, MAS and slow MAS conditions, adopts an a-helical structure in the N-terminus from Gly2 to Leu5 inserted into the membrane at a tilt angle of 211 to the bilayer, suggesting that it interacts with the extracellular loop II of the k-receptor through a helix–helix interaction, whereas a disordered conformation from the centre to the C-terminus is located on the membrane surface.72 High resolution 1H solution NMR methods and 31P and 2H measurements of membrane bicelles (DMPC, DMPG and DHPC) were used to Nucl. Magn. Reson., 2007, 36, 285–308 | 289 This journal is

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establish the location of Antp(43-58) and a variant (with the mutations Trp48Phe and Trp56Phe) which are and are not capable of crossing cell membranes. The results argued for an electroporation-like mechanism for membrane penetration.73 For homeodomain proteins, such as knotted-1, NMR studies indicated that electrostatic surface interactions may be a major determinant for membrane translocation. Their helical conformation in SDS micelles and their localisation with respect to the micelle was determined using Mn++ as a paramagnetic probe.74 The membrane interaction of the neuropeptide Y (the most abundant peptide in the CNS of mammals) was investigated by EPR and NMR spectroscopy in PPC/PPS (phosphatidyl choline/serine). Again the a-helical part (13–36) penetrates the membrane interface whereas the unstructured N-terminal part (1–12) extends into the aqueous phase with occasional contacts with the lipid headgroup region.75 Other studies include: solution structure of the first and second transmembrane segments of the mitochondrial oxoglutarate carrier;76 solubilised membrane proteins such as mammalian rhodopsin77 and vasopressin;78 the dynamic properties of the peptide mastoparan studied in isotropic bicelles using relaxation and amide-water exchange and cross-saturation;79 the morphogenic opiate pentapeptide Leu-enkephalin in hydrated DMPC bilayers was studied using NMR (RDCs) and MD simulations shown to have unexpected flexibility.80 2 H NMR of DMPC-d6 of peptides which mimic the pro- and anti-apoptotic activity of Bak and Bcl-2 (respectively) showed that the spectral changes that have been observed in apoptotic cells include, as expected from what we know about the mechanism of apoptosis, a general increase in lipid signals and a specific increase in the ratio of lipid methylene-to-Me peak intensities.81 A 1H MRS study in vivo on EL-4 tumour cells82 showed transmembrane helices in membranes of reduced thickness and that hydrophobic mismatching occurs in thicker membranes. A heptapeptide derived from the C-terminus of Ras protein that binds to cellular membranes by insertion of two covalently bound post-translational lipid modifications was synthesised with two hexadecyl groups and analysed by 2H SS NMR in DMPC membranes.83 3.3.

Membrane studies of molecules other than proteins/peptides

In addition to protein interactions at the cell membrane there are important studies of drug-membrane and lipid–membrane interactions. Lopes and Castanho84 review common spectroscopic methods including NMR, FTIR, UV-Vis, linear dichroism, time-resolved fluorescent anisotropy and SPR to determine the orientation/alignment of membrane probes and drugs in lipidic bilayers. 2H NMR methods to elucidate the backbone conformation and the interaction of sphingolipids with glycerophospholipids are reviewed.85 Water self diffusion was studied in model membranes of DOPC/DMPC by pulsed field gradient (pfg) NMR.86 The effects of unsaturation on the nanosecond-scale structural and dynamic properties of PC bilayers elucidated by MD simulations on DMPC with oleoyl, linoleoyl or arachidonyl chains gave features consistent with behaviour known from 2H NMR.87 The hypotensive drug 2-hydroxyoleic acid was shown to modify the structural properties of model membranes of 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine.88 Potent anti-leukaemic steroidal esters were studied by 2D NMR and it was shown that the low energy conformers were largely compact with the alkylating aromatic group orienting to either the a- or b- surface of the steroidal plane, the preference being steroid dependent which correlates with 3D QSAR studies.89 The effect of the keratolytic drug salicylic acid on the thermotropic properties and fluidity of mixed lipid membrane was compared by DSC, 1H and 31P NMR, SAXS and dynamic light scattering for DPPC/DPPE90 and DPPA (dipalmitoyl phosphatidic acid)91 membranes. The effect of different concentrations of g-linolenic acid (GLA) and tamoxifen (Tx) for its transcutaneous delivery as a gel was studied by 1H NMR which also showed that complexation was a consequence of preferential p–p orbital interactions 290 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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between the Ph groups of Tx and the GLA.92 Methoxypoly(ethylene glycol)-poly (L-lactic acid copolymer nanoparticles were investigated as delivery vehicles for paclitaxel.93 The Section entitled Materials Science at the end of this review gives more examples in drug delivery and nanoparticles. The chemical synthesis of 24-b-D-galactopyranosides of bile acids of lithocholic, deoxycholic, chenodeoxycholic, ursodeoxycholic and cholic acids (two of which had been recently identified as a novel type of the metabolites of bile acids excreted in human urine) was confirmed by measuring several 1H–1H and 1H–13C correlated 2D NMR.94 In studies of cholesterol in biological membranes the following are notable: 1 H, 2H, 19F pfg NMR spectroscopy in macroscopically oriented lipid bilayers of DOPC and DPPC for investigation of the dynamics of isotopically labelled cholesterol on rafts;95 1H–13C polarization transfer in membrane rafts as a tool for probing lipid dynamics and the effect of cholesterol on rafts;96 diffusion of cholesterol and its precursors in lipid (DPPC) membranes containing lanosterol and desmosterol studied by 1H pfg MAS NMR.97 The ionisation and H-bonding behaviour of PA and LPA in extended lipid bilayers was examined using 31P MAS NMR to explain their importance in biological membranes.98 In a 1H and 31P-NMR study of the preferred membrane orientation of polyisoprenols (dolichol) and the impact of their complex with polyisoprenol recognition sequence peptides (PIRS) on non-lamellar membrane structure it was shown that further molecular modelling calculations suggested that five PIRS peptides could bind cooperatively to a single PI molecule to form a membrane channel of possible functional importance in glycoconjugate translocation.99 The dynamic behaviour of 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE) bilayer characterised in terms of 2H spin–lattice relaxation rates and lateral diffusion rates showed that NOESY cross-relaxation rates compared well with experimental values, but calculated lateral diffusion rates were lower than those determined by pfg NMR methods.100 The authors further studied101 the lipid-water interface particularly the hydrogen bonding network of the PE head groups of SOPE. These studies are relevant to understanding of the conformations of glycosylphosphatidylinositol (GPI) anchors discussed next with regards to important membrane bound glycoproteins of mammals and trypanosomes.

4. Oligosaccharide conformation, recognition and function 4.1.

GPI anchors, glycoproteins and glycopeptides

The solution 3D structure of a pseudopentasaccharide which constitutes the product of the GPI-phospholipase D cleavage of a GPI anchor has been studied using a protocol which involves a systematic search of the conformational space around the glycosidic linkages using MD simulations with explicit solvent and a full NMR analysis of intramolecular H-bonds.102 The pentasaccharide core is common to all GPI anchors which are varied by other glycosylations which together with the lipid and protein would be expected to reduce the conformational flexibility of the pentasaccharide alone, although the authors suggest that the flexibility may mediate a molecular hinge. CD59 is one such GPI-anchored glycoprotein that plays an important role in regulating the terminal pathway of complement (C) by inhibiting formation of the cytolytic membrane attack complex (MAC composed of complement fragments C5b–C9). An improved NMR model based on scanning mutagenesis data identified a C8/C9 binding interface that is much broader than previously thought103. NMR and MS analysis of the variant surface glycoprotein (VSG) of mutants of the African trypanosome T. brucei deficient in the enzyme glucosidase II revealed flexibility in the mechanism of occupation of N-glycosylation sites in a site specific manner that the authors suggest may conserve dolichol-phosphate-mannose donors for GPI anchor synthesis.104 Complexation of Sb(V) with GDP-mannose has been studied as a means to improve its properties in chemotherapy (antiNucl. Magn. Reson., 2007, 36, 285–308 | 291 This journal is

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leishmanial).105 In other enzyme studies, the stereochemical course of the reaction of a novel glycohydralase of core type I O-glycan specific endo-a-N-acetylgalactosaminidase from Bifidobacterium longum was elucidated by NMR.106 De-N-acetyllactotriaosylceramide (deNAcLc3Cer) was characterised as a novel cationic glycosphingolipid of bovine brain white matter and the de-N-acetylase capable of hydrolyzing GlcNAc to GlcNH2 was detected using N–[14C]acetyl-labelled Lc3Cer as substrate.107 A monosialylated tetrasaccharide unit previously only found in gangliosides GM2 and Gb3 was isolated as the free oligosaccharide from the colostrum of a bottlenose dolphin.108 Following on from previous studies on the affects of sugar on protein conformation in glycopeptides, reviewed previously, further information109 is presented on the peptide influence on the sugar conformation by 13C and 1H NMR of Ac-Asn(b1-N-GlcNAc)-Leu-Thr-NH2 when compared to Asn-Gln and Thr-DThr analogues where the GlcNAc is able to sense the stereochemistry at the remote Thr residue. Parallel solid phase syntheses of mucin-like glycopeptides and NMR analysis showed an increase in conformational organisation of glycopeptides with increased degree of glycosylation110 and a glycosylated (GlcNAc)3 pentapeptide (Asn)5 was the smallest to show conformational preferences for helical structures.111 Chemical synthesis and NMR characterisation of analogues of the glycopeptide venom of cone snails contulakin-G was carried out for investigation of their toxicity.112 Structure calculation strategies were compared113 for membrane proteins using glycophorin A and aquaporin as models, the first is highly glycosylated in its natural state. A simulated glycophorin helix dimer in detergent micelles was shown to be close to the NMR-derived structure.114 A peptide encompassing the heparin binding motif in the second Ig module of the neural cell adhesion molecule (NCAM) was shown by NMR and SPR115 to interfere with the homophilic binding of the first and second Ig modules and hence inhibiting neurite outgrowth in cerebellar granular neurons. MRI of inflammation was studied with a specific selectintargeted contrast agent.116 The hyaluronic acid binding region of the receptor for hyaluronan-mediated motility was studied using octa-peptide ligand mimics.117 Using 13C labelled oligosaccharides of hyaluronan as models, a method for spectral resolution of GAGs was explored using the carboxylate chemical shift: one-bond couplings to correlate the carboxylate carbon with the adjacent carbon and its directly attached proton and a long-range coupling to correlate the carboxylate carbon with anomeric proton and carbon of the same residue.118 Spectral crowding in carbohydrates and peptides was resolved by spin-edited 2D HSQC-TOCSY experiments for the measurement of homonuclear and heteronuclear coupling constants and separate acquisition of single-component TROES/anti-TROESY.119 Hg(II) coordination by sugar uronic acids was studied,120 and 1H and 13C NMR chemical shifts for oligosaccharides from chondroitin and dermatan sulfate were reported.121 Janas and Janas122 review the structure and properties of polysialic acids, their binding with antibodies and membrane ion channels and therapeutic uses. The importance of aromatic groups in proteins in oligosaccharide recognition was explored by NMR.123 Kajiwara and Miyamoto124 review smallangle X-ray scattering and NMR methods currently applied to the structural and conformational characterisation of oligosaccharides and polysaccharides. Saito125 reviews the conformation and dynamics of polysaccharide gels as studied by HR-SS 13 C NMR. 4.2.

Small oligosaccharide and lipid studies

The structural effects of small molecules including trehalose and DMSO interactions in DPPC bilayers were studied in the liquid crystalline phase, and it was shown that the former stabilise and the latter destabilize.126 RDCs were applied for the analysis 292 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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of weak transient binding events between PC bilayers and polyols.127 Unusual ring conformations were shown in the trisaccharide of GlcNAc in non-hydrogen bond accepting solvents.128 Through-bond 1H–13C INEPT transfer in SS NMR were reported for crystalline organic compounds.129 An investigation of weak CH O hydrogen bonds in maltose anomers by a combination of calculation and experimental solid state 1H–13C MAS-J-HMQC NMR spectroscopy showed that directionality is important.130 Serianni’s group131 report 4JCOCCH and 4JCCCH in the analysis of the exocyclic hydroxymethyl group conformation of hexopyranose rings using d. functional theory DFT; B3LYP/6-31G*. NMR experiments were used to follow the stereochemistry of a general strategy for stereoselective glycosylations132 and a one-pot a-glycosidation pathway via the generation in situ of a-glucopyranosyl imidates in DMF having either Br- or Cl- conterions.133 Sugar-oligoamides have been designed and synthesised as structurally simple carbohydrate-based ligands to study carbohydrate–DNA interactions by trNOE NMR:134 Preferential binding to the minor groove and ATAT sequences of one of the sugar oligoamide ligands was as a hairpin providing structural information around the N-glycosidic linkage. The synthesis and conformational analysis of disaccharide analogues containing disulfide and seleno-sulfide functionalities in the inter-glycosidic linkages showed conformational preferences not usually occupied by b-linked disaccharides.135 a-L-Rha-methylphosphonic acid and -methylphosphonates have been synthesised and their conformational preferences compared with the natural phosphate.136 The conformational preferences of a-L-Rhap-(1-2)[a-L-Rhap-(1-3)]- a-L-Rhap-OMe have been studied using one-dimensional 1H, 1H T-ROESY experiments and measurement of trans-glycosidic 3JC,H coupling constants together with MD simulations with a CHARMM22 type of force field modified for carbohydrates in explicit solvent.137 The conformational preferences of the human milk tetrasaccharide LNNT were analysed by MD simulations and NMR, including 1H, 1H T-ROESY and 1H, 13C trans glycosidic J coupling experiments in isotropic solution and in lyotropic liquid crystalline media.138 The similar solid (X-ray) and solution (NMR) state conformations are reported139 for synthesised ()-3-O-acetyl-1,2:4,5-di-O-isopropylidene-allo-inositol and ()-3-Oacetyl-1,2:4,5-di-O-isopropylidene-6-O-methyl-allo-inositol. The 1H NMR spectra of a number of alcohols, diols and inositols were assigned140 in CDCl3 and DMSOd6 to investigate the effects of the OH group on the 1H chemical shifts on changing solvent analysed using the CHARGE model which incorporates the electronic field, magnetic anisotropy and steric effects of functional groups for long-range protons together with functions for the calculation of the 2- and 3-bond effects. Comparison of the observed and calculated OH chemical shifts and CH OH couplings suggested the existence of intramolecular H-bonds in a myo-inositol derivative. Two bidesmonic ursolic saponins bearing a 2,3-branched trisaccharide residue were synthesized and their NMR compared to the natural product.141

5. Metabolomic studies and hyphenated techniques 5.1.

Natural products

Reviews on hyphenated NMR techniques are given in a special issue of Magn. Reson. Chem., edited by Albert.142 For example, Exarchou et al.143 discuss new advances in LC-NMR coupling technology and its application to natural products applied to plants and plant metabolomics by a combination of broad spectrum profiling methods to analyse major components and targeted methods to analyse key metabolites.144 Metabolomics by in vivo NMR145 is the subject of a recent book by Shulman and Rothman (John Wiley and Sons ISBN 0-470-84719-0). Direct (where the NMR spectra are recorded using the HPLC eluate) and indirect (employing an automated solid-phase extraction) HPLC-NMR hyphenation techniques in natural product (plant) research are reviewed by Jaroszewski146 and Nucl. Magn. Reson., 2007, 36, 285–308 | 293 This journal is

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high-throughout isolation, purification and analysis methods applied to natural product libraries.147 5.2.

Pharmaceuticals

Reviews have been published on NMR based methods to screen for high-affinity ligands with particular focus on: the STD experiment;148 the use of multiple sample probes for SS NMR studies of pharmaceuticals;149 metabonomics in preclinical drug development;150 and, NMR screening methods used in drug delivery.151 Conformational changes, post-translational modifications or interactions with drugs inside living cells was reported by in-cell NMR spectroscopy.152 A four-prong approach for the analysis of live bacterial and mycobacterial cells allowing observation of drug effects, gene mutation, differentiation and environmental effects is presented by Li et al.153 using 3D HCCH-TOCSY and HCCH-COSY HR-MAS NMR to unravel the complex whole cell spectra. 5.3.

Mammalian profiles in vivo

A review on the progress towards a metabonomics database using NMR spectroscopy of rodent urine and blood serum enabled the authors to build a predictive expert system for target organ toxicity.154 The biophysical techniques of NMR, MS and SPR as proteomic tools in the study of rheumatoid and osteoarthritis are reviewed to reveal new biomarkers of therapeutic relevance.155 The regulatory phosphorylation sites in the tryptic fragment of the substrate of ZAP protein kinase involved in T cell activation (ALAGADDSYYTAR) was studied by 1H and 13C NMR at 600 MHz using a capillary HPLC-NMR microprobe156 with the four possible peptides phosphorylated at one or other, both or neither of the Tyr residues being synthesised and analysed. Korir et al.157 report on the use of solenoidal microcoils that have greatly enhanced the mass limits of detection of NMR enabling the online coupling of microseparation and concentration techniques such as capillary isotachophoresis (cITP) to provide new insights into the relationships between biological function and GAG microstructures. Zu and Alexander158 discuss the design of an on-line semi-preparative LC-SPE-NMR system for trace analysis. The versatility of 1H NMR as a tool for phenotyping mouse models of disease was shown from studies on Batten disease.159 Multivariate statistical processing of composite metabonomics data sets was investigated using multiple factor analysis integrating complementary aspects from NMR (1H–13C HMBC) and MS (pyrolysis metastable atom bombardment TOF) data.160 Plasma lipoprotein subclass profiles studied by an established ultracentrifugation-based method and 1H NMR data gave partial least squares regression models to predict cholesterol and triglyceride concentration as well VLDL, IDL, LDL and HDL161 on large numbers of samples. Liver fat content was accurately quantified non-invasively by 1H NMR e.g. as an indicator of risk of type II diabetes.162 The role of cholesterol was investigated on mobile lipid signals in K562 erythroleukaemia cells via microdomains of detergent insoluble glycosphingomyelin complexes such as rafts.163 Recent characterisation of abnormal PC metabolism in tumour cells by NMR has identified novel fingerprints of tumour progression that are potentially useful in diagnosis.164 Altered lipid metabolism in a rat hepatocarcinogenesis model was followed using the resonances of the methylene protons of the glycerol backbones in phospholipids and early stages of carcinogenesis were indicated by a lower degree of double bonds in fatty acyl containing compounds.165 Delayed gadolineum-enhanced MRI of cartilage and synovial fluids was introduced to examine the GAG content of cartilage and loss into the synovium after injury.166 A high field MR spectroscopy study of brain glucose levels in poorly controlled diabetes mellitus failed to show any correlation with blood hyperglycaemia in humans.167 294 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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6. Bacterial polysaccharides Bacterial PS are important not only in typing bacteria and using the genome to characterise related structures in human pathogenic microrganisms discussed in the following paragraphs of this section, but also for vaccine development and understanding immune pathology. Jones168 reviews current NMR assays for carbohydrate-based vaccines and highlights some of the areas where further developments may be expected. On the other hand, recognition of bacterial antigens is an important factor in the molecular mimicry and cytokine production: cross reactive polysaccharide antigens and peptides were studied using Shigella flexneri 5a by trNOE and STD NMR:169 Two oligosaccharides representing linear laminaritetraose and -pentaose were synthesised and their immunostimulatory activity compared with natural b-(1-3)-glucans:170 A lipomannan variant with strong TLR-2-dependent pro-inflammatory (TNF-production by Toll-like receptors on human THP-1 monocyte-macrophage cell lines activity in Saccharothrix aerocolonigenes171 mediated by mannosylphosphatidyl-myo-inositol anchor glycosylated by an a-Manp-(1-6) backbone substituted at 480% of C-2 substituted by side chains composed of [-)-a-Manp-(1-2)-a-Manp]1961. The studies showed that increasing their size can potentiate activity including strong production of TNF-a when compared with other LAM/LM-like molecules and enabled a better understanding of structure activity relationships (SAR) of TLR-2 dependent signalling. HR-MAS NMR could distinguish between LOS isolated from different strains of Bordetella pertussis and a binding epitope was analysed by STD NMR which confirmed that the immunodominant epitope recognised by antibodies which inhibit the secretion of TNF-a, interleukin-6 and NO by LOS-stimulated J774A.1 cells.172 A novel anionic PS from the strongly cytokine producing oral bacterium Porphyromonas gingivalis strain W50 related to Arg-gingipains was identified a-Man-(1-2)-a-Man-(1-phosphate) attached to a mannan backbone as the main antigenic determinant.173 The acylation state of mycobacterial lipomannan modulating innate immunity response through TLR 2 was characterised by 2D 1H–31P NMR and MS.174 In studies of capsular polysaccharide (CPS) and lipopolysaccharide (LPS) structure and biosynthesis: the CPS of the HS:1 serostrain of Campylobacter jejuni has a complex teichoic acid-like structure with non-stoichiometric Fruf branches and Omethyl phosphoramidate groups175 and identical structural features were found for cell bound CPS on intact cells using 1H and 31P 2D HR-MAS NMR. C. jejeuni and C. coli are the main causes of bacterial diarrhoea worldwide and in the pathogenic strains of these and Helicobactor pylorides, the flagellin proteins are heavily glycosylated with a 2-keto-3-deoxy acid, pseudaminic acid (5,7-diacetamido3,5,7,9-tetradeoxy-L-glycero-L-manno-nonulosonic acid) the action of the gene involved in its biosynthesis monitored by 1H and 31P NMR of the isolated PS and shown to be similar to sialate synthase.176 Functional characterisation of dehydratase/aminotransferase pairs from Helicobacter and Campylobacter distinguished the pseudaminic acid and bacillosamine pathways.177 1H NMR was used to characterise acetylated and de-acetylated oligomers of GlcNAc to study the genomic sequences of the peptidoglycan N-acetylglucosamine deacetylases of Bacillus cereus and its closest relative B. anthracis.178 The orange carotinoid staphyloxanthin produced by most Staphylococcus aureus strains was identified as b-D-Glcp-1-O-(4,4 0 -diaponeurosporen-4-oate)-6-O-(12-methyltetradecanoate) and the genes involved in its biosynthesis elucidated.179 The PS of Streptococcus gordonii and S. oralis which are the receptors (hence RPS) for lectin-like surface adhesins involved in biofilm stabilisation are composed of heptasaccharide repeats that are identical except for their host-like motifs. The genes for the glycosyltransferases that catalyse the synthesis of these motifs were identified180 by HR-NMR of genetically altered PS. In ongoing studies of the LPS from non-typeable Haemophilus influenzae, the lipid A was further characterised181 and an investigation carried out of the genes responsible for the addition of phosphoethanolamine to the lipid A by NMR and Nucl. Magn. Reson., 2007, 36, 285–308 | 295 This journal is

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MS of the mutant strain.182 A separate study reported on the 1H, 13C and 15N NMR assignment of the periplasmic domain of peptidoglycan-associated lipoprotein from H. influenzae.183 The OPS from the enteroaggregative Escherichia coli strain 522/C1 was shown184 to have the same structure as O178:H7 and O9:K38, -4)-a-D-GlcpNAc-a-D-GalpA(1-2)-b-D-Ribf-(1-4)-b-D-Galp-(1-3)-b-D-GalpNAc-(1-). The OPS of E. coli O147 has been resolved by recording a tilted projection of a 3D NOESY-HSQC spectrum where the 13C and proton evolutions are linked together.185 Two different OPS from E.coli O86 produced by different polymerization of the same O-repeating unit varied by the anomeric configuration of the linkage, the linkage position and the identity of the residue through which polymerisation occurs.186 Knirel’s group have continued their classification of bacteria of the genus Proteus, a common cause of urinary tract infection. A neutral OPS obtained by mild acid degradation of the LPS of Proteus mirabilis O75 tetrasaccharide repeat unit was shown to have similarity to P. mirabilis O49 explaining the weak cross reactivity with O-antiserum.187 The OPS of P. mirabilis O19 helped reclassify certain Proteus strains that were formerly classified in serogroup O19 of P. vulgaris, P. hauseri and P. penneri.188 The LPS of P. mirabilis 2002 has a common tetrasaccharide fragment with P. mirabilis 52/57 from serogroup O29 and was hence proposed in this serogroup.189 Structure of the OPS and classification of P. genomospecies 4, 5 and 6 puts 5 and 6 into the existing Proteus serogroups O8 and O69, respectively. In 4, a Qui3NAc-containing pentasaccharide repeat was found with weak cross-reactivity with Providencia stuartii 18 and P. vulgaris OX2.190 Also from the same group with others in China,191 structural and genetic characterisation of the Shigella boydii type 18 O antigen showed -3)-b-L-Rhap-(1-4)-a-L-Rhap-(1-2)-a-L-Rhap-(1-2)-a-DGalpA-(1-3)-a-D-GalpNAc-(1-, shigellosis being important in human pathogenesis. In separate studies: Gram-negative phytopathogenic Erwinia persicina bacterial strain HKI 0380 isolated from biofilms located on paleolithic rock paintings in the Cave of Bats in Zuheros, southern Spain notable for its production of considerable quantities of slime.192 The OPS component of the Actinobacillus pleuropneumoniae serotype 15 LPS was characterised193 as a linear unbranched polymer of a pentasaccharide repeat (-3)-a-D-Glcp-(1-2)-b-D-Galf-(1-6)-a-DGalp-(1-6)-b-DGlcp-(1-3)-b-D-Galf-(1-) chemically identical to the LPS of serotypes 3 and 8 whereas the CPS had a linear backbone of phosphodiester linked disaccharide units of D-GlcNAc and D-GalNAc (1:1) with 1/3 of the GalNAc substituted by b-D-Gal. The LPS core and lipid A of a GalU mutant of Pseudomonas aeruginosa were characterized.194 The structure of the phenol soluble PS from a Pseudomonas rubra strain was characterised comprehensively by 1H and 13C NMR including 2D COSY, TOCSY, gNOESY, ROESY, 1H,13C gHMQC and gHMBC experiments to suggest the presence of the novel monosaccharide 2-acetamido-2,6-dideoxy-D-xylo-hexos-4ulose linked between GalN and GlcN also containing novel acetimidoyl and malic acid, respectively.195 The complete 1H and 13C characterisation of the tetrasaccharide repeating unit of the K2 polysaccharide of Klebsiella pneumoniae strain 52145 was reported and a model suggested for its secondary structure on the basis of dynamic and molecular calculations.196 The capsular polysaccharide (CPS) of Shewanella oneidensis strain MR-4 was characterised grown on two different culture media, one enriched with 3-hydroxy-3-methylbutyrate (60%) or with 3-hydroxybutyrate (40%) and the second minimal media containing mostly 3-hydroxybutyrate.197 Revision of the O-acetylation site of the CPS of S. pneumoniae Type 33 a component of the current pneumococcal PS vaccine.198 Leading up to the next two Sections on phytotherapeutics and other natural products are the following examples of antimicrobials from bacteria, mycobacteria and fungus and studies on marine bacteria. Monomeromycolyl-diacylglycerol (MMDAG), a novel triacylglycerol-related lipid isolated from Mycobacterium kansasii, was characterised by 1H-NMR and ES-MS and also studied as the possible 296 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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substrate for the tetrahydrolipostatin (THL) inhibited incorporation of acetate into both mycolic acids and MMDAG suggesting that THL, previously used for treating obesity, and other b-lactones may be promising drugs for the development of new anti-tubercular therapy.199 A new actinomycete strain designated US80 and characterised as belonging to the genus Streptomyces gave three molecules active against Gram+ve and Gramve bacteria and fungi whose structures were established by IR, ESI-MS, 1H and 13C/APT NMR as irumamycin, X-14952B and 17-hydroxyventuricidin A.200 Novel antibiotics active against acid-fast bacteria was isolated from Streptomyces broth, the absolute configuration of caprazamycin I with three glycosidic rings characterised by NMR, one of a family of lipouridyl antibiotics which have been shown to be specific inhibitors of bacterial translocase.201 Strain specific secondary cell wall polymer of Geobacillus tepidamans GS5-97, a Gram+ve moderately thermophilic organism was characterised as [b-D-Manp-2,3-diNAcANH2-(1-6)-a-D-Glcp-(1-4)-b-D-Manp-2,3-diNAcANH2-(1-3)-a-D-GlcNAc(1-]6–(1-O)PO2-(O-6)-MurNAc with acyl modifications of the NH2 groups.202 The marine halophilic bacterium Pseudoalteromonas carrageenovora strain was shown to contain colitose.203 The LPS of a strain of the marine bacterium Arenibacter certesii core structure has Kdo substituted at C-5 by a-Man and at O-4 by a-GalA phosphate and a non-stoichiometric amount of a-D-Rha.204 The LPS of the plant pathogenic bacterium Burkholderia caryophilli showed that a QuiNAc residue is the primer monosaccharide that connects the core oligosaccharide to the caryan (3 units of caryose) O-chain.205 A triglycosidic dibenzofuran metabolite from the slime mould Fuligo cinerea was highly active against Gram+ve bacteria and crown gall tumours.206

7. Phytotherapeutics Plants produce a large range of natural products that have been exploited for therapeutics and used as the basis for modern drug design. It is suggested that these are natural defence mechanisms in the plant against insect, fungal, bacterial and viral onslaught. To defend themselves against fungal pathogens, plants produce numerous anti-fungal proteins and peptides, including defensins, some of which have been proposed to interact with fungal cell surface glycosphingolipid components.207 In this paper neutral glycolipids components were extracted from wild-type and plantdefensin-resistant mutant strains of Neurospora crassa and the structures elucidated by NMR spectroscopy and MS and the main finding was a significant increase in ergosterol b-glucoside in the mutant strain. The fungicidal and insecticidal activity of O-acyl chitosan derivatives with a degree of substitution between 0.02 and 0.28, of e.g. butyryl, decanoyl, were analysed by synthesis and NMR and the activity characterised against the grey mold Botrytis cinerea, the rice leaf pathogen Pyricularia grisea and the cotton leafworm Spodoptera littoralis.208 The lipid extract of the photobiont of the lichen Dictyonema glabratum was analysed by TLC and NMR and shown to contain a complex array of fatty acid esters.209 Six new triterpene saponins were isolated210 from the MeOH extract of the aerial parts of Gynostemma pentaphyllum with a 21, 23 lactone on the cyclophenanthrene skeleton and a branched trisaccharide at C-3, characterised as 2,3 disubstituted, 6-Oacetylglucose (b1-). Immunological-adjuvant dammarane-type saponins were isolated from the roots of Pana notoginseng211 and norlignans from the branches and leaves of Sequoia sempervirens212 one of which showed anti-cancer activity against A549 non-small cell lung cell line (IC50 27 mM): An acetone extract had antifungal activity against Candida glabrata (IC50 16 mg/mL). Anti-proliferative hopane and oleanane saponin glycosides from the roots of Glinus lotoides had IC50 values against cancer cell lines ranging form 18–620 nM.213 Cupanioside, 1-O-[200 ,300 ,400 -tri-Oacetyl-a-Rhap-(1-2)-b-D-Glcp]-hexadecanol from the bark of Cupania glabra had cytotoxic activity against a range of cell lines including Hep G2 and PC-3.214 Nucl. Magn. Reson., 2007, 36, 285–308 | 297 This journal is

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Cycloartane-type triterpene glycosides from Astragalus oleifolius having C-3 b-DXyl-(1-2)-a-D-Ara and C25+ pentahydroxycycloartane were evaluated for trypanocidal, leishmanicidal and antiplasmodial actitivty as well as their cytotoxic potential on primary mammalian (L6) cells.215 New ether diglycosides from the root bark of Matayba guianensis with anti-plasmodial activity with IC50 2.5–8.9 mg/ mL hexadecyl glucopyranosides with 2,3,4-tri-O-acetyl Rha and various acyl groups on the Glc.216 Caged-tetraprenylated xanthones from the MeOH extract of the stem bark of Garcinia scortechinii with MIC of 2 mg/mL were compared by NMR with those described previously.217 Ellagic acid rhamnosides from the bark of Elaeocarpus parvifolius were characterised by 1H and 13C NMR, HMQC, HMBC and MS and SAR for growth inhibition of Babesia gibsoni.218 Two novel intermolecularly rearranged biiridoid glucosides isolated from the roots of Heracleum rapula were characterised by NOESY to establish the stereochemistry and tested for their potential as anti-platelet aggregation with poor results.219 New glycosides of the campestrol derivative of the cyclophenanthrene skeleton(24R,25S)-ergost-5-ene3b,26-diol from the rhizomes of Tacca chanteri with 4–7 Glc units variously at C-3 and C-26 determined by extensive NMR and chemical transformations.220 Studies on specific COX-2 inhibitors include: a new triterpenoid, 2a,3b,19b,23tetrahydroxyolean-12-en-28-O-b-D-glucoside from the seeds of Picrorhiza kurroa;221 phenylbutenoids from the rhizomes of Zingiber cassumunar.222 Myo-inositol-derived glycolipids with anti-inflammatory activity were isolated from the leaves of Solanum lanceolatum and characterised by 2D NMR methods to show the difference in SAR with phospholipase A2 and cyclooxygenase (COX-2) enzymes.223 C-21 steroidal glycosides with Glcp and cymarop from the roots of Cynanchum chekiangense had immunosuppressive activities.224 Anti-inflammatory properties of Aloe vera225 were attributed to veracylglucans containing Glc and malic acid acylated Glc. A new antioxidant isolated from the MeOH extract of the roots of Decalepsis hamiltonii was characterised as bis-2,3,4,6-galloyl-a/b-D-glucopyranoside and designated decalpin.226 Phenylpropanoid glucosides from leaves of Coussarea hydrangeifolia having Rha, Xyl and Glc had anti-oxidant activities of IC50 around 10–20 mM.227 Anti-oxidative compounds from the outer scales of onion (Allium cepa) were characterised by NMR as members of the quercetin glycosides: The flavanoid compounds having o-hydroxy substituent in the B-ring were shown to be effective anti-oxidants against nonenzymic lipid peroxidation.228 Furostanol in Allium ceps L. var. tropeana seeds polar extract had epimers of b-D-Glcp-(25R)-26-a-L-Rhap(12)-a-L-Arap.229 All trans trienoic linolenic acid characterised by NMR and MS was shown to have the strongest growth inhibitory effects on human tumour cells compared to other types of lipid and to more strongly induce lipid peroxide oxidation.230 The first studies of the anti-oxidant properties of water spinach (Ipomoea aquatica Forsk) identified231 7-O-b-D-Glcp-dihydroquercitin-3-O-a-DGlcp. LDL oxidation of flavone C-glycosides of Atractylodes japonica leaves.232 LDL antioxidants from mulberry leaves were flavanol glycosides, the most potent quercetin 3-(6-malonylglucoside, quercetin 3-rutinoside and quercetin 3-glucoside.233 Triterpene glycosides were characterised from Kalopanax septemlobum based on hederagenin having 6-O-caffeyl-b-D-Glc-(1-4)-b-D-Xyl-(1-3)-a-L-Rha-(1-2)b-L-Ara at C-3 and trisaccharide esters at C-28 containing variously a-L-Rha, b-D-Glc and 6-O-acetyl-b-D-Glc.234 Six new pregnane glycosides, four of them sulfated, were isolated from small branches of Periploca graeca in addition to sulfoglucopyranosyl had digitalopyranosyl, oleandropyranosyl and cymaropyranoside groups.235 A new sugar ester (ningposide D, 3-O-acetyl-2-O-p-methoxycinnamoyl-a(b)-L-rhamnopyranose) and a new iridoid glycoside (scrophulside, 6-O-(200 -O-acetyl-300 -O-cinnamoyl-400 -O-p-methoxycinnamoyl-a-L-rhamnopyranosyl) catalpol) from the roots of Scrophularia ningpoensis were found to be toxic against a series of human cancer cell lines with IC50 around10–150 mM.236 A new daphnane diterpenoid, rediocide G, isolated from the roots of Trigonostemon reidiodes, was found to be cytotoxic to a number of cancer 298 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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cell lines.237 New sesquiterpene lactones from the water extract of the roots of Lindera strychnifolia had cytotoxicity against small cell lung cancer cell SBC-3.238 Flavanoid triglycosides from the seeds of Syzygium aromaticum contained apigenin, b-Xyl, b-Gal, b-Glc and O-p-coumaryl-b-Glc.239 A new bioactive furostanol saponin from the leaves of Agave shrevei Gentry 26glucopyranosyloxy-22-methoxy- and Glc (b1-2) [Glc (b1-3){Glc(b1-6)} Glc (b13Glc) at C-3 characterised using COSY, HETCOR and COLOC had significant inhibition of capillary permeability in the absence of haemolysis.240 The effects of natural products from the aerial parts and roots of Zygophyllum gaetulum, Moroccan sahara medicinal plants, on contractions of the ileum of animal models were from new bisdesmosidic triterpene saponins having Rha, Ara, Glc, sulfo Glc and quinovopyranosyl.241 Saponins based on hedergenin with various O-acetylated Xyl and Ara together with non-acetylated Xyl Ara, Gal and Rha from the pericarp of Sapindus trifoliatus reach the level of complexity that can be unraveled by NMR alone according to the authors.242

8. Other natural products 8.1.

Anticoagulents

The structure and anti-coagulant activity243 of a sulfated galactan from the red alga Gelidium crinale helped to elucidate the difference between inhibitors of antithrombin and heparin cofactor II. Similarly, the partial characterisation and anticoagulant activity of a heterofucan from the brown sea weed, Padina gymnospora, was shown to have a central core consisting mainly of 3-O- and 4-O-b-D-GlcA substituted at C-2 with b-D-Xyl and a-L-Fuc-3-sulfate where the sulfation was essential for the anticoagulant activity.244 The structure of a polysaccharide from the red seaweed, Porphyra capensis was shown to have a backbone of alternating 3-linked b-D-Gal and either 4-linked a-L-Gal-6-sulfate or 3, 6-anhydro-a-L-Gal in an approximate 1:1 ratio.245 The sulfated galactofucan from the brown alga Spatoglossum schroederi had a unique structure composed of a central core formed mainly by 4-linked b-Gal partially sulfated at C-3 and with 1/4 having mostly tetrasaccharide branches composed of 3-sulfated 4-linked a-Fuc and one or two nonsulfated 4-linked b-Xyl units. This had no anticoagulant activity but potent antithrombotic activity and was 2-fold more potent than heparin in stimulating the synthesis of an antithrombotic heparan sulfate by endothelial cells.246 Fucoidan from the brown sea weed Fucus serratus L was a branched structure with added Gal, Xyl and O-Ac.247 An osmotic function for digalactosylglycerol was characterised in red alga.248 8.2.

Fungal natural products

The use of DOSY experiments for the study of mushroom polysaccharides249 shows the way for studies of related natural products. In other mushroom studies the water soluble PS fraction of the cell wall alkali extract from the micelial phase of the dimorphic fungus Paracoccidioides brasiliensis had a repeating unit of backbone [(1-6)-a-D-Manp] substituted at C-3 by the disaccharide [a-D-Galf-(1-6)-a-DManp-(1-)] or single Man residues or short chains of (1-2)-Man.250 b-Glucans of Agaricus brasiliensis fruiting bodies in different stages of maturity were isolated and characterised by FTIR and NMR and SAR for potential therapeutic benefits.251 The polysaccharides of Inonotus levis P. Karst mushroom (heterobasidiomycetes) were shown to include a phosphorylated mannan similar to that of Saccharomyces cerevisiae and a novel GlcA and Gal-3-O-Me containing oligosaccharide of 20–40 sugars which the authors suggested252 was linked to protein via Ser/Thr. In the exploration of glycosylhydrolase family 75 a chitosanase was characterised from Aspergillus fumigatus.253 The production of oligoglucuronans from glucuronan by fungal glucuronan lyase was monitored by NMR of the products.254 Nucl. Magn. Reson., 2007, 36, 285–308 | 299 This journal is

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8.3.

Marine natural products

As part of a long term study, the latest glycolipid from sponges showed a rare one having myo-inositol255 and clathosides and isoclathrosides glycosides of a very long chain alcohol.256 Cytotoxic isomalabaicane triterpenes were characterised from the marine sponge Rhabdastrella gloostellata.257 The turbostatins from the Asian marine mollusc Turbo stenogyros cerebrosides were shown to have Glc b1-various lipids which exhibited significant (GI50 0.15–2.6 mg/mL) cell growth inhibition against the marine P388 lymphocytic leukaemia and a panel of human cell lines.258 Other studies include: Two new holostan-type triterpenoidoligoglycosides from the warty sea cucumber Stichopus parvimensis;259 Phrygiasterol, a cytotoxic cyclopropane-containing polyhydroxy steroid; steroid glycoside phrygioside and related compounds from the Pacific starfish Hippasteria phrygiana;260 and, polar steroidal compounds from the Far Eastern starfish Henricia leviuscula.261 The absolute configuration of the marine natural product, bistramide C having three glycosidic rings embedded in a backbone of methyl carboxyl and peptidic bonds was determined from 1024 possible stereoisomers.262

9. Materials science Not all natural products from plants are necessarily anti-microbial or potential phytotherapeutics but are required for colour (e.g. the anthocyanins), stability (e.g. antifreeze compounds), strength (polysaccharides) etc., as reviewed here from selected NMR-based studies. Some of the polysaccharides are essential food sources and useful neutriceuticals. The major anthocyanins from Gladiolus cultivars, malvidin 3,5-di-O-glucoside and pigments based on flavanol 3-O-glycosides of kaempferol, quercetin, myricetin, laricitrin and syringetin were characterized.263 The structure analysis of a set of co-occurring pigments, the nudicaulins, from the yellow petals of the Iceland poppy showed them264 to be acylated glycoside moieties attached to a pentacyclic indole alkyloid skeleton 19-(4-hydroxyphenol)-10H-1,10-ethenochromeno[2,3-b]indole6,8,18-triol. Malto-oligosyltrehalose synthase and malto-oligosyltrehalose trehalohydrolase enzymes catalysing trehalose biosynthesis were identified in Anabaena 7120 exposed to NaCl stress.265 The following lists some of the polysaccharide studies over the past year: Isolation and structural characterisation of xylans and amylopectin in Eucalyptus globules kraft block containing 4-deoxy-b-L-threo-hex-4-enopyranosyl uronic acid.266 Different xyloglucans in the primary cell walls of plants in the subclass Asteridae267 and endogenously O-acetylated xyloglucan from tomato (Lycopersicon esculentum) where the presence of five-bonded scalar coupling in the gCOSY spectra provided a direct method of assigning O-acetylation sites which may prove generally useful.268 Xyloglucans characterised by HMQC NMR from the leaves of Hymenaea courbaril showing an unusual 2-O- and 4-O-substituted Xyl and 4-O substituted Xyl in the oligosaccharide Glc4Xyl3Gal2Fuc obtained by endoglucanase treatment of the polysaccharide.269 The glucuronoxylan isolated by alkali (KOH) or DMSO extraction from the wood of the fast growing tree Acacia mangium characterised by NMR and chemical methods to contain a linear backbone of Xylp with O-2- and O-4methyl GlcA substitutions.270 Hardwood xylans of Eucalyptus and betula were characterised.271 Arabinogalactan type I from potato was shown272 to contain b-DGalp-(1-3)-b-D-Galp structural elements present within the backbone with a frequency ranging from 1 in 160 (potato, soya, citrus) to 1 in 250 (onion). An arabinopyranosyltransferase was characterised from mung bean hypocotyls.273 Different microbial sources of fructosyltransferase which catalyses the production of fructo-olgosaccharides with different linkage to form 1-ketose, 6-ketose and neoketose in varying yields, was characterised by NMR and correlated with the functional properties such as their use as prebiotics, dietary fibre, immune 300 | Nucl. Magn. Reson., 2007, 36, 285–308 This journal is

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stimulation, control of lipid metabolism and diabetes and applications in food formulations.274 9.1.

Nanoparticles, surfactants and drug stability/delivery

A natural dicarboxylic acid (malic acid) was used as a cross-linking reagent for intramolecular covalent condensation reactions to obtain hydrophilic nanoparticles of chitosan.275 Poly(n-butyl acrylate) alone and with chitosan shells were characterised by NMR and FTIR and the latter shown to have excellent (99% reduction) anti-bacterial properties when coated onto textiles.276 The preparation and characterisation by NMR, DLS and TEM of chitosan-based nanoparticles of various particle size formed by reaction of carboxyl groups and pendant amino groups of chitosan at different pHs had potential in different biomedical applications.277 Amino-ethyl chitin was found to breakdown the cell membranes of E. coli and S. aureus as well as having a cytotoxic effect on mammalian cell lines.278 NMR microscopy has been assessed for quality control of alginate hydrogels used to encapsulate cells for the purpose of cell transplantation and to study the long term integrity of alginate/poly-L-lysine/alginate microcapsules.279 Dextran with long alkyl chains substituted on a proportion of the OH groups was characterised by 1H and 13 C NMR to correlate structure and activity for drug delivery.280 In studies of surfactants the use of NMR relaxation, diffusometry and electrophoretic NMR is reviewed to determine characteristics such as micellar size and structure, ion-binding and solubilisation.281 Pfg and electrophoretic NMR and small angle neutron scattering of micellar solutions of tetramethylammonium dodecyl suphate were compared in studies of anionic surfactants with macrocounterions.282 The design and synthesis of a new reverse phase micelle surfactant, 3,3-dimethyl-1butylsulfonsuccinte sodium salt, was optimised for HR-NMR of encapsulated proteins using ubiquitin as an example.283 The formation of glycocylindrical brushes (also known as molecular sugar sticks) with poly-3-O-methacryloyl-a,b-D-Glcp side chains prepared by atom transfer radical polymerisation was followed by GPC-MALS and 1H-NMR and visualised using SFM, cryogenic TEM and DLS.284 Carbohydrate bearing 3-hydroxy-4pyridononato complexes of Ga(III) and In(III) were synthesised and characterised by MS and 1H and 13C NMR as potential radiopharmaceuticals.285 Solution NMR and molecular mechanics calculations have been used to characterise the possible harmful effects of hetero-associations of drugs used in cancer chemotherapy such as actinomycin D, daunomycin and novatrone.286

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Synthetic macromolecules Hiromichi Kurosu and Takeshi Yamanobe DOI: 10.1039/b618331j

1. Introduction For synthetic macromolecules, NMR has been the most powerful method to characterize and to investigate the relationship between the structure and the physical properties. In the field of synthetic macromolecules, NMR is used not only as the routine analytical method but also as the method that has the infinite possibility. In this chapter, NMR applications for synthetic polymers are reviewed. Possibilities of 1H NMR spectroscopy in investigations of structural-dynamic changes and polymer-solvent interactions during the temperature-induced phase transitions in aqueous polymer solutions are reviewed. The rate of dehydration process markedly depends on the polymer concentration for poly(vinyl Me ether), poly(Nisopropyl methacrylamide).1 Methods for the characterization of very large biological macromolecules with molecular weights beyond 100 000 Da are reviewed.2 Griffiths et al. reviewed the principles and potential application of electrophoretic NMR to the multi-component systems.3 The applications of the NMR of xenon is reviewed about the determination of the porosity of micro- and mesoporous solids, the evaluation of the concentrations and sizes of amorphous domains in solid polymers, characterization of liquid crystals, study of combustion processes at high temperature, determination of the structure and dynamics of organic systems and proteins in solutions and assessment of cerebral blood flow.4 Gschwind reviewed the methods to determine the structure and configuration of small organic molecules by using residual dipolar couplings for the partial aligned small organic systems in the gel or liquid crystalline phases.5

2. Primary structure Characterizations of primary structures such as tacticity, regioregularity, end group, sequence distribution, and so on are investigated mainly by solution NMR. Table 1 summarizes the papers in which NMR is used to investigate the primary structure of polymers.

3. Liquid crystalline polymers The dynamics and structure of the side chains of the grafted copolymer which is the chemically modified poly(epichlorohydrin) is investigated by solid state NMR. Temperature dependences of spin–lattice relaxation times are measured and discussed based on the phase characteristics.322 The phase behavior of a liquid crystalline polyetherester derived from 4 0 -hydroxy-1,1 0 -biphenyl-4-carboxylic acid and the ether-diol 4-(3-hydroxypropoxy)butan-1-ol, was studied. The 13C NMR results in the solid-state of the ordered phase show a single TH1r relaxation time. In addition, the low undercooling suggests the formation of a highly ordered mesophase, instead of a three-dimensional crystal.323 1H NMR relaxation studies of molecular dynamics were carried out for a supermolecular liquid crystal dendrimer which exhibits columnar rectangular and smectic-A phases. The spin lattice relaxation time dispersions are interpreted using two mechanisms associated with collective motions and local molecular reorientations of the dendritic segments in the low- and high-frequency ranges, respectively. In the high frequency range, the motions appear to be of similar nature in both phases, while notable differences in the dynamics Department of Textile and Apparel Science, Faculty of Human Life and Environment, Nara Women’s University, KitauoyahigashimachiNara City, Nara, Japan


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Table 1 Polymer, monomer

Nucleus

Contents

Ref.

1,2-polybutadiene 3-[methoxypoly(oxyethylene)]methylene furan a,o-bis(hydrido)polydimethylsiloxane, poly(methylhydridosiloxane-co-dimethylsiloxane) Chlorinated polyethylene

C

Configuration End group End group

6 7 8

Sequence distribution Composition End group

9 10 11

Composition

12

Graft, comb

13

Composition

14

Composition

15

End group Molecular weight

16 17

End group

18

End group, isomer

19

End group

20

Configuration Composition, polydispersity Composition Tacticity Tacticity, regioregularity

21 22 23 24 25

Composition

26

Composition

27

Composition

28

Composition

29

Composition, branch

30

Branch Degree of polymerization Regioregularity

31 32

H,C,Si H

Copolyamide, nylon 6, nylon 6,18 C Dihydroxy-polystyrene, monohydroxypolystyrene, nonhydroxy-polystyrene Fluorinated disulfonated poly(arylene ether benzonitrile) Fluorinated polyimide, poly(pentafluorostyrene), H polystyrene Fluoropolyimide-graft-poly(ethylene glycol)methyl ether methacrylate Galactose-functionalized glycopolymer, H poly(L-glutamic acid) Hydroxy-terminated polybutadiene F Hyperbranched polyester, 3,5-dihydroxybenzoic acid,H 1,3,5-tris(2-hydroxyethyl) cyanuric acid Hyperbranched polyphosphate ester, bisphenol-A H,P and phosphoryl trichloride Phenol/2,6-dimethylphenol-terminated poly(1H,C hexene) Poly((a,a-bis(trifluoromethyl)bicyclo[2.2.1]H hept-5-ene-2-ethanol), poly((a,abis(trifluoromethyl)bicyclo[2.2.1]-hept-5-ene-2ethanol -co-t-butyl carboxylic acid) Poly(1,3-cyclopentylenevinylene) H,C Poly(1,4-butadiene)-block-poly(dimethylsiloxane) H,C Poly(1,4-cyclohexanedimethylene terephthalate) Poly(1-hexene), poly(1-octadecene) C Poly(1-hexene), poly(1-octene), poly(1-decene), C poly(4-methyl-1-pentene) Poly(1-vinyl-2-pyrrolidone-coH,C hydroxyethylmethacrylate) Poly(2-(3-mesityl-3-methylcyclobutyl)-2-ketoethyl H,C methacrylate-co-acrylonitrile), poly(2-(3mesityl-3-methylcyclobutyl)-2-ketoethyl methacrylate-co-styrene) Poly(2-(dimethylamino)ethyl methacrylate)H block-poly(methoxy hexa(ethylene glycol) methacrylate) Poly(2-(dimethylamino)ethyl methacrylate-co-2H (diethylamino)ethyl methacrylate)-co-(poly(propylene oxide) methacrylate) Poly(2-(dimethylamino)ethyl methacrylate H -co-ethylene glycol dimethacrylate), poly(2-(diethylamino)ethyl methacrylate) -co-ethylene glycol dimethacrylate) Poly(2-(N,N-diethyldithiocarbamyl)methylstyrene) Poly(2,5-dialkyl-1,4-phenylene vinylene) H Poly(2,5-dichlorobenzophenone)

C


c


33

Poly(2-aryl-1-methylenecyclopropane ), poly(ethylene-co-2-aryl-1-methylenecyclopropane) Poly(2-hydroxypropyl methacrylate) Poly(2-methoxy-5-(2 0 -ethyl-hexyl oxy)-1,4-phenylene vinylene) Poly(2-methoxy-5-tricyclodecanemethyleneoxy1,4-phenylenevinylene), poly(bis-2,5tricyclodecanemethyleneoxy-1,4-phenylenevinylene) Poly(2-methylene-1,3-dioxepane-co-fluoroalkenes) Poly(2-N-carbazolylethyl acrylate) Poly(2-N-carbazolylethyl acrylate-co-methyl methacrylate) Poly(2-N-carbazolylethyl methacrylate) Poly(2-oxazoline) Poly(2-oxo-12-crown-4-ether), poly(2-oxo-12-crown4-ether-co-pentadecanolactone) Poly(3-[2-((S)-1-methyloctyloxy)ethyl]thiophene) Poly(3-2-[2-(2-hydroxyethoxy)ethoxy] ethoxymethyl-3 0 -methyloxetane) Poly(3-alkoxythiophene) Poly(3-alkylthiophene) Poly(3-alkylthiophenes) Poly(3-Ethyl-3-(hydroxymethyl)oxetane)-starpoly(propylene oxide) Poly(3-hexylthiophene) Poly(3-hydroxybutyrate), poly(3-hydroxybutyrateco-3-hydroxyvalerate) Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Poly(3-octylthiophene) Poly(4-methacryloyloxyazobenzene-comethylmethacrylate) Poly(4-propanoylphenyl acrylate-co-methyl methacrylate) Poly(4-vinylpyridine-co-divinylbenzene), poly(divinylbenzene), poly(trimethylolpropane trimethacrylate) Poly(acetal), polycondensation, methyl a-Dmannopyranoside, terephthalaldehyde, 1,4bis(formylphenoxy)butanes Poly(acrylamide-co-(3-acrylamidopropyl)trimethyl ammonium chloride-co-N-acryloylvaline) Poly(acrylamide-co-glycidyl methacrylate) Poly(acrylic acid) Poly(acrylic acid), polyelectrolyte Poly(acrylic acid)-block-poly(styrene) Poly(acrylonitrile), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), sodium salt of partially carboxymethylated guar gum Poly(acrylonitrile-co-methyl acrylate)

H,C

Composition, sequence distribution Branch Configuration

35 36

H

Composition

37

H,C H,C

Sequence distribution Configuration Composition

38 39 40

H

Tacticity Sequence distribution Sequence distribution

41 42 43

H H,C

Regioregularity Branch

44 45

H H

Regioregularity End group Regioregularity Branch

46 47 48 49

H

50

H

Molecular weight, end group Composition

51

H H H

Composition Regioregularity Configuration

52 53 54

H,C

Composition

55

Cross link

56

H

Regioregularity

57

C

Composition

58

H,C

Composition End group Graft Cross link, dendrimer Graft

59 60 61 62 63

Composition, configuration, sequence distribution Composition, tacticity, configuration End group Branch End group

64

H

H,C

H H H

H

Poly(acrylonitrile-co-n-Bu acrylate)

H,C

Poly(alkylene succinates) Poly(amido amine) Poly(amino ester), 1-(2-aminoethyl)piperazine, 1,4-butanediol diacrylate

H C

34

65 66 67 68


c


Poly(aniline-co-aminoacetophenone) H Poly(arylene ether sulfone) F Poly(arylene ether sulfone)-block-polybutadiene H Poly(arylene oxindole) Poly(benzoylphenyl methacrylate-co-methyl H,C methacrylate) Poly(benzylmethacrylate-co-methacrylicacid-coH vinylbenzylabietate) Poly(benzyloxymethyl methyl glycolide-coC benzyloxymethyl glycolide) Poly(b-hydroxybutyrate-co-b-hydroxyvalerate) H,C Poly(butyl acrylate) Poly(butylene terephthalate) C Poly(cinnamoyloxyethyl methacrylate-co-isooctyl H acrylate) Poly(cyclohexene carbonate) C Poly(cyclohexene oxide)-block-polystyrene H Poly(cyclopentadiene) H Poly(cyclopentene) H,C Poly(cyclopropene) H,C Poly(D,L-lactide-co-glycolide) H Poly(D,L-lactide-co-glycolide), poly(ethylenimine) C Poly(di-n-butylgermane-co-methylphenylsilane), H,C,Si, poly(di-n-butylgermane-co-n-hexylmethylsilane), Sn poly(di-n-butylstannane-co-methylphenylsilane) and poly(methylphenylsilane-co-diphenylgermane), poly(di-n-butylsilane), poly(di-n-butylgermane) Poly(dipropargylfluorene) C Poly(e-caprolactone) H Poly(e-caprolactone) H Poly(e-caprolactone-co-ethylene oxide) H Poly(e-caprolactone) H,C Poly(e-caprolactone) Poly(e-caprolactone), poly(ethylene glycol), H poly(di-Me siloxane), polylactide Poly(e-caprolactone)-block-polystyrene H Poly(e-caprolactone)-block-polystyrene Poly(e-caprolactone-co-2-oxepane-1,5-dione) H,C Poly(e-caprolactone-co-g-butyrolactone), C poly(d-valerolactone-co-g-butyrolactone) and poly(e-caprolactone-co-d-valerolactone) Poly(e-caprolactone-co-glycolide) H,C Poly(ester urethane), poly[(R)-3-hydroxybutyrate], H poly(ethylene glycol) Poly(ester-amide) H,C Poly(ester-amide) H,C Poly(ethane-co-a-olefin) Poly(ethene-co-1-octene) H,C Poly(ether sulfone), poly(ether ether sulfone), C 4,4 0 -dichlorodiphenyl sulfone, 4,4 0 -dihydroxydiphenyl sulfone,hydroquinone Poly(ether-ketone) C Poly(ethyelne-co-1-alkene) C Poly(ethyl a-chloromethylacrylate) Poly(ethyl acrylate), poly(butyl acrylate) Poly(ethyl acrylate-co-hydroxyethyl acrylate), poly(hydroxyethyl acrylate-co-methacrylic acid) Poly(ethyl acrylate-co-methyl methacrylate)

H,C H,C

H

Composition Branch Composition Branch Composition

69 70 71 72 73

Composition

74

Sequence distribution

75

Compostion End group Sequence distribution Composition

76 77 78 79

Tacticity Block Configuration Branch, configuration Tacticity Composition Cross link Composition

80 81 82 83 84 85 86 87

Conjugation End group End group Composition End group End group Block, composition

88 89 90 91 92 93 94

Sequence distribution 95 Block 96 Cross link 97 Degree of polymerization98

Sequence distribution Composition

99 100

Branch Branch Composition, branch, Irregularity Sequence distribution

101 102 103 104 105

Sequence distribution Composition, reactivity ratio Composition Branch Composition

106 107 108 109 110

Composition

111


c


Poly(ethyl methacrylate-co-propyl methacrylate) Poly(ethyl-2-cyanoacrylate) Poly(ethylene 2,6-naphthalate), poly(pentamethylene H terephthalate), poly(ether imide) Poly(ethylene glycol)-block-poly(d-valerolactone) H Poly(ethylene oxide), polyethylene-blockH poly(ethylene oxide) Poly(ethylene oxide)/hydrophobic C6 branched H chitosan Poly(ethylene terephthalate) C Poly(ethylene terephthalate) H,P Poly(ethylene terephthalate-co-hydroquinone) Poly(ethylene terephthalate-co-oxalate-cosebacate) Poly(ethylene terephthalate-co-trimethylene terephthalate) Poly(ethylene terephthalate-co-trimethylene H,C terephthalate) Poly(ethylene-co-norbornene) C Poly(ethylene-co-1,2,3-13C3-butyl acrylate-co-carbon H,C monoxide) Poly(ethylene-co-1-butene), poly(ethylene-co1-hexene) Poly(ethylene-co-propylene) C Poly(ethylene-co-propylene)

C

Poly(ethylene-co-propylene) Poly(ethylene-co-styrene)

C

Poly(ethylene-co-vinyl alcohol) H,C Poly(glycidyl methacrylate-co-butyl acrylate) H Poly(glycolic acid) H Poly(glycolide-co-trimethylene carbonate), H poly(glycolide-co-2,2-dimethyltrimethylene carbonate) Poly(glycolide-co-1,3-trimethylene carbonate) C Poly(glycolide-co-trimethylene carbonate) H,C Poly(g-methylglutamate-co-leucine) H,C Poly(hydroxyethyl aspartamide-co-propyl H aspartamide)-graft-poly(D,L-lactide) Poly(hydroxyethyl-L-asparagine) H Poly(lactic-acid-alt-glycolic acid) , poly(eH caprolactone)-block-poly(lactic-acid-alt-glycolic acid) Poly(lactide-co-caprolactone-co-glycolide) H,C Poly(L-lactic acid) C Poly(L-lactic acid)-block-poly(ethylene oxide)-blockpoly(L-aspartic acid) Poly(L-lactide), 2,2-bis(hydroxymethyl)butyric acid Poly(L-lactide-co-e-caprolactone), poly(L-lactideco-e-caprolactone-co-glycolide) Poly(m-carboranyl-siloxane) Poly(m-carboranyl-siloxane) Poly(methyl acrylate)-block-poly(e-caprolactone)

Composition Composition Transesterification

112 113 114

Block End group

115 116

Composition

117

End group End group Sequence distribution Composition, sequence distribution Sequence distribution

118 119 120 121


123

Sequence distribution Tacticity, sequence distribution Composition

124 125

Composition, ratio Composition, ratio Composition, distribution Composition, distribution Tacticity Composition End group Composition, distribution

122

126

reactivity 127 reactivity 128 sequence

129

sequence

130

sequence

131 132 133 134

Sequence distribution Composition Sequence distribution Graft

135 136 137 138

Composition Degradation

139 140 141 142

H

Sequence distribution Molecular weight, end group, stereosequence Block, composition

H,C

Branch

144

H,C

Composition, sequence distribution Degradation Degradation, cross link End group

145

H,C,B H,C,B H,C

143

146 147 148


c


Poly(methyl methacrylate-co-ethylene glycol dimethacrylate) Poly(methyl methacrylate-co-ethylene glycol dimethacrylate-co-dodecanethiol) Poly(methyl methacrylate-co-glycidyl methacrylate) Poly(methacrylate), carbazole phenoxy Poly(methacrylonitrile-co-2,2,2-trifluoroethyl methacrylate), poly(acrylonitrile-co-2,2,2trifluoroethyl methacrylate), poly(methylvinylidene cyanide-co2,2,2-trifluoroethyl methacrylate) poly(methacrylonitrile-co-vinylidene) Poly(methacryloxymethyl)triethoxysilane), poly ((methacryloxypropyl)trimethoxysilane), hybrid material Poly(methyl acrylate-co-hydroxylethyl acrylate), poly(methyl acrylate-co-hydroxylethyl acrylate)graft-poly(L-lactic acid), poly(methyl acrylate-cohydroxylethyl acrylate)-graft-(poly(L-lactic acid)block-polystyrene) Poly(methyl acrylate-co-methyl methacrylate) Poly(methyl acrylate-co-methyl methacrylate) Poly(methyl bicyclobutane-1-carboxylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate), polystyrene Poly(methyl methacrylate)-graft-poly (caprolactone) Poly(methyl methacrylate)-poly(bis(2methacryloyloxyethyl)disulfide)-co-poly(butyl acrylate) Poly(methyl silsesquioxane-coaminopropylsilsesquioxane) Poly(methylacrylate) Poly(methylhydrosiloxane-co-dimethylsiloxane) Poly(methylmethacrylate) Poly(monohexyl-substituted lactide) Poly(N-(4-a-bromobutyryloxyphenyl)maleimide) Poly(N,N-dimethylacrylamide-cotrimethylolpropyltrimethacrylate), poly(N,Ndimethylacrylamide-co-methacylic acid-cotrimethylolpropyltrimethacrylate) Poly(N-acryloxysuccinimide) Poly(N-alkynylamide) Poly(n-butyl acrylate) Poly(n-butylacrylate), poly(tert-butylacrylate) Poly(N-isopropylacrylamide) Poly(N-isopropylacrylamide) Poly(N-isopropylacrylamide-co-N,Ndimethylacrylamide)-b-poly(D,L-lactide-co-glycolide)

H

Composition, branch

149

H

Composition

150

C

Cross link

151

H H,C,F

Configuration Composition

152 153

H,C

154

C,Si

Composition, configuration Composition

155

H

Branch

156

H H,C H

Composition 157 Sequence distribution 158 End group 159 Degradation 160 End group 161 End group 162 Tacticity 163 Molecular weight 164 Tacticity 165 Tacticity 166 Tacticity 167 End group, polydispersity168 End group 169

H H

H,C C H H

Block, star

170

H,Si

Composition

171

H H H H H,C C

Tacticity Cross link Tacticity End group Molecular weight Cross link

172 173 174 175 176 177

H H H,C

Molecular weight configuration Composition End group, branch Tacticity End group Composition

178 179 180 181 182 183 184


c


Poly(N-isopropylacrylamide-co-N-propylacrylamideco-vinyl pyrrolidone) Poly(N-isopropylacrylamide-graft-poly(ethylene glycol)) Poly(norbornene-2-carboxylic acid alkyl ester) Poly(norbornene-alt-cyclooctene) Poly(norbornene-co-1-hexene), poly(norbornene-co-1-octene) Poly(norbornene-co-methyl acrylate)

H C C H,C

Poly(N-phenylmaleimide) Poly(N-phenylmaleimide-co-acrylic acid), poly(N-phenylmaleimide-co-acrylamide) Poly(N-propargylamide)

C H

Poly(N-propargylbenzamide) Poly(N-vinylcaprolactam-co-glycidyl methacrylate) Poly(N-vinylpyrrolidone)

H

Poly(N-vinylpyrrolidone)

H

Poly(N-vinylpyrrolidone) Poly(p-(chloromethyl)styrene-co-acrylonitrile) Poly(p-chloromethylstyrene-co-2,3,4,5,6-pentafluorostyrene), poly(p-bromomethylstyrene-co2,3,4,5,6-penta-fluorostyrene) Poly(p-cumyl phenyl methacrylate-co-glycidyl methacrylate) poly(pentylene terephthalate), poly(ethylene naphthalate), poly(pentylene terephthalate-coethylene naphthalate) Poly(phenoxycarbonylmethyl methacrylate), poly(phenoxycarbonylmethyl methacrylate-coethylmethacrylate) Poly(phenyl methacrylamide-co-acrylamide) poly(phenyl methacrylate-co-methyl methacrylate) Poly(phenylene oxide) Poly(polyurethane-co-dimethyl maleate) Poly(p-phenylenevinylene) Poly(propylene carbonate) Poly(propylene-co-ethylene) Poly-(R)-3-hydroxybutyrate Poly(styrene-alt-maleic anhydride) Poly(styrene-co-acrylic acid) Poly(styrene-co-ethyl acrylate) Poly(styrene-co-methyl methacrylate) Poly(styrene-co-methyl acrylate) Poly(styrene-co-methyl methacrylate) Poly(styrene-co-n-butyl acrylate) Poly(styrenesulfonic acid) poly(tert-butyl acrylate)-block-poly[(R)-3hydroxybutyrate]-block-poly(tert-butyl acrylate) Poly(trimethylene carbonate-co-2,2dimethyltrimethylene carbonate) Poly(trimethylene sulfide) Poly(trimethylene terephthalate) Poly(trimethylene terephthalate)

H

H

Composition End group

185 186

Stereoregularity Sequence distribution Composition

187 188 189

Composition, sequence distribution Configuration Composition

190

Configuration, stereoregularity Stereoregularity Composition

191 192 193 194 195

H,C,F

Molecular weight, end group End group, molecular weight Tacticity Branch Composition

198 199 200

H

Composition

201

H


202

H,C

Composition

203

H H,C

Composition Composition

204 205

H C H

Branch Sequence distribution End group Sequence distribution Regioselectivity End group Sequence distribution Composition Composition Composition Sequence distribution Composition Composition Branch Block

206 207 208 209 210 211 212 213 214 215 216 217 218 219 220


221

Conformation End group End group

222 223 224

C H

H H H H,C H,C H,C

H,C H H

196 197


c


Poly(trimethylol-propane triacrylate-co-1-(2C aminoethyl)piperazine) Poly(vinyl alcohol), poly(vinyl silyl ethers), poly(vinyl ethers) Poly(vinyl alcohol)-graft-polyacrylamide H Poly(vinyl alcohol-graft-maleic anhydride) H Poly(vinyl chloride) H,C Poly(vinyl chloride-co-chlorotrifluoroethylene) H,F Poly(vinyl chloroacetate-co-vinyl acetate ), H poly(N-vinyl-2-pyrrolidone-co-vinyl acetate) Poly(vinylchloride) C Poly(vinylcyclohexane) C Poly(vinylidene chloride-co-vinyl acetate) H,C Poly(vinylidene fluoride-co-perfluoromethyl vinyl F ether), poly(vinylidene fluoride-co-perfluoropropyl vinyl ether) Poly(vinylpyrrolidone), poly(di(2-(2-oxo-1pyrrolidinyl)ethoxy)phosphazene), poly(vinylpyrrolidone-co-di(2-(2-oxo-1pyrrolidinyl)ethoxy)phosphazene) Poly[(R,S)-3-hydroxybutyrate-co-L-lactic acid] and H poly[(R,S)-3-hydroxybutyrate-co-e-caprolactone] Poly[2,5,8,11,14-pentaoxapentadecamethyleneH,Li (5-alkyloxy-1,3-phenylene)]-block-poly[2oxatrimethylene(5-alkyloxy-1,3-phenylene)] Poly[2-methoxy-5-(2 0 -ethyl-hexyloxy)-1,4H phenylene vinylene], poly(2,5-dibutoxy-pphenylene vinylene), poly[2-methoxy-5-(2 0 ethyl-hexyloxy)-1,4-phenylene vinylene-co-2,5dibutoxy-p-phenylene vinylene] Poly[ethylene-co-(Bu acrylate)-co-(carbon monoxide)]H,C Poly[perfluoro(4-vinyloxyl-1-butene)] Poly-a,b -[N-(2-hydroxyethyl)-L-aspartamide]H graft-poly(e-caprolactone) Polyacetylene Polyacrylamide H Polyacrylonitrile H Polyamide 6-graft-diethyl maleate H Polyamide, triamine,dicarboxylic acids Polyampholyte Polybutadiene H Polybutadiene-block-poly(ethylene glycol) H Polycyclopentene H,C Polyester, hyperbranched polyester H Polyester-block-poly(dimethylsiloxane)-blockH polyester Polyether, glycerol carbonate C Polyethoxysiloxane Si Polyethylene C Polyethylene C Polyethylene Polyethylene Polyethylene- and poly(propylene)-co-a-olefin H,C Polyethylene, poly(ethylene-co-1-hexene) C Polyethylene, poly(ethylene-co-propylene) C Polyethylene, polypropylene H,C Polyethylene, polypropylene C Polyethyleneimine C Polyglycidol H,C

Branch

225

Tacticity

226

Graft Graft Stereoregularity Degradation Compostion

227 228 229 230 231

Tacticity Tacticity Composition Composition

232 233 234 235

Degradation

236

Composition

237

Composition, block

238

Composition

239

Sequence distribution End group graft

240 241 242

Configuration Stereoregularity End group Branch, graft Branch Composition Configuration Block Configuration Branch Composition

243 244 245 246 247 248 249 250 251 252 253

Branch, dendrimer Branch Branch Branch Branch Branch Branch Branch Branch End group Tacticity Graft Branch

254 255 256 257 258 259 260 261 262 263 264 265 266


c


Polyglycidol, poly(methylsilsequioxane-co-1,4bis(ethylsilsesquioxane)benzene) Polyimide-graft-poly(methacrylcyclopentyl silsesquioxane), poly[N,N 0 -(1,4-phenylene)3,3 0 ,4,4 0 -benzophenonetetracarboxylic amic acid] Polyisoprene Polylactic acid, polycaprolactone, starch/ polycaprolactone blend poly(butadiene adipate-co-terephthalate) Polylactide Polylactide Polylactide Polylactide-block-poly(glycolide-co-caprolactone) polylysine conjugate, glycopolyer Polymethacrylate

C

H,C H

H H

Polymethacrylate H,C Polymethacrylate Polymethacrylate-graft-poly(ethylene oxide) H,C Polymethylacrylate-graft-poly(ethylene-co-propylene) Polypentadiene Polypentadiene Polypentadiene Polypropylene Polypropylene C Polypropylene C Polypropylene H Polypropylene poly(ethylene-co-propylene) C Polypropylene, poly(1-butene), poly(1-pentene), C poly(1-hexene), poly(1-octene) Polysaccharides H Polysiloxane, siloxane copolymer O Polysilsesquioxane Polysilsesquioxane Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene Polystyrene, poly(iso-butyl vinyl ether), poly(methyl methacrylate), poly(acrylonitrile), poly(a-methylstyrene), poly(vinyl acetate) Polystyrene-block-poly (propylene glycol) Polystyrene-block-poly(butadiene)-block-polystyrene Polystyrene-block-poly(butadiene)-block-polystyrene poly(butadiene-co-styrene) Polystyrene-block-poly(butyl acrylate) Polystyrene-block-poly(ethylene oxide) Polystyrene-block-poly[methyl(3,3,3trifluoropropyl)siloxane]

C, F, Si C,F,Si H H H H,C C H H C H H

C C H H

Branch

267

Composition

268

End group Degradation

269 270

Conformation 271 Composition, 272 configuration Molecular weight 273 Composition 274 Composition 275 Molecular weight, end 276 group Branch 277 Tacticity, stereoregularity278 Graft 279 Graft, branch 280 Tacticity 281 Tacticity, configuration 282 Tacticity, configuration 283 Tacticity 284 Degradation 285 Tacticity 286 End group 287 Composition 288 Tacticity 289 Composition Composition, molecular weight Composition Composition Composition, end group End group End group End group Tacticity Tacticity End group End group Tacticity End group End group End group End group, stereoregularity Composition Tacticity Composition, sequence distribution Molecular weight Composition Composition

290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306

307 308 309 310 311 312


c


Polystyrene-graft-poly(methyl methacrylate), polystyrene-graft-polystyrene Polystyrene-graft-polyurethane Polyurethane Polyurethane, polystyrene Polyurethane-graft-polystyrene Polyyne Surface-carboxylated polystyrene Urea-formadehyde resin Vinyl ester resin

H,C

Tacticity

313

H C H H

Graft, end group Branch Composition Composition, graft Regioregularity Composition Composition, branch End group

314 315 316 317 318 319 320 321

H C H

between the columnar and layered phases are observed in the low-frequency range.324 The NMR spectra simulation based on the Freedericksz and a nonFreedericksz twist geometry are presented and the factors affecting NMR spectra simulation are discussed for a lyotropic nematic polymer cell.325 For a liquid crystalline polymer containing an ester group in a mesogenic unit, the relaxed torsional potential has been calculated and the corresponding NMR chemical shifts are also calculated. The dihedral angles of the phenyl ring–ester and the ring–ring linkages are discussed.326

4. Imaging and diffusion Pulsed field gradient technique enable use to measure MRI and the self diffusion coefficient. These information is used not only for the medical purposes but also for chemical applications. Imaging techniques are used to characterize local permanent deformation in silicone parts which subject to high compressive strain. The results have been interpreted in the context of studies of model materials of varying crosslink density.327 The resistance properties to aggressive fluids is studied by MRI for polyurethane.328 For designing the water transport property in the polymer electrolyte fuel cells, MRI measurement and a one-dimensional model simulations are carried out. The resulting water distribution of the polymer electrolyte membrane under various operation conditions was consistent with MRI measurements.329 The degradation mechanism of poly(3-hydroxybutyrate-3hydroxyvalerate) is monitored by MRI. The results suggest that at early stages after immersing the scaffolds in the aqueous medium, NMR imaging could underestimate the porosity of the substrate.330 PFG NMR was used to study the change in the cavity sizes within the pore structure of the poly(D,L-lactide-co-glycolide) microspheres over time following initial immersion.331 NMR-MOUSE is used to determine the morphology of polyethylene pipes in the new state, after squeezing them flat and after annealing well below the Tg. An anomalous depths profile was observed by the NMR-MOUSE.332 Self-diffusion coefficients of poly((2,5-didodecyl-p-phenylene)ethynylene)333 and poly(b-benzyl L-aspartate)334 are measured by the PFG technique. Based on these data, the shape of polymers in the solution is discussed. The diffusion behavior of molecular probe such as poly(ethylene glycol)(PEG) gives information about the surrounding structure. The self-diffusion coefficients of PEG were measured in whey protein solutions335 and in casein suspensions.336 The dependence of the selfdiffusion coefficient on the concentration of protein and casein are interpreted based on the solution and gel structure. The self-diffusion anisotropy of n-paraffin in uniaxially compressed natural rubber with different crosslink density was observed. The anisotropy of diffusion of small penetrant molecules in elastomers could be used as the basis for NMR study of deformation of polymer networks by changes in the shape of the free volume.337 Salt dissociation conditions and dynamic properties of ionic species in liquid crystalline electrolytes of Li were studied by a combination of 318 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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NMR spectra and diffusion coefficient. Activation energies of diffusion of ionic species changed with the phase. The diffusion behavior is explained in terms of motional restriction and molecular orientation configuration.338 Ionic conductivity and the lithium self-diffusion coefficients were measured for the polymeric gel electrolytes based on a blend of poly(methyl methacrylate)/poly(vinylidene fluoride), ethylene carbonate/propylene carbonate (EC/PC) as plasticizer and lithium perchlorate as electrolyte. A maximum of lithium mobility is obtained for the composition of PMMA 60%-PVDF 40%.339 The self-diffusion coefficients of H2O and methanol were determined over a wide temperature range for the recast composite and bare Nafion membranes. The transport mechanism is influenced by the surface properties of the inorganic fillers.340 The self-diffusion of poly(carbosilane) dendrimer solutions in the high-concentration region was investigated by pulsed field gradient NMR techniques. A restriction of diffusion was observed for the concentration region of 50–95 wt% of dendrimer in tetrachloride solutions. This phenomenon has been explained by the formation of solutions at a thermodynamical nonequilibrium.341 The dynamics of water in poly(NIPAM) microgel dispersions is discussed. The dependence of molecular diffusion on the network density is established.342 A new MRI method to measure membrane gas phase diffusion coefficients is presented. The diffusion coefficients of both hydrogen gas and sulfur-hexafluoride in a model polymeric membrane of potential interest as a gas separator in metal hydride batteries are measured.343 The diffusion of water into solid poly(ditetrahydrofurfuryl itaconate) films was measured. A Fickian mechanism is observed for the initial stages of uptake, while a non-Fickian mechanism is present when the equilibrium is approached.344 Magnetic resonance imaging was used to study the diffusion of a water solution of HCl and NaOH into hydroxypropyl Me cellulose matrixes. The data showed the effects of the pH solvent and of the molecular mass of the polymer on the swelling process, spin–spin relaxation time, and diffusion of solvent molecules into hydroxypropyl methyle cellulose matrixes.345 A lot of contrast agents for MRI were developed.346–364

5. Characterization of the synthetic macromolecules Physisorbed cyanopropyl-methyl-phenyl-methyl-siloxane polymer on a SiO2 surface was characterized by 1- and 2-dimensional(2D) solid state NMR techniques including heteronuclear proton-Si correlation spectroscopy. Spin–lattice relaxations of protons of the siloxane polymer exhibited only small changes upon anchoring to the SiO2 surface indicating somewhat altered molecular dynamics of proton moieties that contribute to the relaxation process. However, the same relaxation rates of the siloxane polymer’s SiO2 atoms were reduced due to restricted mobility of the polymer. Proton-Si heteronuclear correlation spectroscopy (HETCOR) revealed strong correlations of silanol protons with both Q3 and Q4 sites of the SiO2 surface. A correlation between methyl protons and the Q3 site of the SiO2 surface was observed when HETCOR experiments with very small mixing time (5 ms) were performed. The presence of these correlations is indicative of the coherent magnetization transfer mainly through dipolar mechanisms. Since magnetization transfer through the dipolar mechanism is 1/r3 dependent, methyl protons must lie in close proximity to the SiO2 surface. Hydrogen bonding of the SiO2 surface’s hydroxyl protons with the bridging oxygen of the siloxane polymer is most likely responsible for positioning the methyl protons closer to the surface. Additional correlations between 29Si nuclei and methylene protons next to cyano group was also observed with mixing time indicating the closer proximity of these protons to the SiO2 surface as well. This juxtaposition of methylene protons is most likely due to hydrogen bonding of the siloxane polymer through the cyano moiety. Also, the hydrogen bonding through the cyano group is most likely to be in parallel orientation to the surface. Finally, the aromatic protons exhibited weak correlations only with Q3 sites, indicating that these protons must also lie in close proximity of the SiO2 surface.365 Nucl. Magn. Reson., 2007, 36, 309–343 | 319 This journal is

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Physical and gas transport properties of novel hyperbranched polyimide-silica hybrid membranes were investigated and compared with those of linear-type polyimide-silica hybrid membranes with similar chemical structures. Hyperbranched polyamic acid, as a precursor, was prepared by polycondensation of a triamine, 1,3,5-tris(4-aminophenoxy)benzene (TAPOB), and a dianhydride, 4,4 0 -(hexafluoroisopropylidene)diphthalic anhydride (6FDA). 6FDA-TAPOB hyperbranched polyimide-silica hybrids were prepared using the polyamic acid, water, and tetramethoxysilane (TMOS) by sol-gel reaction. 5% weight-loss temperature of the 6FDA-TAPOB hyperbranched polyimide-silica hybrids determined by TG-DTA measurement considerably increased with increasing silica content, indicating effective crosslinking at polymer-silica interface. CO2, O2, N2, and CH4 permeability coeffs. of the 6FDA-based polyimide-silica hybrids increased with increasing silica content. In addn., CO2/CH4 selectivity of the 6FDA-TAPOB-silica hybrids remarkably increased with increasing silica content. From 129Xe NMR analysis, characteristic distribution and interconnectivity of cavities created around polymersilica interface were suggested in the 6FDA-TAPOB-silica hybrids. It was indicated that size-selective separation ability is effectively brought by the incorporation of silica for the 6FDA-TAPOB hyperbranched polyimide-silica hybrid membranes.366 In order to illustrate the capacity of NMR to monitor compression-induced changes in the morphology of nanocomposites, solid-state NMR results were directly contrasted with optical microscopy. Increases in the interfacial area of Laponite clay in cis 1,4-polyisoprene composites were monitored during uniaxial compression. Interaction of the Co+2 in the clay galleries with the polymer decreases the polymer’s 1 H spin–lattice relaxation time const. (T1). The composite showed a decrease in T1 time const. with increasing compressive strain. This behaviour is consistent with an increase in interfacial area of the aggregate as it breaks apart. Increases in interfacial area of the aggregate were confirmed with optical micrographs.367 The chemical microstructure of poly(butylene terephthalate) (PBT) copolymers obtained by incorporation of a rigid diol, 2,2-bis[4-(2-hydroxyethoxy)phenyl]propane (Dianol 220), into PBT using solid-state polymerization (SSP) and melt polymerization (MP) was analyzed. 13C NMR sequence distribution analysis showed that Dianol was randomly incorporated in the PBT-Dianol copolymers obtained by MP. However, the used 13C NMR sequence distribution analysis method was based on solution NMR. As a consequence, the obtained chemical microstructure reflects both the crystalline and amorphous part. For PBT-Dianol copolymers obtained by SSP, the modification only took place in the amorphous phase of PBT. Hence, knowledge of the chemical microstructure of the amorphous phase is important for tailoring the final properties of these copolymers obtained by SSP. Therefore, a calculation method was developed to adjust the solution 13C NMR peak integral values of the dyad sequences in such a way that only the amorphous fraction, which participates in the transesterification process, was taken into consideration for calculating the degree of randomness. The semicrystalline PBT-Dianol copolymers as obtained by SSP were initially represented by the often-used two-phase (crystalline/amorphous) model. The resulting chemical microstructure of the amorphous phase gave a strong indication that part of the amorphous phase was not accessible for incorporation of Dianol by SSP. Therefore, a three-phase (crystalline, rigid amorphous and mobile amorphous) model was used to represent the morphology of the PBT-Dianol copolymers. Crystalline, mobile amorphous, and rigid amorphous fractions were determined by DSC. Using this three-phase model, the calculation method showed that only the mobile amorphous fraction was accessible for incorporation of Dianol by SSP. At the used solid-state polymerization temperature of 180 1C, the PBT chains in the rigid amorphous and crystallne phase are not mobile enough to participate in the transesterification reaction. Furthermore, determination of the chemical microstructure of the mobile amorphous fraction showed that Dianol was fully randomly incorporated in this fraction.368 The torsion angles of the OC–CO bonds in crystalline poly(ethylene oxide), PEO, were 320 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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investigated by solid-state NMR. Two-dimensional double-quantum (DOQSY) spectra indicate that the OC–CO bonds are all gauche with an average torsion angle of w = 74 41 and a narrow torsion-angle distribution, rw o 81. This is contradictory to the wider range of gauche torsion angles in the distorted helical structure previously proposed based on X-ray fiber diffraction. The low-temperature magic-angle-spinning (MAS) 13C NMR spectrum of unlabeled PEO contains four maxima and several shoulders, over a range of 3.1 ppm. Deconvolution of this spectrum, together with two-dimensional 13C INADEQUATE NMR and exchange MAS spectra, suggests a possible assignment of chemical shifts to the 14 carbons in the 72 helical repeat unit. The small line widths of the individual peaks indicate that the helical repeat unit is accurately replicated throughout the crystals. The results show that packing effects or small conformational differences can change chemical shifts by amounts that had previously been ascribed only to trans/gauche differences.369 The reversible protonation of C single-walled nanotubes (SWNTs) in H2SO4 and Nafion was studied using solid-state NMR and Raman spectroscopies. MAS was used to obtain high-resolution 13C and 1H–13C CP NMR spectra. The 13C NMR chemical shifts are reported for bulk SWNTs, H2SO4-treated SWNTs, SWNT-Nafion polymer composites, SWNT-AQ55 polymer composites, and SWNTs in contact with H2O. Protonation occurs without irreversible oxidation of the nanotube substrate via a charge-transfer process. This is the first report of a chemical induced change in a SWNT 13C resonance brought about by a reversible interaction with an acidic proton, providing additional evidence that C nanotubes behave as weak bases. Cross polarization is a powerful technique for providing an additional contrast mechanism for studying nanotubes in contact with other chemical species. The CP studies confirmed polarization transfer from nearby protons to nanotube C atoms. The CP technique was also applied to study H2O adsorbed on C nanotube surfaces. The degree of bundling of the SWNTs in Nafion films was probed with the 1H–13C CP/MAS technique.370 DSC and 13C NMR observations of bulk, zeolite-evaporated, and zeolite-adsorbed polyethylene (PE) and isotactic polypropylene (iPP) samples clearly point to significant inclusion of the adsorbed polyolefins in the internal nanopores of zeolites (SH-300 and CBV-780). The zeolites were packed in LC columns and repeatedly injected with PE/decalin and iPP/diphenyl ether solutions maintained at 140 1C. DSC scans show an absence of melting endotherms for both PE and iPP when adsorbed by these zeolites packed in LC columns, which are, however, evident in their bulk and evaporated control samples. This supports the view that the adsorbed polymers were separated by penetration and inclusion and are absorbed in the narrow zeolite pores and therefore are unable to aggregate and crystallize, as would be possible if they were simply adsorbed on the zeolite surfaces.371 The first detailed study of polyaniline (PANI) and reduced PANI (R-PANI) before and after reaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) by using solid-state 13C CP/MAS, NQS (nonquaternary suppressed) and CPPI (cross-polarization phase inversion) NMR techniques is reported. These techniques reveal relatively subtle structural changes that occur upon reaction with DPPH free radicals and confirm the radical scavenging ability of PANI. The integrated intensity of the PANI CP MAS spectrum after reaction with DPPH is about 8% larger than that of PANI and this cannot be explained by an oxidation process alone. The increase is attributed to a decrease in the polaron concentration in the polymer, which is consistent with ESR (EPR) data that show a decrease of the EPR signal intensity after reaction of chemical synthesized PANI with DPPH.372 A quantitative study of local segmental order in vulcanized natural and butadiene rubber far above the glass transition is reported. Network chain order is dependent on the density of cross-links and is here derived from proton homonuclear residual dipolar couplings measured by static multiplequantum NMR spectroscopy at low field. On the basis of a reasonable model of local chain structure and fast, uniaxially symmetrical local motions, spin dynamics simulations are used to investigate the relationship between the experimental Nucl. Magn. Reson., 2007, 36, 309–343 | 321 This journal is

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determined residual coupling and the order parameter of the polymer backbone. The model is verified by site-resolved determinations of inter- and intraresonance residual couplings at high field. For both types of rubber, it is found that the distributions of the chain order parameter are rather narrow and in all cases well explained by the local coupling topology, thus excluding distributions of end-to-end separations or network chains lengths as important sources of broadening. This suggests that the NMR-detected order phenomenon cannot simply be captured with single-chain concepts. For natural rubber and poly(dimethylsiloxane), the relationship of the cross-link densities derived from the NMR-determined order parameter and from Flory-Rehner swelling experiments is linear as expected, yet the prefactors differ from the prediction by factors of 2 in different directions. The implications and the validity of the various models and approximations used for data analysis in light of recent results from computer simulations are discussed.373 The low molecular weight samples were examined to assign the NMR signals, and to study the cyclic structure and the end group structure for poly[perfluoro(4-vinyloxyl-1-butene)]. While the penta-cyclic structure was dominant, the hexa-cyclic structure also existed. The ratio was penta/hexa = 0.84/0.16. No preference of cyclic structure (penta- or hexa-cyclic) changed from the initial to the final stage of polymerization. The polymerization temperature did not affect to the ratio of cyclic structures, whereas the modification at side chain part could. The end group was observed, (CH3)2CHOCOO– for initiator end, –CF2Cl for chain transfer end, then only initiator end group changed to –CF3 with fluorination.374 A certain portion of spatially restricted bound water (HDO) was established for concentrated poly(vinyl methyl ether) PVME/D2O solutions at temperature above the LCST transition from the measurements of 1 H NMR spectra and 1H spin–spin relaxation times T2 of HDO. The fast and slow exchange regime between bound and free water was revealed for polymer concentrations c = 2–10 wt% and c = 20–60 wt%, respectively. For the latter case, the residence time of bound HDO t c 2.7 ms and relatively weak hydrogen bonding follow from the position of the sep. NMR signal of bound HDO. For polymer concns. c = 20–60 wt%, the spin–spin relaxation time T2 of bound HDO and the molar ratio [PVME monomeric unit]/[bound D2O] remain virtually constant and equal to T2 = 40 ms and [PVME]/[bound D2O] = 2.7 on average, thus indicating a direct connection of the fraction of bound water with the conformational structure of phase-separated PVME.375 The mechanism of the crosslinking reaction occurring between an non-linear optic chromophore copolymerized with a glycidyl epoxide unit (polymer PIII) was studied using MAS NMR spectroscopy. A first study conducted on a system composed of a model chromophore and a simple epoxy molecule evaluated the NMR changes that accompany the epoxy ring opening. Further, the use of a guest-host system made of an azo chromophore dispersed in a methyl methacrylate (MMA)-glycidyl methacrylate (GMA) copolymer matrix indicated a quantitative yield of the carboxyl/epoxy anchorage reaction after 30 min of heating at 1401. A 13C CP/MAS NMR spectroscopic study showed unambiguously that the crosslinking reaction in polymer PIII is due to a nucleophilic opening of the epoxy rings by the carboxylic groups of the chromophores resulting in carboxylic ester bond formation. The blue shift of the ca. 500 nm absorption band was modeled with a computational study. The esterification of the acid carboxylic group of the chromophore causes the torsion of the azo molecule.376 The orientational distribution function for polymer chain segments in plain-strain compressed glassy PMMA was evaluated, as a function of two polar angles, from a series of one-dimensional deuterium NMR spectra. The experimental data were analyzed using a tailored regulatory approach. For low degrees of orientational order, the choice of the regularization scheme becomes critical and two-dimensional Tikhonov-Phillips regularization yielded the best results.377 Poly[ethylene-co-(butyl acrylate)-co-(carbon monoxide)] (polyEBC) samples, prepared from 13C-labeled carbon monoxide, were characterized using 2D pulsed field gradient (PFG) 750 MHz NMR spectroscopy. To elucidate the complex mixture of structures present in 322 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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this terpolymer, 2D 1H/13C-heteronuclear multiple bond correlation (HMBC) experiments were conducted by selectively exciting the enhanced peaks resulting from 13C-labeling. High resolution 2D NMR combined with 13C-labeling of the polymer greatly simplifies the 2D NMR spectra, selectively enhances the weak peaks from low occurrence C-centered triad structures and aids in their resonance assignments.378 The microstructure analysis of poly(vinylidene chloride-co-vinyl acetate) was done using chemical shift modeling and 2D NMR spectroscopy. Chemical shift modeling was applied to analyze the compositional sensitive resonances of quaternary carbon of vinylidene chloride unit. Reactivity ratios determination was done from the diad and triad fractions. To resolve the complex 1H and 13C {1H} NMR spectra of copolymers, 2D 1H/13C hetero-nuclear single quantum coherence (HSQC), 1H /1H total correlation spectroscopy (TOCSY) and hetero-nuclear multiple bond correlation (HMBC) experiments were conducted. The combination of 2D NMR experiments supported by chemical shift modeling enabled to assign the complex and overlapping proton and carbon-13 resonances unambiguously.379 The preparation and characterization of interpenetrating polymer networks (IPNs) composed of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAAc) formed by a sequential method are reported. Interpolymer interactions were examined using 13C CP/MAS NMR and DSC methods. Evidence on the formation of a PVA–PAAc complex through hydrogen bonds between the hydroxyl groups of the PVA chains and the carbonyl group of the PAAc chains was obtained. The existence of polymer interactions between PVA and PAAc and its effect on the molecular motion of polymer chains, was further investigated by means of the analysis of the 13C spin– lattice relaxation times in the rotating frame, TC 1r. To elucidate the scale of the mixing in the PVA/PAAc IPNs, proton spin–lattice relaxation times in the rotating frame, TH 1r, were also investigated. The analysis of the results reveals the compatibility between the PVA and the PAAc polymer networks at low PVA concentrations and the occurrence of phase separation at relatively high PVA concentrations.380 Solution 17O NMR spectroscopy was used for structure elucidation of siloxane copolymers with the natural abundance of 17O, i.e. without any enrichment prior to spectroscopy. Homo, co, and terpolymers, as well as linear chains, cyclic oligomers, and graft polymers were investigated. All relevant chemical shifts and corresponding linewidths were reported for siloxane polymers substituted with methyl, phenyl, 3-cyanopropyl, 2-cyanoethyl, 3,3,3-trifluoropropyl, and polyethylene glycol ligands and with the backbone stiffening groups tetramethyl-p-silphenylene, tetramethylp,p 0 -sildiphenylene ether, and m-carborane. An increment system was extended to predict the chemical shifts of substituted siloxane copolymers. 17O NMR spectroscopy of polysiloxanes provided information concerning their chemical composition, average molecular weight, and microstructure.381 The structure of amorphous poly(carbonsuboxide) (C3O2)x was studied by 13C solid-state NMR spectroscopy supported by IR spectroscopy and chemical analysis. Poly(carbonsuboxide) was obtained by polymerization of carbonsuboxide C3O2, which in turn was synthesized from malonic acid bis(trimethylsilyl ester). Two different 13C labeling schemes were applied to probe inter—and intramonomeric bonds in the polymer by dipolar solidstate NMR methods and also to allow quantitative 13C MAS NMR spectra. Four types of carbon environments can be distinguished in the NMR spectra. Doublequantum and triple-quantum 2D correlation experiments were used to assign the observed peaks using the through-space and through-bond dipolar coupling. In order to obtain distance constraints for the intermonomeric bonds, double-quantum constant-time experiments were performed. In these experiments an additional filter step was applied to suppress contributions from not directly bonded 13C, 13C spin pairs. The 13C NMR intensity, chemical shift, connectivity and distances gave constraints for both the polymerization mechanism and the short-range order of the polymer. The experimental results were complemented by bond lengths predicted by density functional theory methods for several previously suggested models. Based Nucl. Magn. Reson., 2007, 36, 309–343 | 323 This journal is

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on the evidence, models based on g-pyronic units can be unambiguously excluded and models based on a-pyronic units are supported.382 Composites of polyvinylene difluoride (PVdF) and single walled carbon nanotubes (SWNTs) produced by evaporation of suspensions of PVdF and SWNTs in acetone while being subjected to sonication are characterized. Variable temperature 19F NMR measurements show differences in the line widths of the PVdF/SWNT composite compared to the pristine polymer but no differences were observed in the spin–lattice relaxation time. Composites containing 6.7% SWNTs by weight showed a 30% increase in hardness and a resistivity of 3.38 O cm. Ferromagnetic resonance and magnetization measurements indicated the composites were ferromagnetic due to presence of iron nanoparticles used as catalysts in the synthesis of the carbon nanotubes.383 PFGNMR was used to study the chemical exchange of linear PHEMA having a range of molecular weights with water in DMSO containing varying quantities of water. The aim was to investigate the use of PFG-NMR to study chemical exchange between a polymer with exchangeable protons and a small fast diffusing molecular to provide insight into the conformation adopted by a polymer in solution. The experimental data were simulated closely for the two-site exchange case using the Bloch equations modified for chemical exchange and diffusion. The exchange rate could be used to detect changes in polymer conformation resulting from changes in the solvent. PHEMA of MW 10 000 showed significant time-dependent changes in exchange rate, resulting from preferential solvation of the OH sites by water, and subsequent conformational changes which altered accessibility of the OH sites to water. This behaviour was not observed for larger MW PHEMA, which adopted a stable conformation immediately. Large changes in the exchange rate were not reflected in changes to the hydrodynamic radius, suggesting that a minimal overall change in the chain dimensions occurred. DMSO was found to be a poor solvent for PHEMA, which adopts a compact conformation in DMSO. This work has demonstrated that PFG-NMR is a sensitive method for detecting subtle changes in polymer conformation in polymers with exchangeable protons.384 In cold-drawn, necked high-density polyethylene, solid-state NMR has identified a major fraction of chain segments intermediate to the ordered crystalline and the almost isotropic amorphous phases. This partially mobile and disordered all-trans fraction in the strain-hardened sample contains 38 6% of all chain segments in the bulk. Thus, it represents the second largest component in the system, ahead of the disordered gauche-containing or amorphous (17 4%) and the monoclinic crystalline (4 2%) phases. A series of one- and two-dimensional NMR experiments, several of which make use of an ‘‘inverse 13C T1 relaxation time filter’’ for selective observation of the intermediatecomponent signals, show the intermediate component (or components) to consist of all-trans chains with disordered packing. While the crystalline component has a standard deviation of the chain axis from the draw direction of 11, the intermediate components exhibit an approximately 81 spread of chain-axis orientations from the draw axis. The chains in the intermediate components undergo fast rotational motions around their axes, with motional amplitudes of ca. 201.385 Polydimethylsiloxane (PDMS) elastomers reinforced with fumed silica exhibit unusual strength characteristics that are necessary for their designed applications. The microscopic details of the surface interaction between the polymer and silica are not well characterized. 1H /29Si CP experiments are used to characterize cured and uncured samples of Dow Corning silastic 745. Changes to the cp dynamics upon curing are evident by the variation in peak intensities in the variable contact-time spectra of the two samples. Estimates of the CP relaxation parameters are reported for the cured sample. Additional information can be obtained by expanding the 1 H/29Si CP to a two-dimensional heteronuclear correlation experiment. Dramatic differences between the cured and uncured 1H /29Si HetCor spectra are observed that are not visible in the 1D spectra. These changes can be rationalized as a dehydration of the silica surface and an increased hardening of the polymer after the curing process. Furthermore, isolation of the NMR signal corresponding to nuclei at or 324 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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near the polymer-filler interface may be achieved in the 2D 1H/29Si HetCor spectrum.386 Methyl acrylate (A)/methyl methacrylate (B) copolymers of different compositions were synthesized in bulk at 50 1C and the compositions were determined from 1H NMR spectra. Reactivity ratios were optimized using the least square methodol. Compositional and configurational assignments were done using 2D Heteronuclear Single Quantum Correlation (HSQC) and Total Correlation Spectroscopy (TOCSY) experiments. Methylene proton and carbon resonances were assigned for compositional and configurational sensitivity at tetrad level. Carbon resonances of methine group of methyl acrylate were assigned for compositional sensitivity up to triad level with the help of 2D HSQC spectra. a-methyl group of methyl methacrylate was assigned up to triad level of compositional and configurational placements for carbon and proton resonances by 2D HSQC spectroscopy. A comprehensive two-dimensional heteronuclear multi bond correlation (HMBC) spectral analysis of methyl acrylate-methyl methacrylate copolymers is also reported. The methylene carbon and methine carbon resonances assigned from the 2D HSQC spectroscopy were established by analyzing the two and three bond order couplings with a-methyl protons, methylene protons, and methine protons. Quaternary carbon resonances of the B unit were assigned by investigating the two bond order couplings with a-methyl protons and methylene protons. Assignments of carbonyl carbon resonances based on the analysis of three bond couplings with a-methyl protons and methylene protons are reported. The analyses present comprehensive assignments of the carbonyl carbon resonances showing the critical contribution of 2D HMBC spectroscopy in the indirect analysis of carbon resonances.387,388 The monomer conversion dependence of the formation of the various types of defect structures in radical suspension polymerization of vinyl chloride was examined via both 1H and 13C NMR spectrometry. The rate coefficients for model propagation and intra- and intermolecular hydrogen abstraction reactions were obtained via high-level ab initio MO calculations. An enormous increase in the formation of both branched and internal unsaturated structures was observed at conversions above 85%, and this is mirrored by a sudden decrease in stability of the resulting PVC polymer. Above this threshold-conversion, the monomer is depleted from the polymer-rich phase, and the propagation rate is thus substantially reduced, thereby allowing the chain-transfer processes to compete more effectively. In contrast to the other defects, the chloroallylic end groups were found to decrease at high conversions. On the basis of the theoretical and experimental data obtained in this study, this decrease was attributed to copolymerization and abstraction reactions that are expected to be favored at high monomer conversions. Although a definitive explanation for this behavior is yet to be obtained, the involvement of transfer reactions of an intra- or intermolecular nature seems likely, and (in the latter case) these could lead to the presence of tertiary chlorine in these defects.389 Different polycarboxylate polymers (PCPs) have been characterized and their microstructure investigated by size exclusion chromatography, 1H and 13C NMR spectroscopy. These polymers are comb-like with a sodium polymethacrylate backbone (PMAANa) on which poly(ethylene oxide) (PEO) chains are randomly grafted as shown by 13C NMR measurements. Since they are mostly used as superplasticisers in cementeous applications, their behavior has been investigated at high pH in various salt solutions; average radii were determined at room temperature by static and dynamic light scattering and phase diagrams were determined as a function of temp. We tried to evaluate the influence of different parameters (ion valence, cations, anions, PCP molecular weight, PEO length and grafting degree). A few experiments on homopolymers (PEO and PMAANa) have been equally performed in order to better understand the behavior of PCPs in solution.390 The sequence distribution and the crystal structure of copolyesters synthesized from ethylene glycol, 1,3-propanediol, and di-methyl terephthalate with different molar volume ratios were studied. The triad sequence probabilities of ethylene/trimethylene terephthalate were characterized from the aromatic quaternary carbons by 13C NMR. The composition Nucl. Magn. Reson., 2007, 36, 309–343 | 325 This journal is

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of the copolyesters was determined from the aromatic quaternary carbons by 13C NMR, and the methylene protons by 1H NMR. Results show that 1,3-propanediol reacted faster with terephthalic acid in copolyester polymerization than ethylene glycol. The difference in monomer reactivity is significant in the polymerization. Although the constitutional units revealed a random distribution in the molecular chain by 13C NMR, crystallites formed across the full range of ethylene glycol/ 1,3-propanediol composition by use of DSC, a hot stage polarizing microscope, and a wide angle X-ray diffraction method. The WAXD deconvolution results show that the major constitutional repeating unit in the molecular chain dominates the crystal structure as a host crystal. The crystal structure was examined by a scanning electron microscope after a solvent etching. Photomicrographs show that the random distribution of the third constitutional unit in the molecular chain of copolyester significantly disturbs the host crystal formation and lamellar orientation.391 Unstabilized polypropylene (PP) films having selective 13C isotopic labeling were subjected to thermal aging at 50, 80, and 109 1C and to g-irradiation at 24 and 80 1C. The oxidized films were examined using solid-state 13C NMR spectroscopy. Dramatic differences were found in the type and distribution of oxidation products originating from the three carbon atom sites within the PP macromolecule (tertiary carbon, secondary carbon, and methyl side group). Most of the oxidation products that formed on the polymer chain originated through chem. reactions at the PP tertiary carbons. Under all of the aging conditions examined, tertiary peroxides (from the PP tertiary site) were the most abundant functional group produced. Also originating from the PP tertiary carbon were significant amounts of tertiary alcohols, together with several more minor products that included ‘‘chain-end’’ methyl ketones. No significant amount of peroxides or alcohols associated with the PP secondary carbon sites was detected. A substantial yield of carboxylate groups was identified (acids, esters, etc.). The majority of these originated from the PP secondary carbon site, from which other minor products also formed, including in-chain ketones. We found no measurable yield of oxidation products originating from reaction at the PP methyl group. Remarkably similar distributions of the major oxidation products were obtained for thermal aging at different temperatures, whereas the product distributions obtained for irradiation at the different temperatures exhibited significant differences. Time-dependent concentration plots have been obtained, which show the amounts of the various oxidation products originating at the different PP sites, as a function of the extent of material oxidation.392

6. Polymer blend of the synthetic macromolecules Blends of poly(trimethylene terephthalate)/bisphenol A polycarbonate (PTT/PC) with different compositions were prepared by melt blending. The effect of transesterification on the miscibility and phase behavior of the blends was studied using DSC, DMA, and 1H NMR. The DMA results revealed a two-phase system with partial miscibility. DSC thermograms of the first heating scan showed a crystallizable system in which addition of PC-phase reduces the degree of crystallinity. However, the cooling and also the second heating scans revealed the complete miscibility of all the blends. It was concluded that annealing at 300 1C (to remove thermal history of the blends) caused the constituents to undergo the transesterification reaction, which changes the blend to a miscible system. The miscibility is due to formation of block copolymers with different block lengths which also suppress the crystallization of the system. The degree of randomness and sequence lengths of the copolymers were determined to analyze the extent of transesterification reaction and structure of the system. It was observed that as the reaction progresses, the degree of randomness increases and the sequence length of the copolymers decreases. Moreover, both increase of reaction time and temperature increased the extent of reaction. The results of DSC and 1H NMR showed that a small amount of reaction is needed to change this system to a miscible blend.393 SEM, solid-state proton NMR 326 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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spectroscopy and static mechanical analysis have been performed in order to evaluate the compatibilizing action of random copolymers of polystyrene and polybutadiene and triblock copolymers of poly(styrene-butadiene-styrene) in incompatible polystyrene/polybutadiene (PS/PB) blends. Scanning electron microscopic examination of the cryofractured and etched surfaces showed high degree of compatibilizing action of the triblock copolymers as evidenced by the very sharp decrease of the domain size of the dispersed phase followed by an increase at higher concentrations. This is a clear indication of interfacial saturation. These results were in agreement with the theoretical predictions of Noolandi and Hong. The random copolymer was not effective in compatibilizing the system. Solid-state proton NMR experiments were performed on the un-compatibilized and compatibilized blends. The proton spin–lattice relaxation times in the laboratry frame, T1(H), and in the rotating frame, T1r(H), and spin–spin relaxation times, T2(H), were carefully measured for the systems. Significant changes were observed for the systems compatibilized with triblock copolymers due to the preferential localization of the copolymers at the PS/PB interface. However, the random copolymer did not have any compositional drift and is not an effective interface modifier in agreement with microscopy study. The static mech. properties of the blends have also been analyzed. The addition of triblock copolymers increased the mechanical properties of the blends. Attempts have been made to correlate the NMR results with the microstructure and mechanical properties of the blends.394 Deuterium solid echo line shapes were measured on deuterated poly(ethylene oxide) (d4PEO) in a blend with protonated poly(methyl methacrylate) to characterize chain dynamics of this component in the blend. Line shapes were observed as a function of temperature from 183–243 K and echo delay times from 10–100 ms on a blend containing 20% d4PEO. The line shapes and the associated relative intensities were quantitatively interpreted in terms of segmental motion and libration. The results of the interpretation are compared to an earlier study of deuterium spin–lattice relaxation times over the temperature range of 313–413 K. A combined interpretation of both sets of data is developed based on bimodal distribution of correlation times that are separated by about 2 orders of magnitude in time. The faster mode is 30% of the correlation function with a stretched exponent near one while the slower mode is characterized by an exponent of 0.5. The source of the bimodal character is not revealed by the line shape and relaxation data but is consistent with the presence of 2 glass transition temperatures in this miscible blend and anomalous translational diffusion of diethyl ether through the blend.395 The hydrogen bonding, miscibility, crystallization, and thermal stability of poly(3-hydroxybutyrate) (PHB)/4-tertbutylphenol (BOH) blends and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [P(3HB-3HHx)]/BOH blends were investigated by FTIR spectroscopy, solid-state 13 C-NMR, DSC, WAXD, and thermogravimetric analysis. The results of FTIR spectroscopy and solid-state 13C-NMR show that intermolecular hydrogen bonds existed between the two components in the blends and that the interaction was caused by the carbonyl groups in the amorphous phase of both polyesters and the hydroxyl groups of BOH. With increasing BOH content, the chain mobility of both the PHB and P(3HB-3HHx) components was improved. After the samples were quenched, the detected single glass-transition temperatures decreased with composition, indicating that both PHB/BOH and P(3HB-3HHx)/BOH were miscible blends in the melt. Moreover, as BOH content increased, the melting temperatures of PHB and P(3HB-3HHx) clearly decreased, which implied that their crystallization was suppressed by the addition of BOH. Although the crystallinity of PHB and P(3HB-3HHx) components decreased with increasing BOH content in the blends, their crystal structures were hardly affected after they were blended with BOH, which was further proven by WAXD results.396 Poly(n-propyl methacrylate) (PPMA) is miscible with poly(vinyl alcohol) (PVA) over the whole composition range as shown by the existence of a single glass transition temperature in each blend. The interaction between PPMA and PVA was Nucl. Magn. Reson., 2007, 36, 309–343 | 327 This journal is

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examined by FTIR spectroscopy and solid-state NMR spectroscopy. The interactions mainly involve the hydroxyl groups of PVA and the carbonyl groups of PPMA. The measurements of proton spin–lattice relaxation time reveal that PPMA and PVA do not mix intimately on a scale of 1–3 nm, but are miscible on a scale of 20–30 nm. A small negative interaction parameter value has been obtained by melting point depression measurement.397 Solid-state CODEX NMR experiments directly probe chain dynamics in pure polyisobutylene (PIB), head-to-head polypropylene (hhPP), and their binary blend. The conclusions we draw from the results of the CODEX experiments, which are conducted at 210–300 K and which probe frequencies of 5–10 Hz, indicate that the overall chain dynamics of the blend system exceeds that of the two unmixed polymers. This is in agreement with our previous work on miscible PIB/polyethylene-co-butene blends [Macromols., 2003, 36, 4844–4850], in which configurational entropy was shown to increase for miscible polyolefins. The CODEX experiments on PIB/hhPP, which offer the advantage of direct and simultaneous observation of both chains in the blend, show that conformational reorientation in hhPP increases significantly upon blending with PIB, while PIB chain dynamics are relatively unchanged. Rotating frame spin–lattice relaxation experiments support this conclusion. The benefits of direct chain observation of both polymer blend components at mech. relevant frequencies (hertz) are compounded by the lack of any isotopic labeling requirements. These results on PIB/hhPP further support an entropically driven miscibility as a general phenomenon in nonpolar polyolefins.398 Low-density polyethylene (LDPE) and isotactic polypropylene (PP) and their blends with compositions 90/10, 70/30, 50/50, 30/70 and 10/90 wt % were studied by means of mech. and NMR methods. The three types of tapes were prepared: undrawn, drawn up to complete neck development and ultimately drawn up to break. The macroscopic properties characterized by tensile modulus, ultimate strength and drawability as well as phase structure and macromolecular orientation were studied by these methods. It was found out that properties of studied materials vary with composition and with degree of drawing. Quantitative relations were found out between macroscopic properties obtained from mechanical measurement and parameters characterizing phase structure and macromolecular orientation obtained from NMR measurements.399 Molecular dynamics simulations of model miscible polymer blends consisting of 1,4-polybutadiene (PBD) (slow component) and PBD chains with reduced or eliminated dihedral barriers (fast component) were performed in order to study the influence of blending on segmental relaxation processes in the fast component. We find that blending with a slow (high glass transition temperature, or Tg) component significantly increases the separation between the a- and b-relaxations of the fast (low Tg) component, which may be unresolvable or nearly unresolvable in the pure melt. The a-relaxation of the fast component is strongly influenced by blending, moving to longer relaxation times with increasing concentration of the slow component. In contrast, the relaxation time of the b-process of the fast component is only weakly influenced by blending. We speculate that this separation of relaxations processes in the fast component with blending can explain segmental relaxation behavior observed in dielectric and NMR relaxation studies of miscible polymer blends with disparate component dynamics.400

7. Dynamics of the synthetic macromolecules Molecular dynamics of a series of poly(ethylene 2,6-naphthalate)-polycarbonate blends with changing weight ratio of copolymers are examined by off-resonance NMR technique. It was shown that this technique provides information about the correlation times of the internal motions. The spectral density function amplitudes were estimated on the basis of the dispersion of the spin–lattice relaxation time offresonance Toff 1r . The measurements were performed for two series of blends which had been injection molded with and without compatibilizer. The new polymer 328 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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materials were also characterized using differential scanning calorimetry. Samples obtained after injection molding and annealing became amorphous, which indicates that a reaction of transesterification process between the two polymers occurred.401 Although molecular mobility is usually probed by measurement of the T1 relaxation time, it is not the case for methylene groups of grafted acyl chains because each methylene group has a different mobility and hence, a different T1 relaxation time depending on the distance from the junction between organic molecule and nonorganic particle. Silica-supported poly(octadecyl acrylate) (Sil-ODAn), polymeric octadecylsilyl silica (polymeric ODS), and monomeric octadecylsilyl silica (monomeric ODS) were studied by comparing the intensity of NMR peaks from grafted molecules with the same amount of nongrafted molecules. In the case of Sil-ODAn, with a gradual increase in temperature, the intensity of the proton signals (1H NMR) of the octadecyl moieties (mainly methylene groups) rose dramatically. This dramatic rise was at the same temperature as that of an endothermic peak detectable in its DSC thermogram, indicating a relatively complete solid to liquid phase transition. Sil-ODAn, as the stationary phase in RP-HPLC, showed analogous temperature dependencies of the separation factor between naphthacene and triphenylene (as a simple indicator of shape selectivity). Using this method, the liquid phase percentage (LPP) was determined in Sil-ODAn, polymeric ODS, and monomeric ODS at various temperatures. The LPP as a semiquantitative index of mobility for grafted organic layers.402 The dynamics of solvent inside swelling microgel particles is studied using 1H NMR. Solvent relaxation is sensitive to the microgel volume transition after temperature changes, showing the effect of the local environmental conditions on solvent confinement. A microscopic view of the volume phase transition of microgel particles is then shown. NMR measurements indicate that solvent dynamics is controlled only by the swelling degree of the microgel particles. Along the volume phase transition, the collapse of the polymer network restricts the mobility of bound water defining the confinement state. The effect of the amount of microgel polymer on the solvent molecules mobility is also investigated. In the collapsed state, water molecules still exist inside the microgel particles, being strongly confined within the polymer network. Despite that there are not many bound molecules under this circumstance, they contribute so strongly to the total averaged relaxation time that the behavior is controlled by the presence of those. On the other hand, the solvent moleciles were found to be weakly constrained for swollen microgels.403 2H NMR relaxation time measurements were used to study the segmental dynamics of polystyrene chains in six miscible polymer blends in the limit of low PS concentration. These data are combined with previously reported results for the segmental dynamics of dilute PS chains in four solvents. PS dynamics in these 10 hosts are strongly correlated with the glass transition temperature Tg of the host, but the dilute chain dynamics are not slaved to the host matrix dynamics. The Lodge-McLeish model, using a single value for the self-concentration jself = 0.35, reasonably describes PS segmental dynamics in all 10 hosts and also describes previously reported dynamics of dilute polyisoprene chains in four miscible blends. The dilute PS segmental dynamics can be more accurately described if jself is allowed to depend on blending partner, with the resulting variation of jself from 0.14 to 0.48.404 Pulsed-gradient spin-echo NMR experiments on zinc oxide filled polyethylene were carried out. The molecular weights of the polyethylene samples ranged between 808 and 33 000 g/mol, and four different zinc oxide samples were used: 27-, 33-, 51-, and 2500-nm-diameter particles. The results of these experiments showed that the diffusion coefficients of the polyethylene chains did not change with nanofiller content, but a drastic change is observed in the NMR relaxation spectrum in spin–spin-relaxation experiments. At fixed zinc oxide content and polyethylene molecular weight (close to entanglement), the system with the smallest zinc oxide showed the most rigid environment. At high polyethylene molecular weights, this effect was still observable but the difference between the three investigated systems was very small, suggesting that the system was dominated by entanglements.405 The Nucl. Magn. Reson., 2007, 36, 309–343 | 329 This journal is

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molecular dynamics of ethylene-norbornene copolymer was studied using NMR, broadband dielectric spectroscopy, and dynamic-mechanical thermal analysis methods. The data indicates three motion processes denoted as a, b, and g, in order of decreasing temperature. The a relaxation is related to the dynamic glass transition, while the b relaxation is assigned to short range segmental motions involving norbornene units. The g relaxation is due to local motions of ethylene units e.g. trans-gauche isomerization, similar to those responsible for g relaxation in polyethylene. The rate of motion accountable for the g process, follows the VogelFulcher-Tammann equation, similarly to the a transition, indicating cooperative nature of the motion.406 Segmental dynamics are measured in pure polyisobutylene (PIB), pure deuterium-labeled head-to-head poly(propylene) (hhPP), and a blend containing 70% PIB/30% hhPP by mass using 13C spin–lattice relaxation, 2H spin– lattice relaxation, and dielectric spectroscopy (DS). The NMR measurements are made between 313 K and 413 K (T1 measurements are sensitive to motions in the nanosecond range), while the DS measurements (which span the second to microsecond range) are made between 225 K and 325 K. While NMR and DS monitor local dynamics over a wide range of temperature and time, NMR has the additional advantage of being able to determine the local motion of each component in the blend through isotopic labeling. The spin–lattice relaxation data are interpreted using a modified Kohlrausch-Williams-Watts (KWW) correlation function with a Vogel-Fulcher-Tammann-Hesse (VFTH) temperature dependence of relaxation time, giving temperature-dependent segmental correlation times from NMR in the short time (high temperature) range that are compared to dielectric segmental correlation times at lower temperatures. Because of the small PIB dipole moment, DS on hhPP/PIB blends is dominated by the dynamics of hhPP. NMR measurements show very little shift in the component dynamics upon blending, but the shift becomes larger at lower temperatures. One factor in the variation of the separation between the dynamics of the two polymers with temperature is the unusual VFTH parameters for pure PIB, which signify its small fragility. The Lodge-McLeish model is unsuccessful in predicting the changes in component dynamics upon blending for hhPP, while it describes the temperature-dependent dynamics of PIB over the limited temperature range studied by NMR.407 The sidebands observed in the MAS NMR spectrum of a spin I = 1 2H nucleus may be very strongly broadened if motion is present in the solid. The broadening arises from interference between the line-narrowing effects of MAS and the dynamics-driven reorientation of the 2H quadrupole tensor. This motional broadening is absent or much reduced in the corresponding double-quantum MAS NMR spectrum. This observation suggests a new approach to studying dynamics in solids and examples are drawn from 2H MAS NMR of oxalic acid dihydrate, sodium tetrathionate dihydrate, and PMMA. Observation of a 2H single-quantum MAS linewidth that is broader than the double-quantum MAS linewidth may be taken as unambiguous evidence of the presence of dynamics on the ms timescale, while the narrow doublequantum linewidths are useful in themselves for obtaining increased resolution in the two-dimensional double-quantum MAS spectrum as in the PMMA spectrum.408 Polymer melts confined in micrometer thick layers were examined with the aid of field-cycling NMR relaxometry. It is shown that chain dynamics under such moderate confinement conditions are perceptibly different from those observed in the bulk material. This is considered to be a consequence of the corset effect, which predicts a crossover between Rouse and reptation like dynamics for molecular weights below the critical value at confinement length scales much larger than 10 RF, where RF is the Flory radius of the bulk polymer coil. For the polymer species studied, a perfluoropolyether with a molecular weight of 11 000, the Flory radius is of the order 10 nm, so that the experiment refers to the far end of the predicted crossover region from confined to bulk chain dynamics. Remarkably the confinement effect is shown to reach polymer-wall distances of the order 100 Flory radii.409 Proton mobilities in Nafion and sulfonated poly(ether ether ketone) (S-PEEK) have 330 | Nucl. Magn. Reson., 2007, 36, 309–343 This journal is

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been studied using high-resolution solid-state 1H NMR under fast MAS. These studies demonstrated proton exchange between sulfonic acid groups and water within both Nafion and S-PEEK. Variable temperature experiments were used to determine the activation energy for proton transport in pure Nafion, found to be 11.0 kJ/mol, which is lower than those determined for S-PEEKs with different degrees of sulfonation. Increasing proton exchange rates with increasing temperature indicate the expected dependence of proton mobility on temperature. A rotorsynchronized homonuclear double quantum filter sequence (BaBa) was used to disclose the nature of the H-bonding interactions in the two polymers, from which a model of the proton interactions in the polymers is developed.410 The segmental dynamics of bulk poly(methyl acrylate) (PMA) were studied as a function of mol. mass in the glass-transition region using 2H NMR and modulated differential scanning calorimetry (MDSC). Quadrupole-echo 2H NMR spectra were obtained for four samples of methyl-deuterated PMA-d3 with different molecular masses. The resulting spectra were fit using superpositions of simulated spectra generated from the MXQET simulation program, based on a model incorporating nearest-neighbor jumps from positions on the vertices of a truncated icosahedron (soccer-ball shape). The lower mol.-mass samples, influenced by the presence of more chain ends, showed more heterogeneity (broader distribution) and lower glass transitions than the higher molecular-mass samples. The MDSC experiments on both protonated and deuterated samples showed behavior consistent with the NMR results, but temperature shifted due to the different frequency range of the measurements in terms of both the position and breadth of the glass transition as a function of molecular mass.411 The local dynamics of aromatic cores was analyzed for a homologous series of polyamides in the solid phase incorporating phenyl, biphenyl and naphthyl groups. Preliminary wide-line and spin–relaxation variable-temperature 1H NMR measurements revealed the presence of thermally activated mol. motions for each polymer studied. A number of 13C NMR experiments were then implemented to further clarify the nature and extent of such motions. These included 1H–13C 2D separate-local-field measurements, whose line shapes revealed that motions involved for all cases a superposition of states. These could in principle be associated with rigid and mobile populations in these semi-crystalline aramides, a model that yielded a proper description of the spectra at all temperatures. To further probe this model the relaxation behavior of the aramides 0 13C spins was monitored in the rotating frame as a function of temperature, in both the presence and absence of homonuclear 1H–1H decoupling. The variations observed in these measurements evidenced a thermally activated, relatively broad distribution of motional rates in the polymers. Editing the 2D local-field data according to the 13C relaxation also supported this heterogeneous dynamic model.412 Some polybutadienes with different vinyl contents were observed by NMR methods in order to disclose the influence of the microstructure of the polymeric chains on the relaxation of the longitudinal and transverse magnetization. The relaxation process is correlated with the dynamic properties of the polymeric chains. The residual dipolar interaction determined by the rigidity of the polymeric chains is observed by the pseudo-solid echo method and is associated with the vinyl contents of the samples.413 Solid-state NMR methods were used to study molecular dynamics of MEH-PPV at different frequency ranges varying from 1 Hz to 100 MHz. The results showed that in the 213 to 323 K temperature range, the motion in the polymer backbone is predominantly slow (Hz–kHz) involving small angle librations, which occurs with a distribution of correlation times. In the side chain, two motional regimes were identified: Intermediate regime motion (1–50 kHz) for all chemical groups and, additional, fast rotation (E100 MHz) for the terminal CH3 group. A correlation between the motional parameters and the photoluminescent behaviors as a function of temperature was observed.414 Solid-state 2H NMR spectroscopy was used to examine the chain dynamics of perdeuterated poly (oxyethylene) (d-POE) inside a-cyclodextrin (a-CD) nanotubes. The nanotubes were Nucl. Magn. Reson., 2007, 36, 309–343 | 331 This journal is

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prepared by aqueous self-assembly of a-CD onto either low-molecular-weight (1.5 kg/mol) or high-molecular-weight (25.8 kg/mol) monodisperse d-POE. At a given temperature, POE chain segments exhibit faster dynamics when included inside the CD nanotubes as compared to the bulk. Even at 150 K, when no largeangle dynamics are detected in bulk POE, evidence for chain motions in the nanotube-confined POE is observed. The 2H line shapes representing this motion were modeled by a discrete 3-site jump using a In-Gaussian distribution of correlation times. An activation energy of 15 1 kJ/mol was determined and the motion envisioned as gauche defects propagating along the primarily trans chains included within CD nanotubes. As the nanotube length decreased, the jump angle became much less defined and more isotropic motions were observed for POE segments at elevated temperatures (4270 K).415

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388 A. S. Brar, G. Singh and R. Shankar, Journal of Applied Polymer Science, 2006, 99(5), 2174–2181. 389 J. Purmova, K. F. D. Pauwels, W. Van Zoelen, E. J. Vorenkamp, A. J. Schouten and M. L. Coote, Macromolecules, 2005, 38(15), 6352–6366. 390 P. Borget, L. Galmiche, J.-F. Le Meins and F. Lafuma, Colloids and Surfaces, A: Physicochemical and Engineering Aspects, 2005, 260(1–3), 173–182. 391 T.-W. Shyr, C.-M. Lo and S.-R. Ye, Polymer, 2005, 46(14), 5284–5298. 392 D.-M. Mowery, R. A. Assink, D. K. Derzon, S. B. Klamo, R. L. Clough and R. Bernstein, Macromolecules, 2005, 38(12), 5035–5046. 393 A. Yavari, A. Asadinezhad, S. H. Jafari, H. A. Khonakdar and F. H. Boehme, European Polymer Journal, 2005, 41(12), 2880–2886. 394 S. Joseph, F. Laupretre, C. Negrell and S. Thomas, Polymer, 2005, 46(22), 9385–9395. 395 H. Cao, G. Lin and A. A. Jones, Journal of Polymer Science, Part B: Polymer Physics, 2005, 43(18), 2433–2444. 396 C. Chen, P. H. F. Yu and M. K. Cheung, Journal of Applied Polymer Science, 2005, 98(2), 736–745. 397 J. Z. Yi and S. H. Goh, Polymer, 2005, 46(21), 9170–9175. 398 J. E. Wolak and J. L. White, Macromolecules, 2005, 38(25), 10466–10471. 399 J. Murin, J. Uhrin, L. Sevcovic, L. Horvath, I. Chodak and Z. Nogellova, Acta Physica Slovaca, 2005, 55(6), 577–587. 400 D. Bedrov and G. D. Smith, Macromolecules, 2005, 38(24), 10314–10319. 401 A. Wozniak-Braszak, M. Szostak, K. Jurga, J. Jurga, A. Piekarz and M. Baranowski, Applied Magnetic Resonance, 2005, 29(2), 221–229. 402 M. Derakhshan, H. R. Ansarian, M. M. Rahman, T. Sakurai, M. Takafuji and H. Ihara, Canadian Journal of Chemistry, 2005, 83(10), 1792–1798. 403 B. Sierra-Martin, M. S. Romero-Cano, T. Cosgrove, B. Vincent and A. FernandezBarbero, Colloids and Surfaces, A: Physicochemical and Engineering Aspects, 2005, 270–271, 296–300. 404 T. R. Lutz, Y. He and M. D. Ediger, Macromolecules, 2005, 38(23), 9826–9835. 405 R. Ozisik, J. Zheng, P. J. Dionne, C. R. Picu and E. D. Von Meerwall, Journal of Chemical Physics, 2005, 123(13), 134901/1–134901/8. 406 M. Makrocka-Rydzyk, B. Orozbaev, G. Nowaczyk, S. Glowinkowski and S. Jurga, Acta Physica Polonica, A, 2005, 108(2), 385–393. 407 E. Krygier, G. Lin, J. Mendes, G. Mukandela, D. Azar, A. A. Jones, J. A. Pathak, R. H. Colby, S. K. Kumar and G. Floudas, Macromolecules, 2005, 38(18), 7721–7729. 408 M. Cutajar, S. E. Ashbrook and S. Wimperis, Chemical Physics Letters, 2006, 423(4–6), 276–281. 409 R. Kausik, C. Mattea, N. Fatkullin and R. Kimmich, Journal of Chemical Physics, 2006, 124(11), 114903/1–114903/5. 410 G. Ye, N. Janzen and G. R. Goward, Macromolecules, 2006, 39(9), 3283–3290. 411 B. Metin and F. D. Blum, Journal of Chemical Physics, 2006, 124(5), 054908/1–054908/ 10. 412 D. McElheny, V. Frydman and L. Frydman, Solid State Nuclear Magnetic Resonance, 2006, 29(1–3), 132–141. 413 M. Todica, International Journal of Modern Physics B: Condensed Matter Physics, Statistical Physics, Applied Physics, 2005, 19(13), 2167–2174. 414 A. C. Bloise, E. R. de Azevedo, R. F. Cossiello, R. F. Bianchi, D. T. Balogh, R. M. Faria, T. D. Z. Atvars and T. J. Bonagamba, Physical Review B: Condensed Matter and Materials Physics, 2005, 71(17), 174202/1–174202/4. 415 T. E. Girardeau, J. Leisen and H. W. Beckham, Macromolecular Chemistry and Physics, 2005, 206(10), 998–1005.


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NMR in living systems Malcolm J. W. Prior DOI: 10.1039/b618327c

1

General applications and methodologies

1.1 Pulse sequences and spectral editing A fast proton spectroscopic imaging pulse sequence based on the condition of steady-state free precession has been developed. The method achieved 3D spatial and temporal resolution using simultaneous detection of one spatial and one spectral dimension using a time-dependent gradient cycle known from echo planar imaging. Additionally, in order to increase the spectral width of the measurement, an interleaved acquisition scheme was presented for use with either systems with limited gradient switching capabilities or applications with a wide chemical shift range. The pulse sequence was implemented on a standard 4.7 T animal imaging system with a total measurement time of less than 2.5 min and a nominal voxel size of 1.5 1.5 3 mm in phantoms and healthy rat brain in vivo.1 A new chemical shift imaging (CSI) data acquisition strategy and reconstruction algorithm is been developed that eliminates intervoxel signal leakage and intravoxel phase dispersion effects caused by magnetic field inhomogeneity. The approach is based on acquired CSI data, highresolution images, and magnetic field maps. The data are reconstructed based on the imaged object structure and a reconstruction matrix that takes into account the inhomogeneous field distribution inside anatomically homogeneous compartments. Results were presented from phantoms and from healthy volunteers.2 A threedimensional localized spectroscopic imaging sequence, optimized for the detection of glutamate resonances at moderate echo times, has been evaluated. Volume localization was achieved with reduced J-modulation losses of Glu. Using tissue segmentation and regression analysis, the concentration of Glu was found to be 8.8 2.1 mM in hippocampal and temporal grey matter and 3.7 1.1 mM in temporal white matter. The approach was used in a group of 5 patients with unilateral hippocampal epilepsy.3 Localised two-dimensional J-resolved spectroscopy has been optimised for the detection of J-coupled metabolites in vivo at 3 T. Maximum-echo sampling was employed to increase sensitivity and decreases overlap of peak tails, alleviating baseline problems. Reconstruction issues were discussed, and the sensitivity was compared analytically with that of 1D PRESS.4 A new single-voxel proton NMR spectrally-selective refocusing method for measuring Glu and Gln in the human brain at 3 T has been reported. Tripleresonance selective 180 degrees r.f. pulses with a bandwidth of 12 Hz were implemented within PRESS for selective detection of Glu or Gln. Simultaneous acquisition of signals from total creatine (tCr) was used as a reference for phase correction. The carriers of the spectrally-selective 180 degrees pulses and the echo times were optimized with both numerical and experimental analyses of the filtering performance to minimise contamination from N-acetyl aspartate containing compounds (NAA) and glutathione. The concentrations of Glu and Gln in the prefrontal cortex were estimated to be 9.7 0.5 and 3.0 0.7 mM, respectively, with reference to tCr at 8 mM.5 A new spectral editing strategy for the rapid measurement of myoinositol in single-voxel 1H NMR of human brain has been proposed. The method detects the 4.06 ppm, weakly coupled resonance by means of selective J rewinding. An 84.6 ms, quadruple-resonance selective 180 degrees radiofrequency pulse, implemented within an adiabatic-refocused localization sequence, induced an inphase triplet at 4.06 ppm. Contribution from tCr, phosphoethanolamine, lactate and Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, University Pary, Nottingham, UK NG7 2RD


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serine in this spectral region were eliminated. The myo-inositol (mI) concentration in human prefrontal cortex was estimated to be 5.7 0.9 mmol g 1 (mean SD, n = 7) with reference to NAA at 10 mmol g 1.6 A pulse sequence has been developed that accomplishes spatial localization of 1H-decoupled-13C NMR signals using optimized three-dimensional outer volume suppression with one-dimensional image-selected spectroscopy and surface coil detection. The localization performance of the sequence was validated at 4 T with double chambered phantoms and 13C MRI. Furthermore, localized 13C spectra were acquired from human brain and muscle.7 The use of localised 13C NMR without decoupling for the study of brain metabolism has been investigated at 9.4 T. The data were analysed using LCModel incorporating prior knowledge of J-coupling constants.8 An ultra short-echo-time STEAM pulse sequence with interleaved outer volume suppression has been redesigned and optimized for human applications at 4 and 7 T. The effects of first- and secondorder shimming, single-scan averaging, frequency and phase corrections, and eddy currents have been described. More than 15 metabolites were quantified using LCModel to analyse spectra from the human brain.9 An r.f. phase rotation technique has been produced for use in stimulated echo localization experiments. The technique allows removal of the crusher gradients during the echo time intervals (TE) leading to a reduction of the minimum TE to only 6 ms. Experiments carried out with a TE of 6 ms on six healthy volunteers in a 1.5 T whole-body NMR system showed significant increases in the concentrations of metabolite detected compared to concentrations measured with data collected using TE values of 15 and 20 ms: NAA increased 12%, tCr increased 15%, and the signal from Glu plus Gln (Glx) increased 92%.10 A constant time PRESS sequence has been implemented at 3 T and optimized for the detection of the C4 resonance of Glu. By simulating the sequence using the full density matrix, the optimal number of chemical shift encoding steps to resolve the C4 peak of Glu was found. The sequence was tested on phantoms containing solutions of various brain metabolites and on healthy human volunteers. Besides Glu, other resonances detected in vivo were NAA, tCr, Cho, and mI. However, Gln resonances could not be resolved due to severe signal overlap from Glu and NAA.11 A new two-scan method for localized 1H NMR without water suppression has been developed. In one of the scans, two chemical shift selective 180 degrees pulses are applied prior to a standard localization sequence to invert all metabolite signals upfield and downfield from water. The difference spectrum records the metabolites whereas water and accompanying gradient induced artifacts are widely suppressed. Phantom measurements were used to test the feasibility of absolute quantification using water as an internal reference. Measurements using the technique in healthy rat brain yielded comparable spectrum quality compared to measurements made with water presaturation. The method does not require additional adjustments or sophisticated data post processing and scales favorably with increasing B0 field.12 A theoretical and experimental evaluation of existing broadband decoupling methods with respect to their utility for in vivo 1H–13C NMR spectroscopy has been presented. Simulations were based on a modified product operator formalism, while experimental evaluations were performed on samples in vitro and on human leg and rat brain in vivo. The performance of broadband decoupling methods was evaluated with respect to the required peak and average r.f. powers, decoupling bandwidth, decoupling side bands, heteronuclear scalar coupling constant, and sensitivity toward B2 inhomogeneity. In human applications, only the WALTZ and MLEV decoupling methods provide adequate decoupling performance at r.f. power levels that satisfy the F.D.A. guidelines on local tissue heating. At higher r.f. power levels, which may be acceptable for animal studies, additional decoupling techniques with superior performance become available. B2 inhomogeneity was found to degrade the decoupling performance of all methods, but the decoupling bandwidths for WALTZ-16, and especially adiabatic methods, were found to be satisfactory for useful in vivo decoupling with a surface coil.13 The effect of strong Nucl. Magn. Reson., 2007, 36, 344–362 | 345 This journal is

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homonuclear 1H coupling on measurements of 13C incorporation (into glutamate) by either indirect or direct means has been investigated at 3.0 T. The indirect 13C detection method incorporated proton observe carbon edited spectroscopy into PRESS (POCE-PRESS), and direct 13C detection utilised the DEPT sequence appended to PRESS (DEPT-PRESS). Analysis and experiments were used to show that, when strong homonuclear coupling of 1H is additional to heteronuclear coupling with 13C spins, the measurements of 13C incorporation using PRESSPOCE or PRESS-DEPT are significantly modified. Specifically, the lineshapes of 13 C-bonded and non-bonded 1H are changed by 13C-incorporation, giving rise, for example, to a potential cross-contamination of o30% between glutamate 13C3 and 13 C4 using the PRESS-POCE method. Using DEPT-PRESS, the DEPT enhancement is reduced for glutamate 13C2, 13C3, and 13C4, but not equally, and the reduction is further exacerbated by PRESS localization, which gives rise to enhancements that are strong functions of PRESS TE1 and TE2.14 A new dual suppression technique has been developed that uses the hyperbolic secant waveform as a 901 saturation pulse. Two hyperbolic secant pulses with opposite frequency offsets were employed, either sequentially or simultaneously, to saturate resonance frequencies corresponding to water and lipid while leaving the target spins untouched. The excitation bandwidth can be controlled by the frequency sweep and offset of each pulse, while varying the pulse length will control the transition bandwidth. Spectroscopic images of the human brain were obtained.15 A singleshot, proton-localized, polarization transfer 13C spectroscopic method has been implemented on a 4.7 T scanner. The polarization transfer sequence was mostly adiabatic and the r.f. pulses in the polarization transfer, in combination with field gradients, were used for voxel selection. The transferred 13C magnetization was refocused by additional refocusing adiabatic pulses. Following the intravenous infusion of D-[1-13C]glucose, 13C NMR spectra showing resonances from Glu, Gln, Asp, g-aminobutyric acid (GABA), NAA and lactate were observed. The time-resolved turnover of Glu, Gln and Asp from intravenously infused 13 D-[1- C]glucose at a temporal resolution of 12 min was demonstrated. Typically, the half-height linewidth of the decoupled 13C peaks was about 4 Hz. Data were also obtained using the polarization transfer method following an infusion of sodium [2-13C]acetate.16 The dispersion of T1 relaxation in the rotating frame (T1r) at B1 values from 620 to 160 500 rad s 1 has been quantified in the rat brain. Furthermore, the effects of ischaemia on T1r relaxation and the role of physico-chemical mechanisms underlying the relaxation changes have been investigated. A biphasic effect was observed on the dispersion of R1r (1/T1r) in ischaemic brain. When low B1 values (less than 5000 rad s 1) were used, an increase in R1r was detected, whilst in high B1 experiments R1r was reduced. This was accompanied by a change in the fitted values describing the dispersion characteristics. Injection of a superparamagnetic contrast agent, AMI-227, before ischaemia shifted the R1r curve upwards by 4%, but showed no effect on the shape of the R1r dispersion curve.17 The use of tissue water for quantitation of metabolites in 1H NMR spectroscopic imaging has been investigated and the potential errors that may arise have been examined. The sensitivity of the method to errors in estimates of the different water compartment relaxation times is shown to be small at short echo times. Data from healthy human subjects showed that different image segmentation approaches that are commonly used to account for partial volume effects (SIPM2, FSL’s FAST, and K-means) lead to different estimates of metabolite levels, particularly in grey matter, owing primarily to variability in the estimates of the cerebrospinal fluid fraction. A multi-spectral segmentation approach using FAST yielded the lowest intersubject variability in the estimates of grey matter metabolites. The mean grey matter levels of NAA, Cho and tCr using the method with FAST were 17.16 1.19 mM, 3.27 0.47 mM, 13.98 1.20 mM, respectively. Whereas, those for white matter were 14.26 1.38 mM, 2.65 0.25 mM and 7.10 0.67 mM, respectively.18


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1.2 Data analysis A review of methods for the analysis of metabolic fluxes, detected using 13C NMR in the brain, has been produced.19 A new time domain method for analysis for in vivo NMR data has been presented in which the circular trajectories that result when spectral peaks are projected onto the complex plane, are fitted with active circle models. The method allows incorporation of prior knowledge as constraint on energy terms. Using the method, problems of phasing spectra were eliminated and baseline artifacts were dealt with using active contours-snakes. The stability and accuracy of the new technique, CFIT, was compared with a standard time-domain fitting tool, using simulated 31P data with varying amounts of noise and 98 real human chest and heart 31P NMR data sets.20 The analysis of 31P NMR data to assess the thermodynamic status of living tissues has been reassessed. 31P NMR measurements in vitro and computer calculations have been used to assess the stoichiometric equilibrium constant of the creatine kinase reaction. The value was found to be logK(CK) = 8.00 0.07 at T = 310 K and ionic strength I = 0.25 M. The stoichiometric equilibrium constant of ATP hydrolysis has also been reassessed and the value was found to be logK(ATPhyd) = 12.45 at T = 310 K and ionic strength I = 0.25 M. Novel quantitative mathematical expressions of DG of ATP hydrolysis and of the apparent equilibrium constant of the creatine kinase reaction as a function of the concentration of phosphocreatine, pH and the concentration on Mg2+ were formulated for use on data obtained from human skeletal muscle.21 1.3 Methodologies A new experimental setup has been developed that allows strictly non-invasive NMR investigations of muscle function in contracting rat gastrocnemius muscle. The setup produces muscle contractions by transcutaneous stimulation whilst force measurements were made with a dedicated ergometer. Muscle function was investigated in 20 rats through a fatiguing stimulation protocol with the non-invasive setup and with a traditional setup used for in vivo studies. T2-weighted images demonstrated that transcutaneous stimulation activated mainly the gastrocnemius muscle. The changes in force development and in energy metabolism obtained with the non-invasive setup were qualitatively and quantitatively similar to those obtained with the traditional setup.22 1H NMR spectra have been obtained from the liver and heart of a live mouse while the animal was spun at a speed of 4 Hz in a 2 Tesla field using a technique called localized magic angle turning (LOCMAT). It was found that even in this relatively low field, this technique provided isotropic line widths that were a factor of 4–10 fold smaller than those obtained in a stationary animal.23 A new coil design for sensitivity-enhanced 13C NMR of the human brain is presented. The design includes a quadrature transmit/ receive head coil optimized for 13C sensitivity. Loss-less blocking circuits inside the coil conductors allowed the coil to be used inside a homogeneous, circularly polarized 1H B1 field for the acquisition of 1H decoupled 13C NMR spectra. Minimal local heating occurred making it possible to perform broadband 1H decoupling over the entire human brain. Furthermore, this quadrature coil combination facilitated efficient cross polarization; 13C spectra were obtained in vivo to demonstrate the coil set-up.24 A multinuclear spectroscopy and imaging probe, with animal handling capabilities, has been built for use in an 89 mm vertical bore 11.7 T magnet.25 1.4 Intracellular indicators, ions, pH and metabolites A review has been produced on the use of 13C NMR for metabolic studies, which includes in vivo applications of the method.26 The measurement of body temperature from the chemical shift of water has been reviewed.27 A review has been produced that discusses the problems with measurements of lactate in the human brain.28 The Nucl. Magn. Reson., 2007, 36, 344–362 | 347 This journal is

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use of in vivo multinuclear NMR approaches and advanced NMR methodologies has been reviewed. The review discusses NMR applications for determining cerebral metabolism as well as bioenergetics in the resting brain and the dynamic changes in response to brain activation.29 The use of hexamethyldisiloxane, a potential probe for investigating dynamic changes in the partial pressure of oxygen (pO2) in tissue, has been evaluated. Hexamethyldisiloxane has a single proton resonance with a spin-lattice relaxation rate that exhibits a linear dependence on pO2; R1 = 0.1126 + 0.0013 pO2 (torr) at 37 1C. Following administration of hexamethyldisiloxane into healthy rat thigh muscle and tumours, local pO2 was determined by using pulse-burst saturation recovery 1H NMR spectroscopy to assess R1; water and fat signals were effectively suppressed by frequency-selective excitation of the hexamethyldisiloxane resonance. Rat thigh muscle had a mean baseline pO2 of 35 11 torr, with a typical stability of 3 torr over 20 min, when the rats breathed air. Altering the inhaled gas to oxygen produced a significant increase in pO2 to 100–200 torr. In tumours, altering the inspired gas also produced significant changes.30 An investigation has been carried out into the variations in measurement of pH from 31P NMR data that are generated by different analysis techniques. 31P NMR brain spectra were acquired from eight healthy volunteers and three different methods were used to measure the chemical shift of Pi relative to PCr. These were: manual measurements, frequency domain analysis (NMR1) and a prior-knowledge-based time-domain technique (MRUI). To explain the in vivo data, simulations of brain spectra, modified in ways typical of real variations in vivo were produced and the pH was measured using manual measurement and MRUI. Different measurement techniques produced systematically different pH values. Manual measurements produced the lowest variability. Measurements using MRUI more accurately measured the pH of unaltered simulations, but was systematically affected by altering the simulated spectra; manual measurements were unaffected by these alterations.31 Ultrashort echotime STEAM and MEGA-PRESS-edited spectroscopy have been used to validate noninvasive quantification of vitamin C in the developing rat brain. Concentrations of vitamin C quantified from the STEAM spectra were in very good agreement with concentrations calculated from fully resolved vitamin C resonances in MEGA-PRESSedited spectra measured from identical volumes of interest. Despite strong overlap with resonances from Glu, Gln, glutathione and macromolecules, vitamin C was quantified by LC-Model analysis of STEAM. Concentrations of vitamin C measured using STEAM decreased with increasing postnatal rat age, in agreement with published concentrations of vitamin C in the brain measured in vitro using high-performance liquid chromatography.32 The sensitivity of 1H NMR for the detection of lactate during human brain functional experiments at 7 T has been investigated. Stability and reproducibility of the measurements were evaluated from LCModel analysis of time series of spectra measured during a visual stimulation paradigm and by examination of the difference between spectra obtained at rest and during activation. The sensitivity threshold to detect concentration changes was 0.2 mmol g 1 for most of the quantified metabolites. The possible variations of metabolite concentrations during visual stimulation were within the same range (0.2 mmol g 1). In addition, the influence of a small line-narrowing effect due to the blood oxygenation level-dependent changes of T2* on the estimated concentrations was simulated. This indicated that quantification of metabolites was, in general, not affected beyond 1% by line-width changes within 0.5 Hz.33

2

Cells

2.1 Bacteria The use of high resolution-magic angle spinning (HRMAS) NMR for the examination of bacterial cell walls of intact bacteria has been reviewed.39 A review of the use 348 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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of NMR to non-invasively monitor the dynamics of intracellular metabolites and co-factor pools following a glucose pulse in Lactococcus lactis has been produced. The article includes the use of this information to direct metabolic engineering strategies.40 HRMAS NMR has been applied to serogroup A Neisseria meningitidis (NMA) to determine precise structures of capsular polysaccharide expressed on the meningococcal surface. Both the O-acetylated (OAc) NMA parent and a mynC::ophA3 OAc- mutant demonstrated characteristic capsular polysaccharide-derived NMR signals indicating cell-surface expression of capsular polysaccharide, but only the parent expressed 03 and 04 acetylation signals. A capsule-defective strain showed no NMR signals for capsular polysaccharide. The 1H HRMAS NMR spectral patterns correlated with the purified capsular polysaccharide 1H NMR profiles. NMA were found to express 03 and 04 acetylated polymers but not in equimolar ratio amounts in vivo.41 Polyhydroxyalkanoic acid (PHA) inclusion bodies have been analyzed in situ by 13C NMR. The PHA inclusion bodies studied were composed of poly(3-hydroxybutyrate) or poly(3-hydroxybutyrate-co-4-hydroxybutyrate), which were accumulated in Hydrogenophaga pseudoflava, and mediumchain-length PHA, which was accumulated in Pseudomonas fluorescens BM07 from octanoic acid or 11-phenoxyundecanoic acid. Signals were quantify against sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The intracellular degradation of the PHA inclusions was analyzed in terms of first-order reaction kinetics. For the H. pseudoflava cells, the in vivo NMR kinetics analysis of the PHA degradation revealed a first-order degradation rate constant of 0.075 h 1 for the initial 24 h of degradation, which was close to the 0.050 h 1 determined when using a gas chromatographic analysis of chloroform extracts of sulfuric acid/methanol reaction mixtures of dried whole cells.42 2.2 Reproductive A combination of a high field magnet and a home-built microscopy probe with large gradient field strengths has been used to perform localised spectroscopy with voxel sizes of 180 mm3. The technique was applied to measurements in oocytes of the frog (Xenopus laevis). The voxels were small enough to allow the recording of the first compartment-selective in vivo spectra from the animal and vegetal cytoplasm as well as the nucleus. The two cytoplasmic regions differed in their lipid contents and NMR lineshape characteristics. In the nucleus, the signal appeared to be dominated by water, whereas other contributions were negligible. Localized spectroscopy was also used to monitor the uptake of diminazene acturate, an antitrypanosomal agent, into compartments of a single living oocyte. The resulting spectra from the nucleus revealed different uptake kinetics for the two components of the drug.43 2.3 Tumour 1

H NMR spectroscopic imaging has been used to investigate microscopic pH heterogeneity within tumor spheroids. High resolution microscopic images of intraspheroidal pH were obtained using chemical shift selective excitation of the H2 resonance of imidazole added to the incubation medium. Imidazole accumulated in the intraspheroidal space in a pH dependent manner. Maps of intraspheroidal pH revealed that spheroids were more acidic, by around 0.6 pH units, in the necrotic core than in the periphery for spheroids of 600 mm diameter. The presence of concentric regions having similar intraspheroidal pH was consistently observed.34 The metabolic changes that occur in MG-63 osteosarcoma small spheroids (about 50–80 mm in diameter with no hypoxic centre) exposed to 2 Gy of ionizing radiation, have been studied using 1H NMR. Whole MG-63 spheroids as well as the perchloric acid extracts of these systems were evaluated; cell damage was also examined by lactate dehydrogenase release and changes in cell growth. No cell damage was Nucl. Magn. Reson., 2007, 36, 344–362 | 349 This journal is

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observed, but metabolic changes took place in spheroids including significant increases in signals from CH2 and CH3 of mobile lipids. However, the chromatin dye Hoechst 33258 and DNA fragmentation assays showed no overt apoptosis up to 7 days after irradiation. Detailed analysis of the other metabolic changes observed suggested that the cell death program was initiated but not completed.35 Increases in lipid signals and, specifically, increases in the ratio of the lipid methylene/methyl peak intensities during apoptosis have been investigated following drug treatment in a murine lymphoma cell line (EL-4) and in vivo following implantation of these cells to form subcutaneous tumours. Fluorescence microscopy and flow cytometric measurements with a lipophilic dye revealed an accumulation of cytoplasmic lipid droplets in isolated EL-4 cells undergoing etoposide-induced apoptosis. 1H NMR and diffusion-weighted 1H NMR spectra showed an increase in lipid signals, but the methylene/methyl peak ratio showed only minimal changes. Localized in vivo spectroscopy of EL-4 tumours also showed an increase in lipid signals, including a signal from polyunsaturated lipid at 2.8 ppm, after 16–24 h of drug treatment. However, there was no significant change in the methylene/methyl peak ratio.36 1H NMR has been used to measure cellular metabolic profiles of subpopulations of murine mammary 4 T1 cells that differ in their metastatic potential. Subpopulations with differing metastatic phenotypes were identified by sorting for the expression of the cell surface adhesion oligosaccharide sialylated Lewis x (sLe(x)). The sLe(x)negative subpopulation metastasizes to the lung of syngeneic mice more rapidly than the sLe(x)-positive subpopulations. The metabolic profile of the sLe(x)-negative subpopulation indicated higher levels of lactate and total choline metabolites (Cho) than the sLe(x)-positive subpopulation, suggesting that altered metabolism is a critical component of the malignant phenotype. Analysis of shed cellular material from the sLe(x)-negative subpopulation displayed an increased ratio of phosphocholine to glycerophosphocholine when compared to the parental line and the sLe(x)-positive subpopulation.37 The time scale of uptake of fluorescent and nonfluorescent 19F-octaarginines has been monitored by 19F NMR in human Jurkat cells. A peptide concentration as low as 10 mM was detected with a time resolution of 1–2 min. The presence of the fluorophore, fluorescein isothiocyanate, induced different kinetics for the peptide uptake into the cells.38

2.4 Yeast and fungi The application of NMR to the study of Cryptococcus and cryptococcosis has been reviewed.44 The combined use of in vivo NMR experiments and mathematical modeling has been developed to analyze the metabolic response of Saccharomyces cerevisiae to ethanol stress. The model was developed to describe the modulation of the whole system induced by increasing concentrations of exogenous ethanol. This approach was able to interpret the experimental results in terms of metabolic response to exogenous ethanol in the yeast. The model was found to work correctly at different initial exogenous ethanol concentrations.45 The effect of anoxia and treatment with azide or cyanide on the polyphosphate content of Phycomyces has been studied by 31 P NMR. Anoxia caused a decrease in polyphosphates (PPi) and increase of intracellular Pi. Normalized changes in PPi/Pi ratio between control and nitrogenpurged mycelia indicated that the sensitivity to anoxia differed with growth phase. Treatment with azide caused a decrease in the PPi/Pi ratio, while cyanide causes an increase.46

3

Plants

A review of strategies for the measurement of metabolic fluxes in plants has been produced.47 350 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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Solid-state 13C NMR has been used to measure metabolite levels in intact soybean leaves labeled by [13C]CO2 at subambient concentrations. Excess glycine from the photorespiratory C-2 cycle (i.e. glycine not part of the production of glycerate in support of photosynthesis) is either fully decarboxylated or inserted as 13C-labeled glycyl residues in proteins. This incorporation of 13C in leaf protein, which is uniformly 15N-labeled by [15N]NH4 or [15]NO3, occurs as soon as 2 min after the start of [13C]CO2-labeling. In those leaves with lower levels of available nitrogen, the excess glycine was used primarily as glycyl residues in protein.48 13C HRMAS NMR has been used to profile a range of primary and secondary metabolites in intact whole seeds of eight different conifer species native to North America; six of the Pinaceae family and two of the Cupressaceae family. The total seed oil content and fatty acid composition of the major storage lipids was detected. In addition, a number of monoterpenes were identified. In imbibed conifer seeds, spectra showed the presence of considerable amounts of dissolved sucrose. The free amino acids Arg and Asn, generated as a result of storage protein mobilization, were detected during seed germination and early seedling growth.49 A 13C–31P rotational-echo doubleresonance (REDOR) measurement has been used to track the incorporation of 13 C-label into intermediates in the Calvin cycle as a function of time; the first direct assessment of the level of photorespiration in a functioning plant. For labeling times of 5 min or less, the isotopic enrichment of the Calvin cycle depended on the flux of labeled carbon from [13C]CO2 relative to the flux of unlabeled carbon from glycerate returned from the photorespiratory cycle. Comparisons of these two rates for a fixed value of the [13C]CO2 concentration indicated that the ratio of the rate of photosynthesis to the rate of photorespiration of ribulose-1,5-bisphosphate carboxylase/ oxygenase (RuBisCo) in soybean leaves is 5.7. The ratio of rates is reduced at low external CO2 concentrations when measured by net carbon assimilation rates. The carbon assimilation was determined from 13C-label spin counts converted into total carbon by the REDOR-determined isotopic enrichments of the Calvin cycle. The net carbon assimilation rates indicate that the rate of decarboxylation of glycine is not directly proportional to the oxygenase activity of RuBisCo as is commonly assumed.50

4

Tissues

4.1 Brain The cerebral metabolic rate of glucose (CMRglc) and the tricarboxylic acid (TCA) cycle flux (VTCA) have been measured simultaneously in monkeys using [18F]fluorodeoxyglucose positron emission tomography (PET) and 13C NMR spectroscopy, respectively. Registration of NMR and PET data were used for comparison of CMRglc and VTCA in the same area of the brain. Both fluxes were in good agreement with literature values; CMRglc = 0.23 0.03 mmol g 1 min 1, VTCA = 0.53 + 0.13 mmol g 1 min 1. The ratio of CMRglc/VTCA was 0.46 0.12.51 13C NMR in vivo magnetization transfer has been used to investigate the reactions for the conversion of Glu to a-ketoglutarate and the conversion of oxaloacetate and aspartate in the rat brain following an i.v. infusion of [1,6-13C2]glucose. By saturating the carbonyl carbon of a-ketoglutarate at 206 ppm in alpha-chloralose anesthetized adult rat brain, the unidirectional glutamate to a-ketoglutarate flux was determined to be 78 9 mmol g 1 min 1. Because of the large chemical shift separation between the a-carbons of the amino acids and the carbonyl carbons of the corresponding keto acids, the spillover of the saturation radiofrequency pulses to the alpha-carbon resonances was negligible.52 [2-13C]GABA has been spectrally resolved in vivo and detected simultaneously with [4-13C]Glu and [4-13C]Gln in spectra obtained from a 40 mm3 voxel in the rat neocortex. An adiabatic 1H-observed, 13C-edited spectroscopy method was used to measure the time-resolved kinetics of 13C label incorporation from intravenously infused [1-13C]glucose into [4-13C]Glu, [4-13C]Gln and Nucl. Magn. Reson., 2007, 36, 344–362 | 351 This journal is

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[2-13C]GABA after acute administration of gabaculine, a specific inhibitor of GABA-transaminase. The rate of 13C incorporation from [1-13C]glucose into [2-13C]GABA in the gabaculine-treated rats was found to be significantly reduced as a result of the blockade of the GABA shunt.53 Localized 1H NMR has been used to measure the time courses of the rise in GABA and the times to reach steady-state levels of GABA in anesthetized rat brain after vigibratin treatment. Rates of GABA synthesis were estimated for the period of constant GABA levels from the accumulation of [2-13C]GABA following a 20 min intravenous infusion of either [1,6-13C]glucose or [2-13C]acetate. No evidence of product inhibition of glutamate decarboxylase by the increased GABA concentration or reduced synthesis from [1,6-13C]glucose was found. Fractional changes in steady-state GABA levels and GABA transaminase activities 5–6 h after vigibratin treatment were approximately equal.54 1H-observe–13C-edited NMR and 1H NMR have been used to quantify the effects of acute phenelzine administration on cortical energetics, Glu neurotransmission, and GABA synthesis flux in alpha-chloralose anesthetized rats four hours after phenelzine treatment. The time-resolved kinetics of cortical [4-13C]Glu, [4-13C]Gln, and [2-13C]GABA turnover from an i.v. infusion of [1,6-13C]glucose was measured at 11.7 T. The rate of the tricarboxylic acid cycle flux following treatment was not different between treated (0.46 0.05 mmol g 1 min 1) and controls (0.50 0.05 mmol g 1 min 1). However, the rate of the glutamate-glutamine cycling flux between neurons and glia in the phenelzine-treated group was significantly reduced from 0.16 0.04 in controls to 0.10 0.03 mmol g 1 min 1. Following phenelzine treatment, the cortical GABA concentration increased significantly from 1.02 0.17 to 2.30 0.26 mmol g 1, while the GABA synthesis flux was unchanged from 0.07 0.02 to 0.06 0.02 mmol g 1 min 1.55 The role of the 65-kDa isoform of glutamate decarboxylase (GAD(65)) in activity-dependent GABA synthesis, as invoked by seizures in anesthetized rats, has been investigated. GABA synthesis was measured following acute GABA-transaminase inhibition by gabaculine using spatially localized 1H NMR before and after bicuculline-induced seizures. Experiments were conducted with animals pre-treated with vigibratin 24 h earlier in order to reduce the 67-kDa isoform of glutamate decarboxylase GAD(67) protein and also with nontreated controls. GAD isoform content was quantified by immunoblotting. GABA was higher in vigibratin-treated rats compared to non-treated controls. In vigibratintreated animals, GABA synthesis was 28% lower compared to controls and GAD(67) was 60% lower. No difference between groups was observed for GAD(65). Seizures increased GABA synthesis in both control and vigibratin-treated rats. GAD(67) could account for at least half of basal GABA synthesis but only 20% of the two-fold increase observed in vigibratin-treated rats during seizures.56 Release of glial Gln to the extracellular fluid has been studied by 15N NMR to measure intracellular Gln (Glni) in conjunction with microdialysis to measure Gln in the extracellular fluid (Glnecf). Glnecf was elevated to 2.4 0.2 mm after 4.5 h of intravenous ammonium acetate infusion. Furthermore, the [Glni]/[Glnecf)] ratio was 9.6 0.9, whereas values in the range of 17–20 were found in normal brain. Glnecf decreased substantially after 4.9 h. Perfusion of alpha-(methylamino)isobutyrate, which inhibits neuronal uptake of Glnecf mediated by sodium-coupled amino acid transporter, caused an elevation of Glnecf to 1.9 mm, resulting in a [Glni]/[ Glnecf] ratio of 8.4.57 A method has been developed for direct determination of acetylcholine synthesis in living brain tissue. The method is based on administration of choline, enriched with 13C in the two methylene positions, and detection of labeled acetylcholine and all other metabolic fates of choline, by 13C NMR. The method was tested in rat brain slices and found to be specific for acetylcholine synthesis in both the cortex and hippocampus.58 1 H NMR has been used to investigate brain development in mice by monitoring metabolite concentrations in different brain regions at post-natal day 5, 10, 15 and 21. Developmental changes of metabolite concentrations were measured using PRESS at 9.4 T in the thalamus, the olfactory bulb and the cerebellum. The absolute 352 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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concentrations of tCr, Taurine, Cho, NAA and Glx were determined. Variations observed during brain development were in accordance with those previously reported in mice using ex vivo NMR studies, and also those reported in rats and humans in vivo.59 Metabolic changes in the rat brain after oxygen deprivation during deep hypothermia (15 1C rectal temperature) have been monitored by 31P NMR. A correlation was established between the bioenergetic status of the brain and physiological descriptors of tolerance (survival and revival times) determined in parallel experiments. Peak integrals were transformed into absolute concentrations by comparison to biochemically determined data obtained in freeze-clamp experiments conducted under identical conditions. Serial spectra were used to reconstruct the time-course kinetics of intracellular brain pH and of changes in inorganic phosphate (Pi), phosphocreatine (PCr), ATP, and ADP.60 4.2 Eye 1

H NMR measurements of lactate have been used to determine vitreous lactate concentrations in conditions of increased intraocular pressure. Intra-anterior chamber injections of 20 mm latex beads were used to impede aqueous drainage in New Zealand White rabbits, causing an elevation of intraocular pressure. Group I consisted of 12 rabbits in which unilateral elevations in intraocular pressure were achieved. Group II consisted of 6 rabbits in which treatment did not cause a change in intraocular pressure. The contralateral eye served as a control in both groups and received an equal volume injection of vehicle only. Post-mortem histochemical analysis at the light microscope level was used to quantify changes in the retinal nerve fiber layer thickness and in the numbers of retinal ganglion cells, and correlate them with intraocular pressure and percent change in lactate levels. Between days 5 and 9 post-treatment, the intraocular pressure in Group I treated eyes rose to 23.9 4.2 mmHg. Intraocular pressure in the control eyes remained unchanged. Vitreous lactate levels in Group I treated eyes increased by 100%. In Group I, intraocular pressure and percent change in lactate concentration in treated eyes were closely correlated throughout the study period (r = 0.95; p r 0.05). Group II control and treated eyes showed no significant changes in either intraocular pressure or lactate. Group I treated eyes had a reduced nerve fiber layer thickness at the temporal medullary ray and decreased numbers of retinal ganglion cells.61 The potential 19F NMR for monitoring fluorinated drugs used in eye treatment has been evaluated at 2.35 T. Using 1H-decoupling, the signal from dexamethasone phosphate was enhanced by 56%, however, decoupling did not enhance the signal from ciprofloxacin. Despite signal enhancement, the drugs could not be detected at therapeutic doses in this experimental eye model.62 4.3 Heart, kidney and liver The effects of chronic activation of protein kinase B on glucose uptake, glycogen storage, and relevant glucose transporters have been investigated in the hearts of transgenic mice. Chronic cardiac activation of protein kinase B led to a substantial increase in the rate of basal glucose uptake, but blunted the response to insulin in perfused hearts. Basal glucose uptake was also increased in protein kinase B transgenic mice in vivo. These changes were associated with an increase on glycogen deposition.63 1H spectroscopic imaging has been used to detect boronophenylalanine in the mouse kidney following an infusion of the compound.64 A systematic method for the identification and quantitation of signature signals from lipid metabolites using 1D NMR proton spectroscopy has been presented. Lipid metabolites were measured in an epigenetic rat hepatocarcinogenesis model induced by treatment with a choline-deficient diet over a period of 1 year, from the formation of steatosis to the development of nodules and adenomas. A comparable choline-sufficient diet was used for the controls. Resonances of the methylene protons of the glycerol backbone Nucl. Magn. Reson., 2007, 36, 344–362 | 353 This journal is

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in phospholipids were used to quantify the total concentration of lipids. Livers from choline-deficient rats were found to have significantly higher levels of phospholipids throughout the entire carcinogenesis period. Choline was quantified from its trimethyl protons, and the vinyl and bis-allyl resonances were used to quantify fatty acid concentrations and to determine the number of double bonds in fatty acids. Measurements in early stages of carcinogenesis indicated a lower degree of double bonds in fatty acyl containing compounds.65 4.4 Muscle Burn trauma has been investigated with 1H NMR and ex vivo, HRMAS 1H NMR on intact excised mouse muscle samples before and 1 and 3 days after burn in mice. Samples were then analyzed for apoptotic nuclei using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Transcriptome analysis demonstrated that burn trauma altered the expression of genes involved in lipid metabolism and apoptosis. Burn injury resulted in a localized intramyocellular lipid (IMCL) accumulation, which in turn was accompanied by burninduced apoptosis and mitochondrial dysfunction.66 The distribution of IMCL within the rat tibialis anterior muscle has been investigated in vivo using single-voxel 1 H NMR and ex vivo using immunohistological assays to determined the muscle fiber distribution. Levels of IMCL differed by up to a factor of 3 depending on the position of the voxel. The distribution of IMCL over the tibialis anterior muscle cross section was not random, but emerged in a pattern similar to the distribution of the predominantly oxidative muscle fiber types. Dietary interventions, such as high fat diet and 15 h of fasting, did not significantly change this typical fiber typedependent pattern of IMCL content.67 The transverse relaxation times of IMCL and extramyocellular lipid (EMCL) have been measured in the Zucker rat at 7 tesla.68 4.5 Reproductive Localized in vivo 1H NMR spectroscopy has been used to measure metabolite levels in rat testes. Spectra obtained using STEAM with a short echo time contained large lipid signals that dominated the chemical shift range of 0.89–2.78 ppm, preventing the observation of metabolite signals in this region. Lipid signals were suppressed using short-inversion-time inversion recovery combined with STEAM. The optimal inversion time was typically 320 ms. In normal testes, Cho, tCr, Glu, and Gly were detected. Additionally, lactate was observed in ischemic testes.69 4.6 Tumour A review of NMR methods for the study of cancer, with particular reference to the detection of Cho, has been produce.70 Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells have been examined by 1H and 31P NMR before and after treatment with MN58b in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. Treatment of tumours caused significant growth delays and caused a significant decreases in Cho and the ratio of phosphomonoesters (PME) to the total phosphorous signal.71 The diffusion characteristics of lactate and alanine in a brain tumor model have been compared to those of normal brain metabolites known to be mainly intracellular such as NAA or tCr. 13C-labeled glucose was administered and the apparent diffusion coefficients of the glycolytic products, [13C]lactate and [13C]alanine, were determined in rat intracerebral 9L glioma. Multi-exponential diffusion attenuation of lactate signals was observed. The persistence of a lactate signal at very large diffusion weighting provided direct experimental evidence of significant intracellular lactate concentration. To investigate the spatial distribution of lactate and other metabolites, 1H NMR spectroscopic 354 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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images were also acquired. Lactate and Cho were consistently elevated in tumor tissue, but not in necrotic regions and surrounding normal-appearing brain.72 4.7 Whole organisms The role of oxygen limitation in defining thermal tolerance has been investigated in the European cuttlefish (Sepia officinalis). Mantle muscle organ metabolic status and intracellular pH (pHi) were monitored with 31P NMR, while mantle muscle performance was determined by recording mantle cavity pressure oscillations during ventilation and spontaneous exercise. Under control conditions (15 1C), changes in muscle phospho-L-arginine (PA) and Pi levels could be linearly related to frequently occurring, high-pressure mantle contractions with pressure amplitudes of 40.2 kPa. No more than 20% of muscle PA was depleted during spontaneous exercise under control conditions. Subjecting animals to acute thermal change at an average rate of 1 1C h 1 lead to an accumulation of Pi and decreases in the free energy of ATP hydrolysis. Frequent groups of high-pressure mantle contractions in warm conditions could not be related to net PA breakdown in mantle muscle; contractions in cold conditions could only be partially related to net PA breakdown.73 The effects of dinoseb (2-sec-butyl-4.6-dinitrophenol), a substituted dinitrophenol herbicide, on metabolism of Japanese medaka (Oryzias latipes) embryos has been investigated with in vivo 31P NMR, HPLC, and 1H NMR metabolomics. The metabolism of ATP and PCr was characterized within intact embryos by 31P NMR in vivo; concentrations of ATP, guanosine triphosphate, ADP, guanosine diphosphate, AMP and PCr were determined by HPLC; and changes in numerous polar metabolites were characterized by 1H NMR-based metabolomics. Range finding exposures determined two sublethal doses of dinoseb, 50 and 75 ppb, in which embryos survived from 1-day post fertilization through the duration of embryogenesis. In vivo 31P NMR data were acquired from 900 embryos in 50 or 75 ppb dinoseb at 14, 62 and 110 h after initiation of exposure. After 110 h, embryos were observed for development and hatching success, then either preserved in 10% formalin for growth analysis or flash frozen and extracted for HPLC and 1H NMR analysis. Dinoseb exposure at both concentrations resulted in significant declines in [ATP] and [PCr] at 110 h as measured by 31P NMR in vivo, HPLC and NMR-based metabolomics. Reduced eye growth and diminished heart rate occurred in a concentrationdependent fashion. Metabolic effects measured by 31P NMR in vivo showed a significant increase in Pi levels, and significant decreases in [ATP], [PCr] and the PCr/Pi ratio.74

5

Clinical

The current clinical applications of NMR and NMR spectroscopic imaging have been reviewed.75 A review of the application of 13C NMR in clinical investigations at 1.5 T and 3 T has been produced. The article discusses adverse effects related to the higher field strength such as increased field inhomogeneities, sequence restrictions caused by safety limitations and chemical shift misregistration, which may lead to incorrect localization or loss of signals of certain metabolites.76 A review of the use of 13P NMR for the study of the human liver has been produced.77 5.1 Brain The measurement of NAA and the neurobiology of schizophrenia have been reviewed.78 A review has been produced on the use of 1H NMR for measurement of NAA levels in multiple sclerosis.79 The use of MRI and NMR in studies of the brain has been reviewed.80 A study has been carried out to evaluate inter- and intra-subject variability and scan-rescan reproducibility of PRESS 1H NMR (TE = 30 ms, TR = 3000 ms, Nucl. Magn. Reson., 2007, 36, 344–362 | 355 This journal is

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oblique voxel orientation, voxel size 2 cm3) in hippocampal structures at 1.5 T. Thirty healthy adults were studied bilaterally and spectral analysis and absolute metabolite quantitation of NAA, Cho, tCr, Glx and mI were carried out by LCModel. Inter- and intra-individual reproducibility of these metabolite values were investigated by calculation of mean, standard deviation, coefficient of variation (CV), and by analysis of variance for repeated measurements. The smallest CV in intersubject variability was obtained for NAA, followed by tCr, Cho, mI and Glx. The results of the analysis of variance for repeated measures showed a marginal effect of scan repetition for tCr (p = 0.063) and Glx (p = 0.082). No statistical significant effect of scan repetition was seen for NAA (p = 0.913), Cho (p = 0.857), and mI (p = 0.826).81 Single-voxel 1H NMR spectra from the medial temporal lobe of a single healthy subject have been measured at five sites with 1.5 T NMR systems. The same subject was also examined at one of the sites five times to assess intracentre stability. The protocol included water-suppressed spectra with TE 272 ms and TE 30 ms and unsuppressed spectra for absolute quantification of metabolite concentrations. The intracentre reproducibility of absolute NAA concentration, expressed as a CV, was 1.8%. The CV for the concentrations of tCr, Cho, mI and for the ratios NAA/tCr, NAA/Cho, and mI/NAA were 11–16%. Intercentre CV was 3.9% for NAA and CV were below 10% for all other metabolites and metabolic ratios.82 Localised 1H NMR has been used to measure the ratios of NAA/Cho, NAA/tCr and Cho/tCr from 12 regions in normal brain. PRESS with a TE of 135 ms at 1.5 T was used to measure metabolite ratios from: parieto-occipital white matter, centrum semiovale, frontal white matter, thalamus, basal ganglia, cerebellum (hemisphere, including dentate nucleus), brain stem (including pons, medulla and midbrain), anterior and posterior temporal lobe, parietal, occipital and pre-frontal cortices.83 The SNR, intersubject reproducibility and the intrasubject reproducibility of NAA, tCr, and Cho levels have been compared in 1H NMR spectra with TE values of 30, 144, and 288 ms using three combinations of r.f. coil and field strength. Six volunteers were scanned at 3 T with a single-element quadrature coil, at 1.5 T with single-element quadrature coil and at 1.5 T with a 12-channel phased-array head coil. The best SNR for all metabolites was obtained when TE was 30 ms. A comparable SNR was obtained at 3 and 1.5 T with the phased-array head coil, which gave about 35% better SNR than the single-element quadrature coil at 1.5 T. This SNR difference declined o25% at TE of 144 ms and to equity among all imagers at TE of 288 ms. Reproducibility, reflected in the CV, was best for NAA at TE of 288 ms, 15%–50% better than at TE of 30 ms in either grey or white matter. The CV for tCr was best when TE was 288 ms for grey matter, but the results for tCr in white matter were independent of TE. Metabolite level reproducibility did not depend on coil technology or magnetic field strength.84 The diffusion tensor of NAA, tCr and Cho has been measured at 3 T using diffusion weighted STEAM 1H NMR in the healthy human brain in 6 distinct regions (4 white matter and 2 cortical grey matter). The apparent diffusion coefficient (ADC) of each metabolite was significantly greater in white matter than grey matter. The ADC values of tCr and Cho were found to be significantly greater than NAA in white matter, whereas all 3 metabolites had similar ADC in cortical grey matter. Fractional anisotropy values for all 3 metabolites were consistent with water fractional anisotropy values in the 4 white matter regions, however, metabolite fractional anisotropy values were found to be higher than expected in the cortical grey matter. The principal diffusion direction derived for NAA was in good agreement with expected anatomic tract directions in the white matter.85 A method for measuring brain GABA levels has been presented that combines 2D J-resolved magnetic resonance spectroscopy techniques with chemical-shift imaging at 4 Tesla. Results of phantom and in vivo experiments demonstrated that the C2 GABA (CH2) resonance situated at 2.97 ppm can be resolved from the neighboring tCr resonance at 3.03 ppm and quantified. Single-voxel, J-resolved standard and metabolite-nulled in vivo experiments on six healthy subjects revealed a broad component from 356 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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underlying macromolecules around 3.00 ppm, which was estimated to contribute approximately 15% to the J-resolved GABA resonance. Using 2D J-resolved magnetic resonance, the macromolecule contribution to the GABA measurements was estimated to be 12%. The global brain GABA concentration was found to be 0.76 0.20 mM after correction for 12% the macromolecule contribution.86 Twodimensional, J-resolved chemical-shift imaging sequence has also been used to collect GABA spectroscopic imaging data that has been quantified against tissue tCr. Using image segmentation and a linear-regression analysis relating brain GABA level to tissue-type, mean GABA levels were found to be 0.96 0.24 mm in cortical grey matter compared with 0.44 0.16 mm in white matter in six healthy subjects.87 Reduced glutathione has been quantified at 4 T from short echo STEAM spectra and MEGA-PRESS edited spectra from identical volumes of interest in the anterior cingulate in 10 volunteer subjects. Furthermore, neurochemical profiles were quantified in 9 controls and 13 medicated schizophrenic patients. Reduced glutathione concentrations quantified using STEAM and MEGA-PRESS were 1.6 0.4 mmol g 1 and 1.4 0.4 mmol g 1, respectively. None of the measurements of neurochemical profiles reached sufficient statistical power to detect differences smaller than 10% in schizophrenia versus control.88 The in vivo chemical profile of grey and white matter tissues of 45 children (3 to 4 years old) with autism spectrum disorder, 12 age-matched children with delayed development, and 10 age-matched children with typical development have been measured with 1H NMR spectroscopic imaging. Children with autism spectrum disorder demonstrated decreased grey matter concentrations of Cho (P o 0.001), tCr (P = 0.02), NAA (P = 0.02), and mI (P = 0.008) compared with children with typical development. Grey matter Cho transverse relaxation was also prolonged for the autism spectrum disorder sample compared with the typical development group (P = 0.01). Children with autism spectrum disorder demonstrated significantly decreased levels of Cho (P = 0.04) and mI (P = 0.008) and trend-level NAA (P = 0.09) in grey matter compared with the delayed development group. Children with autism spectrum disorder and children with delayed development showed a similar pattern of decreases in the level of NAA and mI in white matter. In several analyses, cerebral volume contributed significantly as a covariate.89 Levels of GABA have been measured in the brains of 16 control subjects and eight patients with stiffperson syndrome with high titers of circulating anti-glutamic acid decarboxylase antibodies and typical clinical symptoms of stiff-person syndrome. No abnormalities were observed in brain magnetic resonance images. A significant decrease in GABA levels was observed in the sensorimotor cortex of patients. A smaller decrease in GABA levels was also observed in the posterior occipital cortex, but not in the cingulate cortex or pons.90 The metabolic profiles of pediatric brain tumours have been evaluated with 1H NMR. The MRI examinations of 60 patients with untreated brain tumours (14 medullablastomas, 5 anaplastic astrocytomas, 3 low-grade astrocytomas, 17 pilocytic astrocytomas, 4 anaplastic ependymomas, 5 ependymomas, 3 choroid plexus papillomas, 3 choroid plexus carcinomas, and 6 pineal germinomas) were reviewed. Single-voxel 1H NMR with a TE of 35 ms was performed and absolute metabolite concentrations were determined by using fully automated quantitation. The level of taurine was significantly elevated in medullablastomas compared with all other tumours. Taurine was also observed consistently, at lower concentration, in pineal germinomas. The level of tCr was significantly reduced in pilocytic astrocytomas, distinguishing them from other tumours. The NMR spectra of choroid plexus papillomas exhibited low tCr concentrations, however, myo-inositol was elevated and Cho was reduced relative to other tumours. Choroid plexus carcinomas had low tCr and the lowest tCr/Cho ratio amongst all tumours studied. Guanidinoacetate was reduced in low-grade astrocytomas and anaplastic astrocytomas, whereas ependymoma and anaplastic ependymomas exhibited particularly low NAA.91 Localised 1H NMR has been used to measure Glu and Gln in 14 pediatric major depressive disorder patients versus 14 case-matched Nucl. Magn. Reson., 2007, 36, 344–362 | 357 This journal is

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healthy control subjects. Data was acquired at 1.5 T and LCModel was used for data fitting. Reduced anterior cingulate Glu was observed in major depressive disorder patients versus control subjects (8.79 1.68 vs. 11.46 1.55 mmol dm 3, respectively). Anterior cingulate Gln did not differ significantly between patients with major depressive disorder and control subjects.92 The mechanisms responsible for the progressive failure of hypoglycaemia counter regulation in long-standing type 1 diabetes have been investigated in type 1 diabetic patients and healthy volunteers. 1H NMR of the occipital lobe of the brain was performed before, during and after a hypoglycaemic (5 mg cm 3) hyperinsulinaemic (1.5 mU kg 1 min 1) clamp test. During hypoglycaemia, patients showed blunted endocrine counter regulation. At baseline the brain tissue glucose/tCr ratio was lower in controls (0.13 0.05) than in patients (0.19 0.11). During hypoglycaemia glucose/tCr ratios decreased in both groups and were 0.07 0.08 and 0.03 0.03 in controls and patients, respectively. A significant drop in the Glu/tCr ratio was found in controls during hypoglycaemia; in controls the Glu/tCr ratio fell from 1.36 0.08 to 1.26 0.11, whereas in patients the ratio fell from 1.32 0.13 to 1.28 0.15. The ratios of Gln/tCr, NAA/tCr, Cho/ tCr and mI/tCr were not different between groups and did not change throughout the experiment. Moderate hypoglycaemia reduce intracerebral glutamate concentrations only in controls.93 The effects of hyperglycaemia on brain glucose levels in the occipital cortex of patients with poorly controlled diabetes has been measured with 1 H NMR. Fourteen patients with poorly controlled diabetes and 14 healthy volunteers were studied with a plasma glucose level of 30 mg cm 3. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects at 4.7 0.9 and 5.3 1.1 mmol (g wet weight) 1, respectively.94

5.2 Heart In an assessment of whether 31P NMR chemical shift imaging can be used in the diagnoses of cardiac allograft vasculopathy, variations in cardiac high-energy phosphates have been measured in a population of adult heart transplant recipients. Cardiac allograft vasculopathy was defined by coronary angiography as the presence of diffuse coronary irregularities with significant concentric narrowing on epicardial or distal coronary arteries. Eight patients with cardiac allograft vasculopathy (group A), and 18 patients without cardiac allograft vasculopathy (group B) were included in this study and compared to nine healthy volunteers (group C). PCr/ATP was significantly lower in group A (1.51 0.50) than in groups B (1.98 0.53) and C (2.14 0.31), respectively. Time from transplant, number of episodes of acute rejection, and left ventricular ejection fraction were not significantly different between patient groups. A PCr/ATP value of 1.59 was the optimal cut-off value to predict cardiac allograft vasculopathy with a specificity and sensitivity of 100% and 72%, respectively.95 19F NMR at 4 T with external standardization has been used in a multiple-dose study of 23 healthy adult subjects. Surface coil-localized spectra were monitored in the heart and liver at baseline and after oral administration of multiple doses of tecastemizole. Steady-state measurements were made at set time points that depended upon dose; washout measurements were made only on subjects in which in vivo fluorine signal was observed. The method had a lower limit of quantitation of about 2.6 mM and a limit of detection of about 0.3 mM in phantoms. The measurement reproducibility was 6.4% using a 50 mM phantom. NMR signal from fluorine-containing tecastemizole-related moieties was observed in situ only at day 8 in the liver of three out of five subjects dosed at 270 mg day 1. The average in situ concentration was estimated to be 58 22 mM, with an average test-retest reproducibility of 216%. Extrapolation of in vitro results to human measurements suggested a limit of detection of 6 mM. However, the limit of detection in vivo was approximately 20 mM.96 358 | Nucl. Magn. Reson., 2007, 36, 344–362 This journal is

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5.3 Muscle The perfusion, oxygenation, and high-energy phosphate distribution of human skeletal muscle have been measured simultaneously by interleaved 1H NMR, 31P NMR and 1H magnetic resonance imaging. From these, arterial oxygen supply, muscle reoxygenation rate, mitochondrial ATP production, and O2 consumption were deduced at the recovery phase of a short ischemic exercise bout. In addition, muscle maximum O2 extraction was calculated from these parameters.97 The relaxation time constant T1 of phosphocreatine in the human gastrocnemius muscle has been determined at rest and during aerobic exercise. The multipoint saturation recovery technique was used on four acquisition protocols differing in number and duration of repetition times. Furthermore, two mathematical models describing the phenomenon were also evaluated. Protocols and models were tested on a phantom and one protocol only was used on each group of four healthy volunteers at rest and during exercise. Each volunteer repeated the rest-exercise sequence three times. The average T1 values from experiments with the phantom for the various protocols and mathematical models differed widely, ranging from 0.61 s to 7.20 s. The T1 values obtained at rest and during exercise were not significantly different and had an average value of 0.91 s. Correction of this T1 value with the results obtained using the phantom gave a T1 value of 5.73 s, which is comparable with the value reported in the literature for resting conditions only.98 5.4 Tumour The use of 19F NMR to monitor fluoropyrimidine metabolism in solid tumours has been reviewed with 142 references.99 A review that introduces 1H NMR of musculoskeletal tumours and discusses current methods and technical issues has been produced.100 A simple method for lactate quantification in 1H NMR spectra has been presented. The technique uses spectra with long echo times to calculate T2 relaxation time and the absolute concentration of lactate using water as an internal standard. Measurements were made in 12 patients with tumours and 3 patients with cerebral infarctions.101 The metabolite concentrations in normal adult brains and gliomas have been measured by 1H NMR using the fully relaxed water signal as an internal standard. Measurements were made using PRESS in 28 healthy volunteers and 16 patients with gliomas. The calculated concentrations of NAA, tCr, Cho, and H2O in the normal hemispheric white matter were 23.59 2.62 mmol dm 3, 13.06 1.8 mmol dm 3, 4.28 0.8 mmol dm 3 and 47 280.96 5414.85 mmol dm 3, respectively. The concentrations of NAA and tCr decreased in all gliomas. The ratios of NAA/Cho and NAA/H2O showed a significant difference between the normal brain and gliomas, and also between the high and low grades of glioma (P o 0.001).102 The molecular profile of a primitive neuroectodermal tumour in a 3-yearold child has been determined with single voxel 1H NMR and compared to that obtained from 1H HRMAS NMR. A very high amount of Cho and very low level of tCr and NAA were detected in vivo. The ex vivo HRMAS NMR spectra showed that mI, taurine and phosphoethanolamine contributed to the in vivo signal at 3.2 ppm, usually attributed to Cho.103

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74 M. R. Viant, C. A. Pincetich, D. E. Hinton and R. S. Tjeerdema, Aquatic Toxicology, 2006, 76(3–4), 329–42. 75 M. R. Lentz, J. L. Taylor, D. A. Feldman and L. L. Cheng, Current Medical Imaging Reviews, 2005, 1(3), 271–301. 76 U. Dydak and M. Schar, Neuroimaging Clinics of North America, 2006, 16(2), 269. 77 S. F. Solga, A. Horska, J. M. Clark and A. M. Diehl, Liver International, 2005, 25(3), 490–500. 78 S. Marenco, A. Bertolino and D. R. Weinberger, N-Acetylaspartate: A Unique Neuronal Molecule in the Central Nervous System, 2006, 576(227–40). 79 N. De Stefano, M. L. Bartolozzi, L. Guidi, M. L. Stromilloa and A. Federico, Journal of the Neurological Sciences, 2005, 233(1–2), 203–8. 80 I. F. Talos, A. Z. Mian, K. H. Zou, L. Hsu, D. Goldberg-Zimring, S. Haker, J. G. Bhagwat and R. V. Mulkern, Cellular and Molecular Life Sciences, 2006, 63(10), 1106–24. 81 T. Hammen, A. Stadlbauer, B. Tomandl, O. Ganslandt, E. Pauli, W. Huk, B. Neundorfer and H. Stefan, NMR in Biomedicine, 2005, 18(3), 195–201. 82 F. Traber, W. Block, N. Freymann, O. Gur, T. Kucinski, T. Hammen, G. Ende, U. Pilatus, H. Hampel, H. H. Schild, R. Heun and F. Jessen, European Radiology, 2006, 16(5), 1096–103. 83 J. Vion-Dury and P. Michotey, Journal of Neuroradiology, 2005, 32(4), 239–46. 84 M. Inglese, M. Spindler, J. S. Babb, P. Sunenshine, M. Law and O. Gonen, American Journal of Neuroradiology, 2006, 27(3), 684–8. 85 J. Ellegood, C. C. Hanstock and C. Beaulieu, Magnetic Resonance in Medicine, 2006, 55(1), 1–8. 86 J. E. Jensen, B. D. Frederick, L. Q. Wang, J. Brown and P. F. Renshaw, Magnetic Resonance in Medicine, 2005, 54(4), 783–8. 87 J. E. Jensen, B. D. Frederick and P. F. Renshaw, NMR in Biomedicine, 2005, 18(8), 570–6. 88 M. Terpstra, T. J. Vaughan, K. Ugurbil, K. O. Lim, S. C. Schulz and R. Gruetter, Magnetic Resonance Materials in Physics Biology and Medicine, 2005, 18(5), 276–82. 89 S. D. Friedman, D. W. W. Shaw, A. A. Artru, G. Dawson, H. Petropoulos and S. R. Dager, Archives of General Psychiatry, 2006, 63(7), 786–94. 90 L. M. Levy, I. Levy-Reis, M. Fujii and M. C. Dalakas, Archives of Neurology, 2005, 62(6), 970–4. 91 A. Panigrahy, M. D. Krieger, I. Gonzalez-Gomez, X. Liu, J. G. McComb, J. L. Finlay, M. D. Nelson, F. H. Gilles and S. Bluml, American Journal of Neuroradiology, 2006, 27(3), 560–72. 92 D. R. Rosenberg, F. P. MacMaster, Y. Mirza, J. M. Smith, P. C. Easter, S. P. Banerjee, R. Bhandari, C. Boyd, M. Lynch, M. Rose, J. Ivey, R. A. Villafuerte, G. J. Moore and P. Renshaw, Biological Psychiatry, 2005, 58(9), 700–4. 93 M. G. Bischof, A. Brehm, E. Bernroider, M. Krssak, V. Mlynarik, M. Krebs and M. Roden, European Journal of Clinical Investigation, 2006, 36(3), 164–9. 94 E. R. Seaquist, I. Tkac, G. Damberg, W. Thomas and R. Gruetter, Metabolism-Clinical and Experimental, 2005, 54(8), 1008–13. 95 T. Caus, F. Kober, P. Marin, A. Mouly-Bandini, J. Quilici, D. Metras, P. J. Cozzone and M. Bernard, European Journal of Cardio-Thoracic Surgery, 2006, 29(1), 45–9. 96 E. Schneider, N. R. Bolo, B. Frederick, S. Wilkinson, F. Hirashima, L. Nassar, I. K. Lyoo, P. Koch, S. Jones, J. Hwang, Y. Sung, R. A. Villafuerte, G. Maier, R. Hsu, R. Hashoian and P. F. Renshaw, Journal of Clinical Pharmacy and Therapeutics, 2006, 31(3), 261–73. 97 P. G. Carlier, C. Brillault-Salvat, E. Giacomini, C. Wary and G. Bloch, Magnetic Resonance in Medicine, 2005, 54(4), 1010–3. 98 V. Cettolo, C. Piorico, C. Attina and M. P. Francescato, Radiologia Medica, 2006, 111(3), 420–31. 99 H. W. M. van Laarhoven, C. J. A. Punt, Y. J. L. Kamm and A. Heerschap, Critical Reviews in Oncology Hematology, 2005, 56(3), 321–43. 100 C. K. Wang, T. J. Hsieh, T. S. Jaw, J. N. Lin, G. C. Liu and C. W. Li, Spectroscopy-an International Journal, 2005, 19(4), 181–90. 101 A. Matsumura, T. Isobe, S. Takano, H. Kawamura and I. Anno, Clinical Neurology and Neurosurgery, 2005, 107(5), 379–84. 102 Z. Y. Tong, T. Yamaki and Y. J. Wang, Chinese Medical Journal, 2005, 118(15), 1251–7. 103 V. Tugnoli, L. Schenetti, A. Mucci, L. Nocetti, C. Toraci, L. Mavilla, G. Basso, R. Rovati, F. Tavani, E. Zunarelli, V. Righi and M. R. Tosi, International Journal of Molecular Medicine, 2005, 16(2), 301–7.


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Nuclear magnetic resonance imaging By Tokuko Watanabe DOI: 10.1039/b618330c

1. Introduction This review covers the progress in the field of NMR imaging (NMRI), NMR microimaging, NMR microscopy or MR (micro) tomography as well as MRI (Magnetic Resonance Imaging) over a period from June 2005 to may 2006 and is a continuation of the report from last year. The word ‘‘MRI’’ was used mostly in the medical or clinical field, but recently many authors in non-medical field uses ‘‘MRI’’ instead of the NMR imaging. In this review the word used in the original papers will be followed. The topics were limited to mainly basic, technical, and applicable aspects in the non-clinical research field. The following section of this report includes reviews and educational articles (Section 2), recent developments in instruments (Section 3), pulse sequences and data processing (Section 4), and novel applications concerning to other nuclei (Section 5), dynamics (Section 6), polymers (Section 7), plants (Section 8), foods (Section 9) and in vivo applications (Section 10).

2. Introductory articles and reviews 2.1 Challenging One of the most exiting topics in this period is access to an ultra-wide bore (105 mm) 21.1 T magnet, which makes possible numerous advances in NMR spectroscopy and NMR imaging, as well as novel applications.1 This magnet was developed, designed, manufactured and tested at the National High Magnetic Field Laboratory. Commercial and unique homebuilt probes, along with a standard commercial NMR console have been installed and tested with many scientific applications to develop this spectrometer as a user facility. Solution NMR of membrane proteins with enhanced resolution, new pulse sequences for solid state NMR taking advantage of narrowed proton linewidths, and enhanced spatial resolution and contrast leading to improved animal imaging have been documented. In addition, it is demonstrated that spectroscopy of single site 170 labeled macromolecules in a hydrated lipid bilayer environment can be recorded in a remarkably short period of time. Spin-warp imaging: The bulk of MRI is now performed using slice-selective gradients, where radio-frequency energy is applied to excite the hydrogen nuclei. By stepping a phase-encoding gradient during each repetition time and using a frequency-encoding gradient as the data are sampled, the 3D human object can be reduced to many individual points or voxels. By acquiring multiple slices at once, the time efficiency of imaging can be vastly improved. Many newer strategies use variations of this technique to acquire multiple lines of data during a single echo, enshrining spin warp imaging as the most important method of signal acquisition for MRI. Applications of optical pumping and polarization techniques: In certain systems, the application of resonant optical fields may be used to enhance the nuclear spin polarization by several orders of magnitude. Such large, non-equilibrium enhancements can translate directly into dramatic improvements in NMR detection sensitivity, and thus offer a variety of novel experimental possibilities. Realized and Aoyama Gakuin University Women’s College, 4-4-25, Shibuya, Shibuya-ku, Tokyo, 105-8366, Japan


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potential NMR applications include void-space imaging of materials and living organisms, probing structure and dynamics in proteins and inclusion complexes, enhanced NMR of bulk and nanostructured materials, quantum computing, fundamental studies of various photophysical and photochemical processes, and low field and remotely-detected NMR and MRI.3 Magnetic resonance microscopy is receiving increased attention as more researchers in the biological sciences are turning to non-invasive imaging to characterize development, perturbations, phenotypes and pathologies in model organisms ranging from amphibian embryos to adult rodents and even plants. The limits of spatial resolution are being explored as hardware improvements address the need for increased sensitivity. Recent advances and applications in biotechnology, such as in vivo cell tracking, restricted diffusion imaging, functional magnetic resonance microscopy, were summarized.4 2.2 Introductory articles Nobel lecture, ‘‘All science is interdisciplinary—From magnetic moments to molecules to men’’, by Prof. P. C. Lauterbur, was published.5 An analysis of the culture of MRI research in India was analyzed based upon observations of and interviews with scientists working in the MRI and NMR laboratories and government officials who regulate techno-scientific research in India.6 The magnetic resonance in porous media (MRPM) community is now a vast community of scientists from all over the world who recognize magnetic resonance as an instrument of choice for the characterization of pore space and of the distribution, diffusion and flow of fluids inside a vast range of different materials. Introductory aspect on MRPM work at University of Bologna was introduced.7 Spatial-spectral holographic MR interpretation: The fundamental MR imaging equation can be derived from a spatial-spectral holographic wavefront reconstruction formulation similar to that in quantum optics.8 This interpretation has implications on selective RF pulse design, holographic-based high-resolution microscopy applications, and the use of conjugate imaging for field inhomogeneity corrections using the time-reversed component of the readout. 2.3 General reviews The notion of using MRI as a microscopic tool for obtaining three-dimensional images of living and nonliving material was envisioned early in the history of this technology.9 A short discussion is highlighting how imaging time is drastically lengthened as image resolution is increased. Details for imaging types, their characteristics, applications, and experimental details are discussed. In vivo MRS/I: The basic technologies of the current trends in the field of in vivo MRS and MRSI, especially the inherent predilections of individual techniques to the study of certain disease states, were discussed as a review.10 q-Ball imaging: MR diffusion tensor imaging (DTI), which provides a powerful tool for mapping neural histoarchitecture in vivo, can only resolve a single fiber orientation within each imaging voxel due to the constraints of the tensor model. Recently developed high angular resolution diffusion imaging (HARDI) signal can be reconstructed model-independently using a spherical tomographic inversion called the Funk-Radon transform. The resulting imaging method, termed q-ball imaging, can resolve multiple intravoxel fiber orientations and does not require any assumptions on the diffusion process such as Gaussianity or multi-Gaussianity. A paper reviews the theory of q-ball imaging and describes a simple linear matrix formulation for the q-ball reconstruction based on spherical radial basis function interpolation. Open aspects of the q-ball reconstruction algorithm are discussed.11 Diffusion imaging for evaluation of tumor therapies: The increasing development of novel targeted therapies for treating solid tumors has necessitated the 364 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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development of technology to determine their efficacy in preclinical animal models. One such technology that can non-invasively quantify early changes in tumor cellularity as a result of an efficacious therapy is diffusion MRI. Some theories as to the origin of diffusion changes as a result of tumor therapy, a robust methodology for acquisition of apparent diffusion coefficient maps and some applications of determining therapeutic efficacy in a variety therapeutic regimens and animal models were presented and overviewed.12 In vivo 2D MRS of small animals: Two-dimensional methods widely developed for in vitro studies have been proposed as suitable approaches to overcome the limitations in resolution. The different homonuclear and heteronuclear sequences adapted to in vivo studies are reviewed.13 Their specific contributions to the spectral resolution of spectroscopic data and their limitations for in vivo investigations are discussed. The applications to experimental models of pathological processes or pharmacological treatment in mainly brain and muscle are presented. MR thermometry techniques: The feasibility of MR thermometry based on the strong temperature dependence of the hyperfine-shifted 1H signal from the paramagnetic lanthanide complex , TmDOTMA , i.e., thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, was recently demonstrated as noninvasive MR thermometry.14 The use of paramagnetic lanthanide complexes for MR thermometry can be further enhanced by improving the signal-to-noise ratio (SNR) of the observed signal. The application of TmDOTMA for measuring temperature in a subcutaneously implanted tumor model was demonstrated. Lastly, the feasibility of obtaining 3D images from the methyl 1H resonance of TmDOTMA was demonstrated in phantom and live animal experiments.

3. Instruments 3.1 Review Unilateral mobile NMR employs portable instrumentation with sensors, which are applied to the object from one side. Based on the principles of well-logging NMR, a hand-held sensor, the NMR-MOUSE (MObile Universal Surface Explorer) has been developed for nondestructive materials testing. In the following, a number of new applications of unilateral NMR in materials science, such as the state assessment of polyethylene pipes, the characterization of wood, the in situ evaluation of stone conservation treatment, high-resolution profiling of rubber tubes and 2-D imaging for defect analysis in rubber products, are reviewed.15 A miniaturized spiral Helmholtz rf coil was fabricated using standard photolithography and electroplating. A commercial 0.6 T superconductive magnet was used to test the coil performance for both NMR spectroscopy and imaging applications.16 Results obtained demonstrated the prospect of using the Helmholtz rf coil as part of a portable low-field NMR system for applications in analytical chemistry and process measurements in industrial settings. Design and operation of the cryogenic system for cryogenically cooling a rf detector coil, as used in high-resolution MRI to enhance image signal-to-noise ratio, was described.17 By incorporating the rf coil into a Joule-Thomson micro-refrigerator, the coil is precision-cooled to 70 K using only a source of high-pressure nitrogen gas at room temperature. SNR gains of two to three times were obtained, compared to a similar coil at room temperature. The potential of this technology for local high-resolution MRI is discussed.

3.2 Systems Multi-dimensional MRI in a stray magnetic field: Stray field imaging has been extensively utilized in the last 10 years to perform very high resolution imaging of Nucl. Magn. Reson., 2007, 36, 363–396 | 365 This journal is

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samples in a single dimension using the massive field gradient present in the fringe of a superconducting magnet. By spinning the sample around the magic-angle, the acquisition of a full three-dimensional Fourier image, thereby providing the possibility to perform multi-dimensional very high-resolution imaging with standard NMRS equipment, was demonstrated the feasibility of this technique.18 Portable 3He gas polarizer: A portable 3He gas polarizer based on metastability exchange optical pumping is described, which produces 75 ml of highly polarized 3He gas at the pressure of 100 mbar, by implementing a non-magnetic peristaltic compressor.19 About 30% polarization at 1 mbar is achieved in the optical pumping cell in a single run, and 20 compression cycles are needed to reach the final pressure in the storage cell. MRI at low magnetic field: A low magnetic field MRI system for small animal lung imaging using hyperpolarized 3He gas (1 mbar pressure and 30% polarization) was presented.20 The MRI unit is based on a permanent magnet of open geometry, built from a new generation Nd–B–Fe magnetic material, which produces the magnetic field of 88 mT with homogeneity better than 50 ppm in the 10 cm diameter sphere, after application of passive shimming. Noncryogenic atomic magnetometer: Detection of NMR signals using a noncryogenic atomic magnetometer was demonstrate and several novel applications of this technique were described.21 A nuclear spin-precession signal from water is detected using a spin-exchange-relaxation-free potassium magnetometer. NMR signal of less than 1013 129Xe atoms is enhanced by a factor of 540 due to Fermicontact interaction with K atoms. The possibility of using a multichannel atomic magnetometer for fast 3D MRI was also discussed. Portable NMR probe: A portable, NMR probe is described which utilizes the intrinsic inhomogeneity of the field produced by a single-sided magnet to provide spatial encoding of the NMR signal.22 The system has been used to measure NMR relaxation times and one-dimensional NMR profiles of rubber phantoms. Multimodality system: Elucidating complex physiological mechanisms in small animal in vivo requires the development of new investigatory techniques including imaging with multiple modalities.23 Coupling NMR with a radiosensitive betaMicroProbe offers an interesting technical alternative. To assess the feasibility of this new dual-modality system, theoretical and experimental approaches were designed to test the ability of the beta-Microprobe to quantify radioactivity concentration in an intense magnetic field. Physiological monitor: To achieve and maintain stability of physiologic state in rats in the functional MRI environment, a minimally invasive but comprehensive system was developed to monitor body temperature, heart rate, blood pressure, blood oxygen saturation and end-tidal CO2 (ETCO2) of expired gas.24 This set-up could be extended to study in vivo applications in other laboratory animals with only minor modifications. 1D-MRI with GARField magnets: The first in vivo spatially-resolved fieldgradient measurements of water self-diffusivity, D, in the stratum corneum (2.0 10 6 cm2/s) and viable epidermis (8.5 10 6 cm2/s) were reported, as well as spatially resolved measurements of the T1 and T2 of 1H, by one-dimensional MRI (MRI-profiling) with using GARField magnets.25 Strong profile contrast originating from differing molecular mobility is seen for stratum corneum and viable epidermis. Ultra-low fields NMR/MRI/SQUIDs: NMR and MRI at ultra-low magnetic fields (ULF, fields of similar to mu T) have several advantages over their counterparts at higher magnetic fields. In addition, ULF NMR/MRI with SQUIDs (superconducting quantum interference devices) has already been demonstrated, as have measurements of simultaneous MEG and NMR at ULF. Simultaneous magnetocardiography (MCG) or magnetomyography (MMG) with NMR/MRI at ULF were explored to show the possibility of directly measuring magnetic resonance consequences of neuronal signals.26 Mobile NMR: NMR relaxometry is a suitable tool to determine the morphology of semi-crystalline polymers by its ability to discriminate between rigid, mostly 366 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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crystalline and soft, usually amorphous material. The NMR-MOUSE (nuclear magnetic resonance mobile universal surface explorer) was explored to supply morphological data of polyethylene pipes nondestructively.27 A shear-band was detected by destructive high-field NMR imaging in an area of severe deformation of a pipe, where an anomalous depths profile was observed by the NMR-MOUSE. 3-D, multi-nuclear CW-NMR imaging system: The development of a 3-D, multinuclear continuous wave NMR imaging system was described and its imaging capability was demonstrated on a range of materials exhibiting extremely short T2 relaxation values.28 The chemically combined 27Al in a high temperature refractory cement and the penetration of 23Na in salt water into samples of ordinary Portland cement (OPC) was investigated. The solid 13C component in a carbonated cement sample was also imaged, as were the 7Li nuclei in a sample of powdered Li2CO3. A spatial resolution of 1 mm was measured in an image of a rigid polymeric material exhibiting a principal T*2 value of 16.3 mu s. Finally, a high-resolution 3-D image of this rigid polymer is presented. Paired-image radiation transport(PIRT) model: A PIRT model, which provides a more realistic three-dimensional geometry for particle transport in the skeletal site at both microscopic and macroscopic levels of its histology, was introduced.29 The PIRT methodology allows for detailed modeling of the 3D macrostructure of individual marrow-containing bones within the skeleton thus permitting improved estimates of absorbed fractions and radionuclide S values for intermediate-to-high energy beta emitters. Microscale NMR sensors: Microscale NMR sensors for control of food processing was tested by fabricating single-tuned NMR radio frequency microcoils and two planar gradient coils.30 The RF coil was a variant of a Helmholtz pair and tuned to a proton frequency of 25.9 MHz. The magnetic field gradient coil arrangement in the Z and Y directions permits encoding for fluid velocity profile imaging of samples undergoing steady pressure driven flow in tubing inserted into the RF microcoil. The ability to use low magnetic field and microcoils to measure fluid composition and theology has been demonstrated. Field-cycled PEDRI imaging at 450 mT: The design, construction and use of a field-cycled proton-electron double-resonance imaging (FC-PEDRI) system for the detection and imaging of free radicals was described.31 The unique feature of this imager is its use of a 450 mT detection magnetic field in order to achieve good image quality and sensitivity. Field cycling is implemented by switching on and off the current in an internal, coaxial, resistive secondary magnet that partially cancels the superconducting magnet’s field at the sample. EPR irradiation takes place at similar to 5 mT, following which the field is switched to 450 mT in 40 ms for NMR signal detection. Full details of the imager’s subsystems are given. 3.3 Coils and resonators Four-coil phased array for parallel imaging at 14.1 Tesla: Efficient high-frequency phased arrays for small-diameter, vertical-bore magnets were designed for parallel imaging techniques. A four-coil phased array, using arrays of mutually decoupled coils, was constructed for micro-imaging at 600 MHz. Sensitivity encoding (SENSE) and generalized auto-calibrating partially parallel acquisitions (GRAPPA) reconstructions of spin-echo and echo-planar images of the mouse brain were performed to reduce imaging time and susceptibility artifacts, respectively.32 A capacitorsegmented single loop is used as the transmit coil in a four-coil surface array.33 Novel features of the coil design include the use of varactor diodes in the transmit and receive coils for coil isolation and impedance matching. High-resolution in vivo images of mouse spinal cord using this array are shown. Resonator assembly: The development of a composite resonator assembly, consisting with a parallel coil resonator, a field modulation coil and radio-frequency (RF) shielding for EPR imaging, and a solenoidal detection coil for NMR imaging, Nucl. Magn. Reson., 2007, 36, 363–396 | 367 This journal is

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was described with its first application to EPR/NMR coregistration imaging.34 EPR and NMR images were obtained with both phantom and animal tests. Receiver Coil: An eight-channel receive-only brain coil and table-top detunable volume transmit coil were developed and tested at 7 T for human imaging.35 The sensitivity and coverage of the array is demonstrated with high-resolution images of the brain cortex. Surface coil: An open volume, high isolation, RF system suitable for pulsed NMR and EPR spectrometers with reduced dead time was presented.36 It comprises a set of three RF surface coils disposed with mutually parallel RF fields and a doublechannel receiver. Theoretical and experimental results obtained with a prototype operating at about 100 MHz were reported. The geometrical parameters and operating frequency of the RF assembly were selected as a model for potential applications in solid state NMR and in free radical EPR spectroscopy and imaging. MEMS Helmholtz coils: Miniature coils for MRI/S were demonstrated.37 A rectangular Helmholtz arrangement based on a pair of substrates separated by spherical alignment spacers is investigated. An optimal geometry is developed using simple theory and verified by numerical analysis. Prototypes are fabricated using silicon substrates. Q values of 11 are obtained, and devices containing an internal proton source are developed for use as fiducial markers in H-MRI at 1.5 T. MRS is also performed on the internal source, with a SNR of approximate to 85. Gradient coil: A new design approach, i.e., a stream function method, for the construction of gradient coils for MRI was presented.38 The theoretical formulation involves a constraint cost function between the desired field in a particular region of interest in space and an almost arbitrarily defined surface that carries the current configuration based on Biot-Savart’s integral equation. RF head coils at 7 T: The development of 300 MHz RF head coils analogous to those used at field strengths of 1.5 and 3 T is complicated by increased dissipative losses in conductive tissue, effects arising from the short RF wavelength in biological tissue (about 13 cm at 300 MHz), and the constraints imposed by the use of head gradient sets desirable for mitigating increased static field susceptibility effects. Five RF head coils were constructed and tested on a 7 T scanner including 2 TEM designs, 2 birdcage designs and a local receive-only array.39 Signal-to-noise ratio, coil reception profiles and interactions between the coil and dielectric head were examined. The image profile of the surface coil was found to be less dramatically changed from patterns observed at lower field strength. RF coils at 1.5–11.7 Tesla: Experimental and numerical studies of the MR signal were performed at frequencies ranging from 64 MHz to 485 MHz at 1.5 and 8 Tesla whole-body systems, utilizing three different MRI coils: a single-strut transverse electromagnetic (TEM)-based coil, a TEM resonator, and a high-pass birdcage coil.40 The numerical and experimental studies demonstrate the complexity of the electromagnetic fields and their role in the MR signal. Superconductor Tape RF receiver coil: Using industrial silver alloy sheathed Bi(2 x)PbxSr2Ca2Cu3O10 (Bi-2223) high temperature superconductor tapes, a fiveinch single-turn HTS solenoid coil has been developed, and human wrist images have been acquired with this coil.41 Micromechanical expanding coil: A mechanism for a micromechanical expanding coil designed for use for in vivo MRI was demonstrated.42 The mechanism has a small (1 mm) cross-sectional width, and may therefore be passed through a tubular orifice such as the endoscope channel used for accessing a bile duct. Prototypes are fabricated in bonded silicon-on-insulator material by deep reactive ion etching and undercut. Expansion and latching are demonstrated, and performance characteristics are found to be in good agreement with the theoretical models. Free-ringing microimaging RF coils: Electromagnetic simulation using the transmission-line modeling method in conjunction with electric circuit analysis was applied to extract the tuning and matching requirements of RF coils for MRI.43 Free-ringing microimaging RF coils were modeled in the unloaded and KrebsHenseleit physiological buffer solution loaded condition. 368 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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Linear microstrip surface coil: A new design of RF coil based on a quasitransverse electromagnetic field was described.44 The coil was developed for the acquisition of MRI of the rat spinal cord at 4.7 T. Different materials for the construction of the coil were tested, and the best results were obtained with Teflon. Biaxial planar gradient coils for flow profiles: A package of two planar gradient coils combined with an RF coil was microfabricated for low-field MRI measurements of velocity flow profiles.45 The package generates orthogonal gradients in the radial and velocity encoding directions for standard flow imaging experiments. Velocity resolution was 0.13 mm s 1 for several volumetric flow rates of water in tubes with inner diameters of 1.02 mm and 1.4 mm, which are comparable to that achieved with commercial gradient coils. The quality of the velocity profile was sufficient for viscosity calculations, and thus permits future utilization of this coil package in the design of a portable MRI viscometer. Transmit/receive coil: A half-volume quadrature head transverse electromagnetic (TEM) coil has been constructed for 4 T imaging applications.46 This coil produces a sufficiently large homogeneous B1 field region for the use as a volume coil and provides superior transmission efficiency, resulting in significantly lower power deposition, greater sensitivity and suppressing the RIF penetration artifact. These advantages make it possible to apply this device as an efficient transmit/receive coil for high-field imaging with a restricted field of view. Noncircular section birdcage coil design: A general analytical framework was presented for the design of birdcage radiofrequency resonators on cylindrical formers having arbitrary cross-sectional shape.47 The primary objective of such shapes would be to improve the sensitivity of the NMR experiment to noncircular regions of the human anatomy while maintaining field homogeneity and quadrature polarization comparable to those of standard circular birdcage coils. ROC curves: Receiver operating characteristic (ROC) methods are useful tool for evaluating the sensitivity and specificity of various postprocessing algorithms used in fMRI data analysis. New ROC methods using real fMRI data are proposed that improve a previously introduced method by Le and Hu (Le and Hu, NMR Biomed., 1997, 10:160–164). The proposed methods provide more accurate means of estimating the true ROC curve from real data and thereby aid in the comparative evaluation of a wide range of postprocessing tools in fMRI.48 Active shielding of cylindrical saddle-shaped coils: An exact expression for the magnetic field produced by cylindrical saddle-shaped coils and their ideal shield currents in the low-frequency limit was provided.49 The stream function associated with the shield surface current is also determined. The results of the analysis are useful for the design of actively shielded radio-frequency (RF) coils. Examples pertinent to very low field NMR and MRI are presented and discussed. 3.4 Probe Integrated RF probe: Integrated RF probe for in vivo multinuclear spectroscopy and functional imaging of rat brain using an 11.7 Tesla 89 mm bore vertical microimager was specially designed.50 Design concept and practical aspects of probe construction are described in detail. Typical results from fMRI, localized in vivo proton and multinuclear spectroscopy using this probe system are presented. High temperature H-NMR imaging probe: The design of a novel NMR probe suitable for very high temperature samples was described.51 The loop gap resonator is water cooled and tuned to 100 MHz for use in a 2.4 T horizontal bore magnet. The probe has been specifically designed for imaging of the combustion process. In experiment, the behavior of a methane gas jet when both lit and unlit is described. A computational fluid dynamics model is used to verify the distribution of molecular methane, as well as the temperature of the flame. High-resolution liquid-state spectroscopy probe: NMR microscopy is usually achieved at ultra-high-static magnetic field (4= 9.4 Tesla) with the use of homeNucl. Magn. Reson., 2007, 36, 363–396 | 369 This journal is

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built coils adapted to the size of the sample, resulting in well-resolved images with voxel size smaller than 50 mu m. It was shown that high-resolution imaging can be realized at lower field strength (4.7 Tesla) using 5- and 10-mm probes initially dedicated to vertical magnets.52 Isotropic resolutions (450 mu m) on a biomaterial and on mouse femoris are obtained. 3.5 Artifacts Concomitant gradient artifacts: MRI suffers from artifacts caused by concomitant gradients when the product of the magnetic field gradient and the dimension of the sample becomes comparable to the static magnetic field. A non-perturbative, postacquisition phase correction algorithm was developed to eliminate the effects of concomitant gradients in both the simulated and the experimental images.53 Image artifacts in very low magnetic field MRI: MRI at very low magnetic fields may face problems that are not typical for MRI at conventional and high field (0.1– 10 T). Major differences arise due to the presence of concomitant components of inhomogeneous magnetic field (gradients) that are transverse to the major Bz field, B0. A manuscript derives expressions describing geometrical relationships between the imaged object and the obtained MR data.54 In addition to geometrical distortions, image intensity will be modulated in a complex, spatially dependent manner. B1 field focussing effects at 17.6 Tesla: As Larmor frequencies for high-resolution NMR spectroscopy and microimaging approach 1 GHz, effects such as dielectric resonance and sample-induced spatial inhomogeneities in the radiofrequency transmission and reception fields become more prominent.55 These effects have been studied extensively for high field human imaging, but have received less attention in the areas of NMR spectroscopy and microimaging. Computational and analytical simulations as well as experimental data acquired at 17.6 Tesla was analysed to study high frequency effects for high-resolution NMR, in vivo animal imaging, and microimaging of fixed tissue samples.

4. Pulse sequences and data processing 4.1 Pulse sequences Shim pulses for NMR spectroscopy and imaging: A way to use adiabatic radiofrequency pulses and modulated magnetic-field gradient pulses, together constituting a ‘‘shim pulse,’’ for NMRS and NMRI was demonstrated.56 These pulses capitalize on phase shifts derived from probe gradient coils to compensate for nonlinear intrinsic main magnetic field homogeneity for spectroscopy, as well as for deviations from linear gradients for imaging. This approach opens up the possibility of exploiting cheaper, less-than-perfect magnets and gradient coils for NMR applications. Pattern pulses: A novel class of pulses was presented which can be regarded as a generalization of both frequency-selective pulses and B1-selective pulses.57 The presented pulses were designed numerically based on principles of optimal control theory. Flexibility of this approach is demonstrated by simulations and experiments. As the first practical application, a direct approach for calibrating RF pulses was presented. This previously unknown flexibility may trigger novel applications in NMRI/S. Multi-spin-echo J-resolved spectroscopic imaging: The feasibility of J-resolved spectroscopic imaging based on a multi-echo sequence and without water suppression was demonstrated, which has ability to separate the peaks for lactate and mobile lipid in a rat glioma at 7 T.58 Maps of N-acetylaspartate, choline, creatine, lactate and mobile lipids were obtained in vivo on a rat glioma in 70 min. The inplane resolution was 2 mm2. Bayesian image decomposition to relaxographic imaging: T1 relaxographic imaging is a precise and accurate way to characterize tissue. A number of fast MRI 370 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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acquisition techniques allow both spatial and magnetization recoveries to be well sampled in reasonable imaging times. However, there are two common limitations to the analysis of T1 relaxographic imaging data, i.e., the assumption of single exponential behavior for each image voxel and the treatment of each pixel as an independent entity. A new Bayesian Image Decomposition overcomes these limitations.59 A specific advantage of the new method is the ability to determine fractional contributions of tissue subtypes to each image voxel. Acquisition time reduction in MRSI: A new MRSI technique based upon the discrete wavelet transform reduces acquisition time and cross voxel contamination.60 Prototype functions called wavelets are used in wavelet encoding to localize defined regions in localized space by dilations and translations. Wavelet encoding in MRSI is achieved by matching the slice selective RF pulse profiles to a set of dilated and translated wavelets. An inverse wavelet transform is performed on the data to produce the correct spatial MR signal distribution. Rotating-frame intermolecular 2D-T1p,(DQC)-weighted MRI61: A novel MRI methodology based on intermolecular multiple-quantum coherences is demonstrated on a 7.05-T microimaging scanner. Spin-locking techniques were added as a part of intermolecular multiple-quantum experiments, thereby introducing the concept of rotating-frame intermolecular double-quantum spin-lattice relaxation, T1p,-TDQC. The results clearly reveal that T-1p,T-DQC-weighted imaging technique provides an alternative contrast mechanism to conventional imaging. Triple-quantum-filtered imaging of 23Na: These techniques have been recently demonstrated in vivo.62 These techniques have been previously advocated as a means to separate the 23Na NMR signal from different physiological compartments based on the differences of their relaxation rates. While the three-pulse structure has distinct advantages in terms of RF efficiency, the lack of a refocusing pulse in the filter introduces an increased dependence on the main magnetic field inhomogeneities, which can sometimes lead to significant signal loss. In this paper, these dependencies were characterized and a method for their compensation was introduced through the acquisition of a B0 map and the use of a modified phase cycling scheme. Multiple-quantum vector field imaging: A method for non-invasively mapping fiber orientation in materials and biological tissues using intermolecular multiplequantum coherences was introduced.63 The nuclear magnetic dipole field of water molecules is configured by a CRAZED sequence to encode spatial distributions of material heterogeneities. Chemical exchange dependent saturation transfer imaging: Exchangeable solute protons are saturated and the transfer of saturation to water is subsequently detected iIn chemical exchange dependent saturation transfer imaging experiments. The proton transfer (PT) process is modeled using a two-pool system.64 An empirical general proton transfer ratio (PTR) equation for arbitrary RF irradiation power is derived, and its optimal power to maximize the PTR is analyzed. The results are confirmed experimentally on 4.7 T using a poly-L-lysine solution. The theory provides a useful tool for optimizing the irradiation power of the PT sequences in the presence of direct saturation effects. Improved time efficiency and accuracy in diffusion tensor microimaging: In highfield NMR microscopy rapid single-shot imaging methods, for example, echo planar imaging, cannot be used for determination of the apparent diffusion tensor (ADT) due to large magnetic susceptibility effects. A pulse sequence in which a diffusionweighted spin-echo is followed by multiple gradient-echoes with additional diffusion weighting was presented.65 These additional echoes can be used to calculate the ADT and T2* maps. The method was tested oil excised, chemically fixed rat spinal cords. Analysis of b-value calculations in Dw-I and DTI: Diffusion weighted imaging has opened new diagnostic possibilities by using microscopic diffusion of water molecules as a means of image contrast. The directional dependence of diffusion has led to the development of diffusion tensor imaging, which allows us to characterize microscopic tissue geometry. However, in the calculation of b-matrix elements, the Nucl. Magn. Reson., 2007, 36, 363–396 | 371 This journal is

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influence of imaging gradients on each element of the b matrix is often neglected. This may cause errors, which in turn leads to an incorrect extraction of diffusion coefficients. The systematic errors can be avoided by a full b-matrix calculation considering all the gradients of the sequence or by generating cross-term free signals using the geometric average of two diffusion weighted images with opposite polarity.66 Velocity imaging by ex situ NMR: A PFG stimulated spin-echo NMR sequence is combined with imaging methods to spatially resolve velocity distributions and to measure 2D velocity maps ex situ.67 The implementation of these techniques in open sensors provides a powerful non-invasive tool to measure molecular displacement in a large number of applications inaccessible to conventional closed magnets. Different pipe geometries are used to demonstrate that the sequence performs well even in the extremely inhomogeneous B0 and B1 fields of these sensors. Visualization of slow flow: A new pulse sequence for visualizing slow flow was presented, which consists of an initial Stejskal-Tanner flow sensitization part followed by a DEFT pulse and a spoiler gradient.68 A single-shot TSE readout train is then applied to sample the NMR signal. The sequence was initially tested using a simple flow phantom and then both flow-sensitive MRCP and cerebrospinal fluid (CSF) images were produced as potential clinical use. Ultra low temperature (ULT)-MRI, Field Cycling method; Dynamics of the 1st order phase transition between the U2D2 and the high field phases (HFP) was studied by field-cycling method between these phases by using ULT-MRI.68 Single Crystal of U2D2 3He was produced at the bottom of compressional cell in superfluid 3 He-B at about 0.5 mK. Domain distribution in the U2D2 crystal was examined by ULT-MRI. Simultaneous water and lipid suppression: A method to achieve simultaneous water and lipid suppression was described.70 The key feature of the new dual suppression technique is the use of the well-known hyperbolic secant (HS) waveform as a 90 degrees saturation pulse. Two HS pulses with opposite frequency offsets are employed either sequentially or simultaneously to saturate resonance frequencies corresponding to water and lipid, while leaving the target spins untouched. Zero- to low-field MRI: MRI encounters fundamental limits in circumstances in which the static magnetic field is not sufficiently strong to truncate unwanted. The use of pulsed magnetic-field averaging toward relaxing these constraints was introduced.71 It is found that the image of an object can be retrieved by pulsed low fields in the presence of the full spatial variation of the imaging encoding gradient field even in the absence of the typical uniform high-field time-independent contribution. In addition, error-compensation schemes can be introduced through the application of symmetrized pulse sequences. Such schemes substantially mitigate artifacts. 4.2 Data acquisition/data processing Ultrafast acquisition schemes: Recently, an approach that enables the acquisition of multidimensional NMR spectra within a single scan has been proposed and demonstrated. The applicability of such ultrafast acquisition schemes toward the collection of 2D MRI data was explored. The new methodology also offers the possibility of implementing the single-scan acquisition of 2D MRI images using sinusoidal gradients, without having to resort to subsequent interpolation procedures or non-linear sampling of the data.72 Theoretical derivations on the operational principles and imaging characteristics of a number of sequences based on these ideas are derived, and experimentally validated with a series of 2D MRI results collected on a variety of model phantom samples. Optimization of basic parameters: A least square method was demonstrated for optimization of basic parameters for selected physical experiment design where large input parameter measurement and adjustment is needed. The speed of calculation and experimentally verified results are promising to use this method in many 372 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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physical projects. Authors have demonstrated this method for computation of feeding currents of correcting coils for stationary magnetic field used in NMR imaging.73 The proposed method, because of its simplicity and speed of computation, is convenient for basic adjustment of the magnetic field homogeneity by the first magnet installation. It is also suitable for periodic testing and magnet inhomogeneity correction for MRI magnets. Optimal quantification of time signals: The fast Pade transform (FPT) is both a parametric and a nonparametric estimator that is capable of quantifying the input raw time signals without any fitting. The FPT simultaneously interpolates as well as extrapolates, and this is expected to mitigate truncation artifacts. To establish the accuracy, robustness, and efficiency of the FPT within the outlined multi-level strategy, a time signal encoded via MRS at 4 T from the brain of a healthy volunteer was used.74 The convergence rates of the fast Pade transform (FPT) and the fast Fourier transform (FFT) are compared. These two estimators are used to process a timesignal encoded at 4 T by means of one-dimensional MRS for healthy human brain.75 It is found systematically that at any level of truncation of the full signal length, the clinically relevant resonances that determine concentrations of metabolites in the investigated tissue are significantly better resolved in the FPT than in the FFT. Non-invasive MR thermography: Among various proton MR parameters, such as T1, T2, diffusion coefficient and chemical shift, the chemical shift of water protons is recognized as the most reliable indicator of temperature. The chemical shift is the only frequency-based parameter and is independent of the other parameters, which are measured based on the intensity of the MR signal. The basic principle and the recent progress in imaging temperature by spectroscopic techniques using the water proton chemical shift are discussed.76 Methods utilizing various MRS techniques, such as single voxel spectroscopy, conventional MRSI, echo planar spectroscopic imaging (EPSI) and line scan echo planar spectroscopic imaging (LSEPSI) are discussed. Applications of lanthanide complexes for temperature measurement in intact animals and the feasibility of mapping temperatures in phantoms have been demonstrated.77 Among all the lanthanide complexes examined so far, thulium 1, 4, 7, 10-tetramethyl-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetate (TmDOTMA ) appears to be the most attractive for in vivo MR thermometry. The H-1 signal from 12 methyl groups on this complex is relatively intense and provides high temperature sensitivity because of the large paramagnetic shifts induced by thulium. A novel and fast time-domain quantitation algorithm: Quantitation based on semi-parametric quantum estimation (QUEST)-invoking optimal prior knowledge is proposed and tested.78 This nonlinear least-squares algorithm fits a time-domain model function, made up from a basis set of quantum-mechanically simulated whole-metabolite signals, to low-SNR in vivo data. A basis set of in vitro measured signals can be used too. The simulated basis set was created with the software package NMR-SCOPE which can invoke various experimental protocols. Fitting variable spectral line-shapes: Two time-domain models for fitting variable spectral line-shapes are examined, one using B-splines and another using summed sinusoids.79 The methods were verified using both phantom and human data, and Monte Carlo simulations were used to evaluate variations in calculated metabolite amplitudes due to interactions between the baseline and line-shape estimations.

5. Other nuclei 5.1 Review The fluorine atom, 19F, provides an exciting tool for diverse spectroscopic and imaging applications using magnetic resonance.80 The organic chemistry of fluorine Nucl. Magn. Reson., 2007, 36, 363–396 | 373 This journal is

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is widely established and it can provide a stable moiety for interrogating many aspects of physiology and pharmacology in vivo, such as gene activity, pH, metal ion concentrations (e.g., Ca2+, Mg2+, Na+), oxygen tension, hypoxia, vascular flow and vascular volume. 19F-NMR may be used to trace the fate of fluorinated drugs, such as chemotherapeutics (e.g., 5-fluorouracil, gemcitabine), anesthetics (e.g., isoflurane, methoxyflurane) and neuroleptics. Indeed, the large chemical shift range (similar to 300 ppm) can allow multiple agents to be examined, simultaneously, using NMR spectroscopy or chemical shift selective imaging. Results of 87Rb-MRS/I studies of K+ transport were summarized as a review in mammalian cells, organs and in vivo.81 It provides a brief description of K+ transport systems, their interactions with Rb+ and evidence that Rb+ is a best K+ congener. 87Rb-MR studies have focused mostly on isolated perfused rat and pig hearts and to a lesser extent on kidney, skeletal muscle, salivary gland and red blood cells. Three-dimensional (3-D) spectroscopic MRI of isolated beating pig hearts has been used to obtain time series of Rb+ maps of normal and ischemic/infarcted hearts, which showed lower image intensity in the damaged area. Kinetics of Rb+ uptake in the ischemic areas depended on both regional flow and metabolism. 87 Rb-MRI was also able to localize ischemia and infarction in blood-perfused hearts. 87 Rb-MRS/I is an excellent non-invasive research tool for studies of K+ transport in isolated organs and in vivo. Some examples of the applications of the NMR of xenon used as a probe in the study of different chemical environments was presented:82 determination of the porosity of micro-and meso-porous solids, evaluation of the concentrations and sizes of amorphous domains in solid polymers, characterization of liquid crystals, study of combustion processes at high temperature, determination of the structure and dynamics of organic systems and proteins in solution, assessment of cerebral blood flow. The production of hyperpolarized 129Xe by spin-exchange optical pumping is an important experimental issue because of numerous applications in NMR spectroscopy and imaging. The experimental data was compared with a model for threedimensional transport processes within a so-called batch mode pump cell via numerical finite element method simulations.83 In particular, the influence of different experimental parameters, such as temperature, xenon and nitrogen partial pressure, laser power, and radius-to-length ratio of a cylindrical pump cell, is evaluated. The developed numerical method is capable of describing the spinexchange optical pumping process in a realistic manner. 5.2

13

C NMRI

The distortionless enhancement by polarisation transfer (DEPT) NMR technique, combined with magnetic resonance imaging, has been used to provide the in situ spatially-resolved and quantitative measurement of chemical conversion and selectivity within a fixed-bed reactor using natural abundance 13C-NMR.84 In situ 13C DEPT-MRI is also used to provide the first spatial mapping of alkene isomerisation and hydrogenation during an alkene hydrogenation reaction occurring within a trickle-bed reactor.85 The implementation of a pulse sequence combining the spatial resolution of a MRI pulse sequence with a 13C DEPT MRS pulse sequence enables spatially resolved 13C spectra to be recorded of natural abundance 13 C species. In this preliminary study the ability of this technique to identify the effect of changing the hydrogen flow rate on the evolution of isomerisation and hydrogenation processes occurring along the length of the bed is demonstrated. MRS provides information about neuronal loss or dysfunction by measuring decreases in N-acetyl aspartate (NAA), a metabolite widely believed to be a marker of neuronal viability. Multi-slice echo-planar spectroscopic imaging (EPSI) is presented as a promising alternative to single-voxel or nonlocalized spectroscopy for obtaining global metabolite estimates in multiple sclerosis.86 374 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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5.3

23

Na NMRI

A model study on movements of sodium ions in pork, loin during brining was carried out using 23Na-MRI.87 Samples of different pH and post-mortem age were mounted in Plexiglas (R) cylinders with built-in phantoms and cured in 18.9% and 18.1% NaCl (w/v), respectively. One-dimensional 23Na-MRI and apparent diffusion coefficient (ADC) profiles were obtained over 5 days with intervals of 24 h. The diffusion coefficient is suggested to be affected by changes in NaCl concentration, swelling and degree of dehydration. Previous magnetic resonance imaging studies have concentrated on pathologically induced changes in cardiac structure and dynamics by acquiring 1H images. Further information can be gained by studying cardiac function and physiology using other nuclei, for example, 23Na. The first in vivo 23Na microscopic images of the mouse heart, with an isotropic spatial resolution of 1 1 1 mm, acquired in a time of 1.5 h was presented by using density-weighted chemical shift imaging at a high magnetic field strength (17.6 T).88 Sodium imaging of such a small structure presents considerable technical challenges. The ventricles, septum and myocardium are readily distinguishable in these images. Fully relaxed, very short-echo, 23Na twisted projection imaging (TPI) with adiabatic half passage (AHP) excitation was used to quantify tissue sodium concentrations in the human heart.89 23Na signal losses during hard square, composite, and tanh/tan amplitude/frequency-modulated AHP excitation pulses were analyzed over a wide range of RF field strengths and T2 short values. It is concluded possibility to non-invasively quantify tissue sodium concentrations in the human heart with surface coil 23Na-MRI. Sodium imaging with soft inversion recovery fluid attenuation, which may be advantageous for intracellular weighting, was demonstrated with cerebrospinal fluid (CSF) suppression in five healthy volunteers at 4.7 T.90 Long rectangular inversion pulses (10-ms) reduce the average power deposition in an inversion recovery sequence, allowing repetition time to be shortened and more averages acquired for a given scan length.

5.4

27

Al-NMRI

A dynamic in situ study of alpha-methylstyrene catalytic hydrogenation on a single catalyst pellet or in a granular bed is performed using 1H-MRI and spatially resolved 1 H-NMR spectroscopy.91 Owing to reaction exothermicity, a reciprocating motion of the liquid front within the pellet accompanied by pellet temperature oscillations has been observed. Two-dimensional 27Al-NMR images of alumina catalyst supports and other alumina-containing materials have been detected using moderate magnetic field gradients (80 G/cm) and a two-pulse spin-echo sequence. Temperature dependence of signal intensity and 27Al T1 time of alumina are considered as possible temperature sensors for NMR thermometry applications.

5.5

129

Xe-NMRI

Pipeline materials: In order to establish a continuous hyperpolarized 129Xe (HP–129Xe) gas delivery system for MR imaging, the effect of the metallic materials in the gas pipeline on the signal intensity was investigated.92 Five stainless steel tubes with different surface film-forming processes were examined. The MR signal intensities of HP-129Xe gas passed through the tubes were compared. The stainless steel tubes passivated by iron fluoride maintained the highest level of hyperpolarization, whereas that passivated by chromium oxide maintained the lowest. A stainless steel with an appropriate passive film may be a useful alternative to a Pyrex glass pipeline which is a popular material for the HP gas chamber. Nucl. Magn. Reson., 2007, 36, 363–396 | 375 This journal is

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Brute force polarization of 129Xe: As an alternative to the laser optical pumping method of production of hyperpolarized 129Xe gas, the brute force technique have investigated, which uses a very high magnetic field and millikelvin temperatures.93 One obstacle to this technique is the extremely long spin lattice relaxation times of nuclei in solids at very low temperature. The authors exploited the fact that liquid 3He can be used as an effective relaxant to enable 129Xe to be spin polarized on a high surface area substrate in a few hours. The technique could be applied to nuclei other than 129Xe. Optimum field strength for HNG imaging: Theoretical signal-to-noise ratio and spatial resolution dependence on the magnetic field strength for hyperpolarized noble gas (HNG) MRI of human lungs was discussed.94 In this work, the optimum field strength for HNG MR imaging was theoretically calculated in terms of both SNR and spatial resolution. The effects of susceptibility differences, transverse relaxation time, and diffusion were considered in the resolution calculations. The findings suggest that HNG imaging may be optimally performed at much lower field strengths (0.1–0.6 T) than conventional clinical proton MR imaging systems. This could considerably decrease cost, improve patient access, and reduce chemical shift and susceptibility artifacts and rf heating. Polymer gel dosimeters using 129Xe NMR: It was shown that high resolution NMR measurements of 129Xe provide a novel method for probing radiation dose effects in irradiated polymer gels.95 Polymer gel dosimeters consist of monomers, with or without cross-linking agents, dispersed in a gel. Upon exposure to ionizing radiation, polymerization proceeds within the gel matrix, thereby changing several measurable physical properties that can then be related quantitatively to absorbed dose. MRI has been used successfully to measure 3D dose distributions in irradiated polymer gels. The changes of the chemical shift of xenon gas (129Xe) dissolved in a gel with absorbed dose was detected and the potential use of high resolution xenon NMR spectra was indicated for better understanding the dose response of gels. For doses ranging from 0 Gy to 40 Gy, authors found that the mean chemical shift of 129 Xe was linearly related to dose, and that the gel dosimeter could be described in terms of a two-component model undergoing fast exchange.

6. Dynamics: diffusion, flow, and velocity NMR imaging and spectroscopy techniques have been applied to dynamic phenomena, such as diffusion, flow and filtration of liquids, gases and granular solids in various geometries and to the in situ studies of the interplay of mass transport and catalytic reactions in porous media. 6.1 Review Topics are quantitative spatially resolved maps of flow velocities of liquids and gases in the channels of monoliths, a comparative study of the filtration of water and propane through model porous media, the gravity driven flow of liquid-containing solid particles, and the distributions of particle velocities for various flow rates.96 The NMR imaging technique was employed to visualize the propagation of autocatalytic waves for the Belousov-Zhabotinsky reaction carried out in a model porous medium. Iin the catalytic hydrogenation of alpha-methylstyrene on a single catalyst pellet, change of the distribution of the liquid phase within the pellet during the reaction and the accompanying phase transition has been revealed. 6.2 Diffusion Diffusion(hydration) the diffusion of a water solution of hydrochloric acid and sodium hydrochloride into hydroxypropylmethyl cellulose matrices was monitored by MRI at 300 MHz.97 Polymer in the form of a cylinder was hydrated in a water solvent of pH = 2, 7, and 12 at 371. The spatially resolved T2 relaxations times and 376 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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spin densities along with a change in the dimension of the glass core of the polymer were determined for hydroxypropylmethyl cellulose tablets as a function of hydration times. The time dependence of the diffusion front and proton-density analysis clearly indicate a case II diffusion mechanism in the system composed of a water solution of hydrochloric acid (pH = 2) and hydroxypropylmethyl cellulose, whereas in the case of water solutions with pH = 7 and 12 the anomalous and case I diffusion are observed, respectively. Mapping complex tissue architecture by Diffusion: Methods are presented to map complex fiber architectures in tissues by imaging the 3D spectra of tissue water diffusion with NMR.98 First, theoretical considerations show why and under what conditions diffusion contrast is positive. Second, studies of in vitro and in vivo samples demonstrate correspondence between the orientational maxima of the diffusion spectrum and those of the fiber orientation density at each location. In specimens with complex muscular tissue, such as the tongue, diffusion spectrum images show characteristic local heterogeneities of fiber architectures, including angular dispersion and intersection. Finally, the relation between the presented model-free imaging technique and other available diffusion MRI schemes is discussed. Emulsion Droplet Size Distribution: Pulsed field gradient NMR is well established as a tool for determining emulsion droplet-size distributions via measurement of restricted self-diffusion. Most measurements have not been spatially resolved, but have measured an average size distribution for a certain volume of emulsion. A rapid method of performing spatially resolved, restricted diffusion measurements was reported, which enables emulsion droplet sizing to be spatially resolved as a function of radius in cylindrical geometries or pipes.99 This is achieved by the use of an Abel transform. The technique is demonstrated in various annular systems containing two emulsions, with different droplet-size distributions, and/or a pure fluid. It is also shown that by modifying the pulse sequence by the inclusion of flow-compensating magnetic field gradients, the technique can measure spatially resolved droplet-size distributions in flowing emulsions, with potential applications in spatially resolved on-line droplet-size analysis. Cellular size distribution effect: In the magnetic resonance community, the usefulness of diffusion-weighted imaging (DWI) is undisputed. However, the correct interpretation of multicomponent diffusion is not widely agreed upon, and progress in this direction is impeded by several confounding experimental results. In order to resolve possible interfering factors, to examine the influence of a cellular size distribution is objected.100 Using the Karger equations, numerical calculations show that even substantial cellular size variations induce only small changes in the estimated compartmental diffusion constants and volume fractions. Diffusion of water in Nafion membrane: Direct methanol fuel cell (DMFC) is a promising energy source for potable electric devices. However the local structure and the transport mechanism of the water and the methanol in the solid electrolyte membrane have not been well understood. Recent results of the proton NMR spectra and diffusion measurements of water and methanol in Nafion 117 was reported 101 and also, the NMR micro-imaging technique has been applied for the diffusion and exchange of water molecules in the membrane. The chemical shift decreased monotonically as the water content increased at water uptake ratio N similar to 6. Diffusion of the water molecule into and out of the Nafion membrane was visually observed by using NMR micro-imaging technique. Exchange process of the water (H2O) and heavy water (D2O) in a small Nafion ball (3 mm diameter) was observed and density profile of proton was analyzed to give the mutual diffusion coefficient of H2O and D2O in the Nafion ball. Two types of solid polymer electrolyte (SPE) membrane, Nafion(R) and Flemion(R), were investigated at various water contents.102 Self-diffusion coefficients of water in the SPE membrane were measured using pulsed field gradient spin echo NMR measurement. NMR imaging technique can be applied to probe water behaviors in the membrane assembled in fuel cell under operation. It is observed Nucl. Magn. Reson., 2007, 36, 363–396 | 377 This journal is

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that the membrane gradually dried after the fuel cell began to be operated, resulting in decreasing output current. 6.3 Flow Flow an microstructure of concentrated emulsions: New experimental methods for studying flow and microstructure of concentrated emulsions are demonstrated.103 The objective is to present the unique features of this noninvasive technique to accurately measure different properties of flowing particulate opaque systems. Experimental results of velocity profiles, spatial distribution of droplet sizes and spatial homogeneity of an oil-in-water dispersion in a horizontal, concentric cylinder geometry using different pulse sequences are presented. The application of these techniques allowed probing important information on flow and microstructure of multiphase systems of interest in chemical engineering and food science. Time-of-flight flow imaging of gas flow: To obtain spatially and temporally resolved profiles of gas flow in microfluidic devices, remote detection of the NMR signal both overcomes the sensitivity limitation of NMR and enables time-of-flight (TOF) measurement in addition to spatially resolved imaging.104 Thus, detailed insight is gained into the effects of flow, diffusion, and mixing in specific geometries. The ability for noninvasive measurement of microfluidic flow, without the introduction of foreign tracer particles, is unique to this approach and is important for the design and operation of microfluidic devices. This technique extends to liquids, which have higher density. The TOF technique not only facilitates a time-dependent imaging of fluid flow, it also allows a separate optimization of encoding and detection subsystems to enhance overall sensitivity. The technique is demonstrated by imaging gas flow through a porous rock.105 Gas-liquid phase distribution and void fraction measurements: A permanentmagnet MRI system (0.26 T) was used to estimate the integral, spatially- and temporally-resolved void fraction distributions and flow patterns in vertical gasliquid two-phase flow.106 Air was introduced at the bottom of the stagnant liquid column using an accurate and programmable syringe pump (air flow rate: 1 and 200 ml/min). The cylindrical non-conducting test tube in which two-phase flow is characterized was placed in a permanent-magnet MRI unit. No great accuracy is claimed as this was an exploratory proof-of-concept type of experiment. Preliminary results show that MRI can indeed provide qualitative and quantitative data and is especially well suited for characterization of averaged transport processes in adiabatic and diabatic multi-phase and/or multi-component flows. 6.4 Flow/velocity contrast/velocimetry NMR imaging and spectroscopy techniques are applied to study flow and different NMR techniques were combined to obtain the structure and velocity information. Visualizing flow velocity inside a single levitated drop: The internal flow dynamics in single liquid drops, kept in place through levitation by a counterflowing continuous fluid phase in a suitably designed glass cell, is investigated by PFG NMR techniques.107 Velocity distribution functions (propagators) along all three coordinates were obtained and demonstrated the long-time stability of the internal dynamics in terms of the velocity magnitudes occurring in the systems. Finally, different fast velocity imaging techniques were applied to visualize the internal vortex patterns in the drops either as projections onto different planes or within thin slices of selected orientations and the high sensitivity of the internal three-dimensional motion to the cell geometry is demonstrated. Flow field in biofilm reactors: 3-D MRI was used to measure the flow field of water in a packed-bed column containing Serratia sp. biofilm supported on polyurethane foam, and subsequently to follow a reaction which precipitates lanthanum phosphate on the biofilm.108 Sensitizing the MR image contrast to the fluid flow, i.e., 378 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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‘‘velocity contrast’’, along the axis of the bioreactor provided better image-contrast between the foam and fluid compared to that based on MR signal intensity alone. Data acquired during progressive blockage of reactors challenged at two different flow rates accord with reactor theory. MR velocimetry was used to generate data that can be used to model reactors where the efficiency is progressively compromised by blockage due to precipitation. Similar measurements were also demonstrated on glass tubes (16 mm diameter, 70 mm length) packed with cubes of polyurethane foam coated with Citrobacter sp. biofilm.109 Visualization of flow pattern and pore structure: The structure and velocity information for a systematic investigation of fixed beds with low aspect ratio (tube diameter to particle diameter, d(t)/d(p)) in the range 1.4 to 32 was obtained.110,111 The structure of the void space was determined for a variety of packed beds of glass beads or regular and irregular porous pellets. By combining MRI with velocity encoding, velocity profiles and distributions of flow velocity components of a single fluid phase through packed beds have been acquired. Moreover, a visualization of flow pattern in the presence of packed particles was achieved by using a tagging technique, and the stationary flow field could be identified for an experimental time of several hours. Velocity mapping with microscopic resolution: Quasi two-dimensional random site percolation model objects have been prepared using a synchrotron radiation lithography technique with a spatial resolution better than 50 pin and an aspect ratio of up to 17. Flow of water through the pore space was studied with the aid of an NMR velocity mapping method and compared with a computational fluid dynamics simulation.112 In order to be able to measure and map widely distributed flow velocities with microscopic resolution (typically 40 40 mu m), an experimental protocol that permits one to cover an effectively very wide velocity field of view (0.6– 10 mm/s) had to be developed.

6.5 Biofilm structure/metabolite/detachment NMR/optical microscopy technique: Novel procedures and instrumentation, the combined NMR/optical microscopy technique, are developed for the study of live, in situ microbiofilms under known, controlled growth conditions. A perfused NMR/ optical microscope sample chamber containing a planar biofilm support was integrated into a recirculation/dilution flow loop growth reactor system and used to grow in situ Shewanella oneidensis strain MR-1 biofilms.113,114 Localized NMR techniques were developed and used to non-invasively monitor time-resolved metabolite concentrations and to image the biomass volume and distribution. As a first illustration of the feasibility of the methodology an initial 13C-labeled lactate metabolic pathway study was performed, yielding results consistent with existing genomic data for MR-1. These methods are equally applicable to other biofilm systems of interest; thus they may provide a significant contribution toward the understanding of adherent cell metabolism. Detachment of biomass from biofilms is still a nearly unknown process which has to be investigated in more detail. MRI is used as a promising method which supplies information on the structural data of the biofilm, its surface and the hydrodynamic conditions at the bulk/biofilm interface. Both the structural data and the shear stress are key parameters for understanding biofilm detachment. A fast quantitative MRI technique was used to investigate the detachment from a heterotrophic biofilm which was grown in a tube reactor.115 The investigated biofilm was cultivated in a test segment (length 12 cm, diameter 7 mm) of a tube reactor at a constant Reynolds number of 3000 and a substrate load from 6 g glucose/m2 and day. Flow velocity and relaxation time were then measured at laminar flow conditions. The MR images show very impressively the increasing detachment of biomass from the biofilm (1200 mu m thickness) surface with increasing Reynolds number. Nucl. Magn. Reson., 2007, 36, 363–396 | 379 This journal is

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6.6 Process analysis Drying/Heating: The distribution of water in the impregnated monolithic substrates was visualized by 1H-NMR imaging.116 The two-dimensional water content maps along the axial and radial directions have been collected for different monoliths at variation of the drying conditions. Characteristics of drying of alumina monoliths, calcined at 600, 900 and 1200 degrees C having differences in the pore structure and pore distribution, are studied. During drying of the impregnated washcoated monolith the certain part of the introduced active component precursor (H2PtCl6 or H2PdCl4) is transported from the substrate macropores to the mesoporous washcoated layer, which leads to enrichment of the washcoat of the final catalyst by active component. Removal of capillary water: The effects of the nature of oxide component and binder, and thermal treatment temperature (1001 and from 600 to 13001) on textural and physicochemical properties of honeycomb monoliths based on alumina, titania and aluminosilicates have been studied.117 The textural changes of monolith samples at different preparation stages from extrusion to thermal treatment were mostly caused by removal of capillary water (20–1001), sintering of small pores and consolidation of oxide particles (100–7001), and phase transformation of the oxide component or the binder (900–13001). Liquid phase in multiphase catalytic reactors: NMR imaging was used to study the distribution of the liquid phase in an operating trickle bed reactor using hydrogenation of alpha-methylstyrene or n-octene-1 as representative examples. Detection of spatially resolved NMR spectra was used to characterize chemical conversion variations within the operating reactor.118 Preliminary MRI results for an operating monolithic reactor were obtained. It was found that MRI can be used to directly image solid materials using NMR signal detection of nuclei other than 1H. In particular, imaging of alumina using 27Al-NMR signal appears highly promising for the development of novel MRI applications in chemical engineering and catalysis, including spatially resolved NMR thermometry. Initial diffusion of high-amylose starch tablets: The penetration of water into cross-linked high amylose starch tablets was studied at different temperatures by NMR imaging, which follows the changes occurring at the surface and inside the starch tablets during swelling.119 The swelling was anisotropic, whereas water diffusion was almost isotropic. The water proton image profiles at the initial stage of water penetration were used to calculate the initial diffusion coefficient. Diffusion behavior changed from Fickian to Case 11 diffusion with increasing temperature. The observed phenomena are attributed to the gelatinization of starch and the pseudo-cross-linking effect of double helix formation. Water uptake and distribution: The regulation of water uptake of germinating tobacco (Nicotiana tabacum) seeds was studied spatially and temporally by in vivo NMR microimaging and 1H-magic angle spinning NMR spectroscopy.120 Water distribution in the water uptake phases II and III was inhomogeneous. The micropylar seed end is the major entry point of water. The micropylar endosperm and the radicle show the highest hydration. Structural, material and moisture sorption changes in germination of tobacco were followed. Presented results support the proposal that different seed tissues and organs hydrate at different extents and that the micropylar endosperm region of tobacco acts as a water reservoir for the embryo. Swelling and Moisture movement: The water absorption characteristics of small specimens of oriented strandboard (OSB) and solid wood was observed in a NMR microimaging facility.121 The procedure allowed a specimen to be surrounded in water while remaining in a fixed position within the imaging coil, after which the water could be removed and the specimen immediately imaged. This technique permitted images of the specimen to be taken after a number of different periods of water soak without having to remove and replace the specimen, thus easily 380 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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maintaining the same image location. Both the distribution of free water and its movement as a function of time were observed using this technique. Archaeological waterlogged wood: MR Relaxation and MRI are used to obtain detailed information on the pore space structure. These techniques are particularly suitable for Cultural Heritage materials, because interaction with water is one of the main causes of deterioration of Cultural Heritage materials. The study of some wood finds coming from Ercolano’s harbour was undertaken by using NMR and MRI under different conditions, and a characterization of pore space in wood and images of the spatial distribution of the confined water in the wood was demonstrated.122 Hydration and water transport in the surface layers: A portable NMR-MOUSE has been used to follow the hydration of gypsum based plaster, a Portland cement paste and concrete mortar.123 The results compare favourably to those obtained using a standard laboratory bench-top spectrometer. Further, STRAFI based methods have been used with embedded NMR detector coils to study water transport across a mortar/topping interface. The measured signal amplitudes are found to correlate with varying sample conditions. Sucrose solution freezing: Ice formation of a 20% w/v sucrose solution was monitored during the freezing process.124 The NMR signal intensity of particular sampled volumes was observed during the entire cooling period from 0 to 50 1C, showing a peak characteristic to a transition before the loss of the signal. Spatial ice distribution of the frozen matrix was observed by high resolution MRI with an isotropic resolution of 78 78 78 mu m3. MRI has proved to be a novel technique for determining the glass transition temperature of frozen sucrose solutions, in the concentration range where calorimetric measurements are not feasible. Hydrocarbon displacement in a porous soil: The direct detection of hydrocarbon fluid and the discrimination of water through 13C-NMR Imaging would be a significant advance in many scientific fields including food, petrogeological, and environmental sciences. However, the low natural abundance of 13C, low gyromagnetic ratio, and generically short transverse signal lifetimes in realistic porous media all conspire to hinder 13C-MRI. A multiple echo pure phase encode MRI technique was introduced helps to overcome these limitations.125 Viscous hydrocarbon flow through a sand bed, a simple realistic porous medium, was used as our test system. Flow in this model system was driven by capillary suction. The detection limit, spatially resolved, was determined to be 26 mg. Coke residues in porous catalyst pellets: The distribution of coke residues inside porous catalyst pellets was investigated on the molecular as well as the macroscopic scale.126 The presence of coke on the pore surface affects the relaxation properties of adsorbed liquid species; these were determined by field-cycling relaxometry for different polar and nonpolar liquids in metal-doped and metal-free catalyst carrier materials. Not only relaxation times but also the diffusion coefficient is affected by the presence of coke residues in the pores. For macroscopically heterogeneous samples, they offer the possibility to generate maps of the local coke concentration by introducing appropriate filters into NMR imaging sequences. Interfacial properties of asphalts: An NMR imaging method that allows for direct calculation of interfacial surface tensions of asphalts is described.127 The method is based upon acquiring NMR images of water drops on the surface of asphalt as a function of time. By expressing the contact angle for the water drop either in terms of Young’s equation, or the liquid lens equation for the initial placement of the water drop on the asphalt surface, and for a later time when the water drop has penetrated below the asphalt surface, two equations that incorporate the asphalt-air surface and asphalt water interfacial tensions are obtained which can be solved analytically. The NMR imaging method was also used to determine the surface tensions. These results are in general agreement with other asphalt surface tension measurements, such as the du Nouy ring tensiometer, or the Wilhelmy Plate method. Observation of water in concrete structure: A range of MRI measurements of water in concrete samples and their constituent materials is described and it is Nucl. Magn. Reson., 2007, 36, 363–396 | 381 This journal is

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demonstrated that MRI can be used to (1) discriminate the spatial distribution of aggregates within a fresh sample, (2) measure changes in water content during the hardening process of cement, and (3) detect fractures and voids within a watersaturated sample.128 MRI of the internal structure of concrete are presented, which allow the aggregate, sand and matrix to be distinguished as well as any voids that are present. It is shown from experiments that the measurable water present in wet concrete is in two forms, and the amount and proportions of these two components alters during hardening, which allows the progress of the associated chemical reaction to be studied. Noninvasive in situ visualization of supported catalyst preparations was reported via multinuclear magnetic resonance Imaging.129

7. Polymer 7.1 Reviews Pharmaceutical applications of magnetic resonance imaging (MRI) is reviewed.130 Despite widespread use and major advances in clinical MRI, it has seen limited application in the pharmaceutical sciences. In vitro studies have focussed on drug release mechanisms in polymeric delivery systems, but isolated studies of bioadhesion, tablet properties, and extrusion and mixing processes illustrate the wider potential. Perhaps the greatest potential, however, lies in investigations of pharmaceuticals in vivo, where pilot human and animal studies have demonstrated we can obtain unique insights into the behaviour of gastrointestinal, topical, colloidal, and targeted drug delivery systems. By the extraordinary progress of spectroscopic and imaging methods allows the visualization of the performance of drug delivery systems under both in vitro and in vivo conditions. Detailed and quantitative information about the location and concentration of the drug and carrier can be obtained as a function of time, thereby enabling a more profound understanding of biological effects. This information is crucial to the design of optimized drug delivery systems. One issue of ADDR features novel, non-radioactive methods potentially useful for drug delivery scientists in selecting the most appropriate imaging techniques for solving the drug delivery problem at hand.131 Mineralized bone tissue has a significant water component. Bone water is associated with the collagen fibers or mineral fraction or occurring as pore water of the Haversian and lacuno-canalicular system. In addition, bone water plays a key role during mineralization whereby collagen-bound water is gradually replaced by calcium apatite-like mineral. As a review, it is shown how NMR allows the study of various physiologically relevant properties of bone water nondestructively.132 Isotope exchange experiments are described from which the apparent water diffusion coefficient can be calculated. The method is based on monitoring the migration of H2O into the D2O after immersion of the specimen in heavy water. Data obtained from rabbit cortical bone in the normal and mineral-depleted skeleton provide evidence for the hypothesized reciprocal relationship between bone water and mineral. 7.2 Swelling, diffusing into polymer materials Many pharmaceutical tablets are based on hydrophilic polymers, which, after exposure to water, form a gel layer around the tablet that limits the dissolution and diffusion of the drug and provides a mechanism for controlled drug release. Polymer concentration profile during swelling of hydrophilic matrix tablets was quantitatively evaluated by using 1H-NMR and MRI methods, to determine the thickness of the swollen gel layer of matrix tablets and to develop a method for calculating the polymer concentration profile across the gel layer.133 The in situ swelling behaviour of cellulose ether matrix tablets was investigated by MR imaging. The water proton NMR relaxation parameters were combined with the MRI data to 382 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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obtain a quantitative description of the swelling process on the basis of the concentrations and mobilities of water and polymer as functions of time and distance. NMR imaging of ingress of water into copolymers of 2-hydroxyethyl methacrylate (HEMA) and tetrahydrofurfuryl methacrylate (THFMA) loaded with either one of two model drugs, i.e. vitamin B-12 or aspirin, was studied at 310 K using three-dimensional NMR imaging.134 The poly(HEMA) was loaded with 5 wt% of the drugs. From the imaging profiles it was observed that incorporation of vitamin B-12 into the polymers rich in HEMA resulted in crack formation at the interface between the rubbery region and the glassy core on sorption of water, although these cracks were ‘healed’ behind the diffusion front. However, for the copolymers with low HEMA contents and for those containing aspirin, no evidence for similar crack formation was found. The values of the water diffusion coefficients, determined by curve-fitting the relative water concentration profiles from MRI measurements, were found to be smaller than those obtained from a mass uptake study. An ‘‘anisotropic’’ polymer: Two different samples of high-density polyethylene (HDPE) have been studied.135 One (isotropic) is extracted from the material core whereas the other (anisotropic) involves two sides which have been in contact with the injection mold. It is observed by NMR microscopy (using radiofrequency field gradients) that these two sides favor toluene penetration into the material. The distribution of toluene nuclear spin relaxation times (extracted from proton T1 and T2 images) exhibits likewise important differences between the two samples. Finally, in investigating the anisotropic sample (without solvent), three different phases (two amorphous and one crystalline) are revealed by 13C-hemical shift imaging experiments. Each amorphous component is preferentially present at one of the two ‘‘mold sides’’. 7.3 Structure and diffusivity in polymer gels Moisture profile: A method to assess the relationship between water diffusivity and water content was developed.136 This method combines the non-destructive measurement of water distribution in sample by NMR imaging during isothermal drying process and data treatment for shrinking/swelling materials and which needs no a priori on the relationship D = f(X). Gelatine eel samples (60 bloom) were used to test the method. A specific assembly adapted to the small microimaging probehead was built to promote isothermal and unidirectional drying of the samples. Successive steps were developed to calculate local moisture contents from independent calibration and sources of error were evaluated. It was shown that 2D NMR signal amplitude images must be recorded to derive the true 1D moisture content profiles although the time acquisition is longer. The time variation of 1D moisture content profiles with a spatial resolution of 49 mu m and shrinkage was analyzed. Channel cavities in highly oriented polypeptide: Highly-oriented poly(gamma;benzyl L-glutamate) (PBLG) gels prepared by cross-linking PBLG chains by changing the concentration of ethylenediamine as cross-linker in 1,4-dioxane in the presence of the strong magnetic field of an NMR magnet with a strength of 10.5 T have been structural-characterized by three-dimensional (3D) NMR imaging and diffusion NMR.137 It is shown that long channel cavities with mu m-scale diameters in the polypeptides are formed along the direction parallel to the a-helical axis. Diffusion behavior of solvent in the polypeptide gels has been elucidated as associated with channel cavities by diffusion NMR. Morphology and chain dynamics during collapse transition: The temperatureinduced shape transition of poly(N-isopropylacrylamide) (=PNIPAM) gels of different cross-link densities was investigated by a combination of NMR techniques allowing the characterization of both the macroscopic collapse as well as the changes on a molecular scale related to the expulsion of water from the gel network.138 The proton-containing gel phase was visualized by swelling in heavy water, and the Nucl. Magn. Reson., 2007, 36, 363–396 | 383 This journal is

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volume change was monitored by proton imaging for cross-link densities between 0.5% and 2.5%. Two spectral lines of 129Xe are found in the gel state and are assigned to the hydrophobic and hydrophilic parts of the network. In the collapsed state, the hydrophobic peak shows a strong shift while the hydrophilic peak disappears. 7.4 Structural characterization of form The structure of foams and filled polymers can be analyzed by means of MRI.139 It is also possible to observe the deformation behavior of the structure of foams and filled polymers in situ. The NMR images are analyzed by image processing. Information about particle distances and micromechanical deformation can be obtained by NMR imaging methods by combining autocorrelation and cross-correlation.

8. Plant, seed, fruit Imaging of developing barley grains—NMR imaging was used for the non-invasive acquisition of 3D images of developing barley grains from anthesis to maturity, 40 days after anthesis. Quantitative T2 maps were generated, and chemical shift imaging was detected changes in the tissue distribution of water, soluble carbohydrate and lipids. Complete 3D data are accessible on a website.140 Nonvisible internal bruise and spraing symptoms—MRI was applied to detect nonvisible internal bruise and spraing symptoms and to get insight on the chemical and anatomical causes of such defects.141 Cultivar Saturna with internal bruise and cultivar Estima with spraing symptoms were investigated by comparison of different MR images as proton density-, T1- and T2-weighted images and T2 maps. In all these types of MR images, it was possible to identify internal bruise and spraing spots in the potatoes, where these phenomena were present. In conclusion, this study demonstrated that MRI can detect nonvisible internal bruise and spraing symptoms in potatos, which has not been published before. MRI may, therefore, be an appropriate method for detecting and for studying developmental changes of such disorders and related disorders during postharvest storage in water uptake and oil distribution during imbibition (Pine)—Water uptake and oil distribution during imbibition of seeds of western white pine (Pinus monticola Dougl. ex D. Don) was monitored in vivo using magnetic resonance imaging.142 Analyses of the dry seed revealed many of the gross anatomical features of seed structure. Furthermore, the non-invasive nature of MRI allowed for a study of the dynamics of water and oil distribution during in situ imbibition of a single seed with time-lapse chemical shift selective MRI. A model that describes the kinetics of the earlier stages of imbibition is proposed. The potential of MR microimaging for detailed studies of water uptake and distribution during the soaking, moist chilling (‘‘stratification’’), and germination of conifer seeds is discussed. Changes of physical state in growing sapota fruits—1H-NMR images, localized spectral images, T1 maps and 13C-NMR spectra were used to determine water behaviour, and composition of sugars and oils in growing sapota fruit (Manilkara achras L.).143 1H-NMR images showed the difference of water distribution during the early growth of the fruit, both locular regions with seeds and young seeds. The localized spectral images detected sugars in fleshy tissues and oils in seeds at 5 months. Water Flow in Plants and Fluits—The effects of cold girdling of the transport phloem at the hypocotyl of Ricinus communis on solute and water transport were investigated.144 Effects on the chemical composition of saps of phloem and xylem as well as of stem tissue were studied by conventional techniques and the water flow in the phloem was investigated by NMR imaging. Only in the very first period of cold girdling (o15–30 min) was mass flow inhibited, but recovered in the rest of cold treatment period to values similar to the control period before and the recovery 384 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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period after the cold treatment. It is concluded that cold treatment affected phloem transport through two independent and reversible processes: (1) a permanent leaching of sucrose from the phloem stem without normal retrieval during cold treatment, and (2) a short-term inhibition of mass flow at the beginning of cold treatment, possibly involving P proteins. Possible further mechanisms for reversible inhibition of water flow are discussed. Is mass flow inhibited?—The effects of cold girdling of the transport phloem at the hypocotyl of Ricinus communis on solute and water transport were investigated.145 Effects on the chemical composition of saps of phloem and xylem as well as of stem tissue were studied by conventional techniques and the water flow in the phloem was investigated by NMR imaging. It is concluded that cold treatment affected phloem transport through two independent and reversible processes: (1) a permanent leaching of sucrose from the phloem stem without normal retrieval during cold treatment, and (2) a short-term inhibition of mass flow at the beginning of cold treatment, possibly involving P proteins. Possible further mechanisms for reversible inhibition of water flow are discussed. Gene expression in plant seed—An air-dry developmental state with low-hydrated tissues is a characteristic of most plant seeds. Seed dormancy is an intrinsic block of germination and can be released during after-ripening. Very little is known about the molecular mechanisms of after-ripening and whether gene expression is possible in low-hydrated seeds. Transient, low-level b-Glu I transcription and translation was detected during tobacco seed after-ripening.146 1H-NMR 2D micro-imaging showed uneven distribution of proton mobility in seeds. b-Glu I gene expression is associated spatially with the inner testa and temporally with the promotion of testa rupture. Based on the series of experiments, de novo gene expression is proposed to be a novel molecular mechanism for the release of coat-imposed dormancy during oilseed afterripening.

9. Food 9.1 Review This review presents the status of NMR applications in meat science.147 The potential and relevance of relaxation, imaging, and spectroscopic methodologies are covered within the different topics of importance for meat science and related muscle biology. The most widely explored area of NMR in meat science is 1 H- relaxometry, the use of which has been highly successful due to its potential in characterising water and structural features in heterogeneous systems like muscle/ meat. NMR imaging studies have mostly been applied in the elucidation of structural changes and brine dynamic during processing of meat, i.e., freezing, curing and high pressure treatment, which are reviewed. Within NMR spectroscopy, 31 P-NMR spectroscopy has been applied to investigate the effect of genetic, feeding, and slaughter factors on meat quality through their action on phosphorous metabolism post mortem.

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Na-MRI and relaxometry in meat

The combination of 23Na-MRI and 23Na-NMR relaxometry was introduced for the study of meat curing.148 The diffusion of Na+ ions into the meat was measured using MRI on a 1 kg meat sample brined in 10% w/w NaCl for 3–100 h. Diffusion coefficient change after 3 h of curing and subsequently decreasing at longer curing times suggests microscopic structural change of the meat during curing. The microscopic mobility and distribution of sodium was measured using 23Na-relaxometry. Two sodium populations were observed, reflecting a salt-induced swelling and increase in myofibrillar pore sizes. Nucl. Magn. Reson., 2007, 36, 363–396 | 385 This journal is

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9.3 Water and oil in corn The physical states of water and its freezing behaviour in shelled corn during subzero drying were determined by using 2H NMR and 1H MRI techniques.149 In this context, the H-2 NMR spin–lattice relaxation times (T1) and spin–spin relaxation times (T2) of water in corn were measured. The results revealed that there were two main water components in corn of 430% wb (wet basis) with long and short T1. Both components exhibited minima around 20 degrees C. In more dehydrated corn (18.6% wb) only a single water component, with short T1 and T2 was observed. 1H MRI images revealed the location of water and its freezing behaviour in different areas. A new high-throughput method for measuring oil content in intact, single corn kernels is demonstrated using MRI methods.150 This nondestructive technique enables the evaluation of relative oil content in up to 2592 corn kernels in less than 40 min using a 1.5 T clinical MRI scanner. Custom software was developed to process and analyze 3-D MR image data rapidly. The precision and accuracy of the MR method for measuring oil content show very good relative accuracy compared with low-field NMR, NIR transmission, and accelerated solvent extraction measurements.

9.4 Cooking The visualization and quantification of the cooking of rice by NMR imaging is reported for Japonica rice (Oryza sativa. L. Japonica cv. Nipponbare) as a test sample. Rice was cooked in a vial for various times and then studied at room temperature by NMR imaging.151 The multi slice multi echo method was employed to obtain two-dimensional proton images. The total limiting water content within the rice grains was calculated and it agreed with that calculated from the known water/rice ratio used, indicating that both the concentration and distributions of water within the rice grains during cooking obtained from the NMR imaging were quantitatively reliable. Convection cooking of fresh chicken meat: A combination of bulk NMR and MRI measurements of the T2 values of water protons can be used to determine the heat-induced changes in the structure and moisture content of fresh chicken meat which had been cooked in a convection oven at 200 1C for a range of times.152 Multiexponential fitting of the bulk NMR T2 relaxation time data demonstrated three distinct water populations. The T1 and T2 values obtained by MRI for cooked meat decreased progressively with increased heating time. Multinuclear NMR and MRI studies—The maturation of pig articular cartilage was followed by 2H in-phase double quantum filtered (IP-DQF) spectroscopic MRI, 1 H-T2 MRI, and 23Na-DQF and triple quantum filtered MRS.153 The results all lead to the conclusion that the order and density of the collagen fibers in articular cartilage increase from birth to maturity.

9.5 Lipid distribution in brown trout (Salmo trutta) The distribution of lipids in the flesh of large size brown trout (mean body weight 3.8+/ 0.2 kg) was analyzed using MRI scanning.154 Assays were conducted with fish from a control line and from a line selected for growth rate, both fed a low- or a high-energy diet for 4 months. Based on preliminary complete scanning of one fish, 15 different sections were defined in three areas designated by external anatomical references. Lipid content through MRI matched well with those obtained by chemical and NMR analyses of lipid content (r2 4 0.91). Automated image analysis was conducted to calculate lipid content in the different muscle regions. There was no difference in lipid content or localization between the two lines. Feeding a highenergy diet resulted in significantly higher lipid deposition, especially in the anterior region of the muscle. 386 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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10. In vivo application 10.1 Reviews Clinical application of in vivo proton 1H-NMR spectroscopy in musculoskeletal tumors was reviewed, which introduces 1H-MRS of the musculoskeletal tumors, discusses current methods and technical issues, and describes applications for treatment monitoring and lesion diagnosis.155 Biological imaging and spectroscopy of pH: The critical role of pH status in physiology and pathophysiology of living organisms is well recognized. At the microscopic scale, local pH drastically affects the vital activities of cell, cellular organelles and enzymes. Spatially and temporarily addressed pH measurements in vivo are of considerable clinical relevance. At subcellular levels, spatiotemporal pH assessment provides significant insight into the mechanisms of pH regulation in cellular organelles and its role in cellular signaling including cell proliferation and apoptosis. Current methods in biological pH detection and imaging, their limits, advantages and recent applications, as well as further perspectives of their development are discussed.156 Magnetic resonance approaches based on EPR and NMR spectroscopies have the advantage for in vivo applications in animals and humans. Special emphasis is given to EPR spectroscopy due to the rapid development of lowfield EPR techniques and new pH sensitive probes with enhanced spectral properties making in vivo pH detection and imaging possible. NMR characterization of mechanical waves: NMR characterization of biological tissues or materials (MR elastography) is a challenging and promising area of research. Ongoing progress in acoustic wave detection and characterization using NMR is given as a review.157 Loss of cell ion homeostasis and cell viability: It was demonstrated that the use of sodium MRI as a noninvasive, in vivo means to assess metabolic changes that ensue from loss of cell ion homeostasis due to cell death in the brain.158 In the first section, the constraints imposed on the imaging methods by the NMR properties of the sodium ion are discussed and strategies for avoiding their potential limitations are addressed. The second section illustrates the use of sodium MRI for monitoring focal brain ischemia in permanent and temporary primate models of endovascular middle cerebral artery occlusion. Technical aspects of the in vivo 31P-MRS: In vivo 31P-MRS investigations have been widely used in small animals to study skeletal muscle function under normal and pathological conditions. A review is purposed to highlight the technical aspects of the in vivo MR investigations of skeletal muscle function in small animal models.159 The authors more particularly address the issue related to the invasiveness of different procedures used so far in order to show finally that a further step into non-invasiveness can be achieved, in particular with the support of muscle functional 1H-MRI. 10.2 Pulse sequence/tecunique/instrument Simultaneous detection of metabolites and water: A new two-scan method for localized 1H-in vivo NMR spectroscopy without water suppression is described.160 In one of the scans, two chemical shift selective 180 degrees pulses are applied prior to a standard localization sequence to invert all metabolite signals upfield and downfield from water, which remains unaffected. The difference spectrum records the metabolites whereas water and accompanying gradient induced artifacts are widely suppressed. Measurements on healthy rat brain yielded comparable spectrum quality as measurements with water presaturation. Multiple-quantum coherence images in vivo: Until recently, NMR imaging with intermolecular multiple-quantum coherences (iMQCs) has been based on the acquisition of a single echo. In vivo studies of iMQC image contrast would greatly benefit from a method that could acquire several orders of quantum coherence Nucl. Magn. Reson., 2007, 36, 363–396 | 387 This journal is

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during the same acquisition. The effectiveness of the iMQC sequence in vivo using earthworms as specimens was established, and then the multi-CRAZED sequence, which enhances detection of next generation (nanoparticle) contrast agents on excised tumor tissue, was shown.161 Depth-dependent proton magnetization transfer: 1D-proton projection MR images employing a SEI sequence were obtained at 2 T to measure the proton magnetization transfer ratio (MTR) maps in control and collagen-depleted bovine patellar cartilage specimens as a function of cartilage depth during mechanical compression. High-spatial-resolution 2D-MTR images were obtained using a fast spin-echo sequence on a 4 T whole-body scanner and the MTR maps of normal and collagen-depleted bovine patellae was quantified.162 The high MTR in the radial zone not only depends on collagen content, it may also reflect a number of other parameters, such as the arrangement of macromolecules, high solid content, bound water fraction attached to macromolecules, radial orientation, etc. All of the cartilage plugs from the bovine patellae showed that the MTR value increases continuously as a function of cartilage depth and is relatively higher in the radial zone compared to the superficial zone. Spectral line width optimization in 1H-2D MR-CSI at 7 T: High magnetic fields increase the sensitivity and spectral dispersion MRS. In contrast, spectral peaks are broadened in vivo at higher field strength due to stronger susceptibility-induced effects. Strategies to minimize the spectral line width are therefore of critical importance. 1H-2D chemical shift imaging at short echo times was performed in the macaque monkey brain at 7 T.163 The study showed that even in well-shimmed areas assumed to have minimal macroscopic susceptibility variations, spectral line widths are tissue-specific exhibiting considerable regional variation. Therefore, an overall improvement of a gross spectral line width can only be achieved when voxel volumes are significantly reduced. The line width optimization was sufficient to permit clear glutamate (Glu)-glutamine separation, yielding distinct Glu maps for brain areas including regions of greatly different Glu concentration (e.g., ventricles vs. surrounding tissue). Diffusion-weighted 19F-MRI via SF6 in lung: Lung functional MRI has become a reality using different inert hyperpolarized gases, such as 3He and 129Xe, which have provided an extraordinary boost in lung imaging and has also attracted interest to other chemically inert gaseous contrast agents. The first diffusion-weighted images using thermally polarized inhaled sulfur hexafluoride (SF6) in small animals was recently demonstrated.123 The aim of this study was to evaluate whether or not the diffusion coefficient of this fluorinated gas is sensitive to pulmonary structure, gas concentration and air pressure in the airways. As the conclusion after in vivo researches, T2 relaxation is very fast, so gradient systems with very fast switching rate and probably large radiofrequency power and high field systems will be needed for SF6 to be used in human studies. Special-gas mixing for flow: An approach for an animal MRI-compatible ventilator is described, which might be useful for some applications, such as those dependent on gas flow.165 Essential features of this ventilator are a real-time module that also prevents lung overpressure and a specifically designed pneumatic breathing module compatible with hyperpolarized gases. One distinguishing characteristic from previously published approaches is a fast-acting open/close pneumatic valve arrangement (delays are lower than 5 ms after software postcorrection) that allows the system to reproduce animal breathing rates and to generate different breathing patterns and gas mixtures. It has been made using locally available low-cost materials, and no system faults or errors have been reported during 1 year of operation. 10.3 Molecular imaging of cancer Apoptosis plays an important role in cancer. Mechanisms hindering its action are implicated in a number of malignancies. Also, the induction of apoptosis plays a 388 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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pivotal role in non-surgical cancer treatment regimes such as irradiation, chemotherapy, or hormones. Recent advanced in imaging science have made it now possible for us to detect and visualize previously inaccessible and even unrecognized biological phenomena in cells and tissue undergoing apoptosis in vivo.166 Rapid and accurate visualization of apoptotic response in the clinical settings can also be of significant diagnostic and prognostic worth. With the advent of molecular medicine and patient-tailored treatment options and therapeutic agents, such monitoring techniques are becoming paramount. Noninvasive multinuclear MRI and spectroscopic imaging (MRSI) provide an array of capabilities to characterize and understand several of the vascular, metabolic, and physiological characteristics unique to cancer. The availability of targeted contrast agents has widened the scope of MR techniques to include the detection of receptor and gene expression.167 In this paper, we have highlighted the application of several MR techniques in imaging and understanding cancer. 10.4 In vivo other-nuclei imaging Magnetic susceptibility matching: Transverse relaxation of hyperpolarized 3He magnetization in respiratory airways highly depends on local magnetic field gradients induced by the magnetic susceptibility difference between gas and pulmonary tissue. Using intravascular injections of a superparamagnetic contrast agent in rats, it was possible to increase the overall susceptibility of the perfused lung tissues and hence to match it with the gas susceptibility.168 The transverse decay time constant of inhaled hyperpolarized 3He was measured in multiple-spin-echo experiments at 1.5 T as a function of the superparamagnetic contrast agent concentration in the animal blood. The time constant was increased by a factor of 3 when an optimal concentration was reached as predicted for susceptibility matching by combining intrinsic susceptibilities of tissue, blood, and gas. Pharmacokinetics of Li in rat brain: Lithium (Li) and its salts have been demonstrated to be the most effective drug in both acute and prophylactic treatment of bipolar disorder. The exact molecular mechanisms and particular target regions accounting for its mood-stabilizing effect remain unknown. Pharmacokinetic measurements in different anatomical regions of the human brain are not yet available. Using 7Li-MR spectroscopic imaging (SI) technology, Li distribution in brain regions of the rat at therapeutic dosages has been recently demonstrated.169 Feasibility of local pharmacokinetic measurements on brain regions was obtained by MRS/I technology. The results suggest that Li is most active in a region stretching from the anterior cingulate cortex and striatum to the caudal midbrain, with greatest activity including the preoptic area and hypothalamic region. In vivo detection of BPA: 10B-enriched L-p-boronophenylaianine (BPA) is one of the compounds used in boron neutron capture therapy (BNCT). Several variations of NMRS/I were applied to investigate the uptake, clearance and metabolism of the BPA-fructose complex (BPA-F) in normal mouse kidneys, rat oligodendroglioma xenografts, and rat blood. Localized 1H-MRS was capable of following the uptake and clearance of BPA-F in mouse kidneys with temporal resolution of a few minutes, while 1H-MRSI was used to image the BPA distribution in the kidney with a spatial resolution of 9 mm3.170 The results also revealed significant dissociation of the BPA-F complex to free BPA. BPA is used as 10Boron-carrier in boron neutron capture therapy, an experimental cancer radiotherapy. Results of quantitative, noninvasive in vivo detection and imaging of BPA in laboratory animals using 1H-NMR are presented for the first time.171 The purpose of this study was to implement and validate optimized techniques for the efficient detection of BPA. Modified versions of LASER (T-CP = 4.6 ms, TE = 27.6 ms) and double-echo slice-selective 2D MRSI (TE = 12 ms) were implemented for single-voxel spectroscopy and spectroscopic imaging of BIPA, respectively. Nucl. Magn. Reson., 2007, 36, 363–396 | 389 This journal is

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Multiparametric assessment of oxygen efflux: Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (P-iv) and extravascular (P-ev) compartments, multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria) was implemented.172 The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15 O-PET, 17O-NMR, and calibrated fMRI methods. The first In vivo diffusion weighted 19F-MRI: Projection-reconstruction images were acquired by filling the rat lung with a mixture of SF6 and air, during 64 successive apneas.173 Each apnea lasted for 6 s, the time required to perform 100 accumulations of each k-space radial phase step for the five values of the diffusion gradient (TR = 10 ms). After diffusion images were acquired, an apparent diffusion coefficient (ADC) map was generated, yielding an average value for the ADC of 2.22 10 6 m2/s and SD. 19 F-MRI of ventilation and diffusion: Perfluorinated gases, particularly C2F6, are potentially suitable alternatives to hyperpolarized noble gases for pulmonary airspace spin density and diffusion MRI. The work focuses mainly on 19F-imaging of C2F6 gas in healthy and emphysematous explanted lungs, avoiding regulatory issues of human in vivo measurements.174 Three-dimensional gradient echo and spin echo spin density 19F- and 3He-images of human lungs are compared. The low free diffusivity of pure C2F6 (D0 = 0.033 cm2/s) places it in a regime where the ADC measurement allows the surface-to-volume ratio to be determined in each voxel, a potentially valuable quantitative characterization of regional lung tissue destruction in emphysema.

10.5 Typical examples in vivo MRI Angiogenesis inhibition following nitric oxide synthase blockade: Nitric oxide synthase inhibition has antigangiogenic properties. MRI was used to interpret the functional significance of these microvascular changes in a rat model of chronic ischemic myocardium in vivo.175 MR imaging allowed noninvasive quantification of functional microcirculation and angiogenesis in the rat heart in vivo. Nitric oxide synthase blockade results in changes in functional microcirculation and in an inhibition of angiogenesis in both ischemic and nonischemic myocardial tissue. Oxygen supply, uptake, and utilization: Human skeletal muscle perfusion, oxygenation, and high-energy phosphate distribution were measured simultaneously by interleaved 1H- and 31P-NMR spectroscopy and 1H-NMR imaging in vivo.176 From these parameters, arterial oxygen supply (DO2), muscle reoxygenation rate, mitochondrial ATP production, and O2 consumption (VO2) were deduced at the recovery phase. In addition, muscle maximum O2 extraction is also calculated from these parameters. Prostate tumors in mice: High spectral and spatial resolution (HiSS) MRI of rodent tumors has previously been performed using conventional spectroscopic imaging to obtain images with improved contrast and anatomic detail. The use of much faster echo-planar spectroscopic imaging (EPSI) to acquire HiSS data from rodent tumor models of prostate cancer was evaluated.177 Two variants of EPSI were performed; gradient-echo or spin-echo excitation with EPSI readout. The results suggest that HiSS MRI data from small animal models of prostate cancer can be acquired using EPSI, and that this approach improves imaging of heterogeneous tissue and vascular environments inside the tumors compared with conventional MR techniques. 390 | Nucl. Magn. Reson., 2007, 36, 363–396 This journal is

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Evaluation of efficiency and toxicity of gene electrotransfer: In vivo gene electrotransfer (ET) is a simple method of gene delivery in various tissues relying on the injection of plasmid DNA followed by application of electric pulses. Noninvasive tools are needed to evaluate the ET efficiency and the resulting tissue damages. ET of rat tibialis muscle after injection of either a plasmid coding for luciferase or a contrast agent (CA) was detected by using MRI.178 Plasmid expression and CA intracellular trapped quantity were compared throughout the electric field intensity range 0–300 V/cm. In conclusion, MRI measurements may bring multiparametric information upon the efficiency and tissue toxicity of an ET protocol by using a simple and safe contrast agent. Strictly noninvasively skeletal muscle function: A new experimental setup allowing strictly noninvasive MR investigations of muscle function in contracting rat gastrocnernius muscle using 1H-MR imaging and 31P-MR spectroscopy are described.179 The novelty of this setup is the integration of two noninvasive systems allowing muscle contraction by transcutaneous stimulation and force measurement with a dedicated ergometer. Muscle function was investigated in 20 rats (275–300 g) through a fatiguing stimulation protocol, either with this noninvasive setup (n = 10) or with a traditional MR setup (n = 10). Chemical shift imaging in the monkey visual cortex: Functionally distinct anatomic subdivisions of the brain can often be only a few millimeters in one or more dimensions. The study of metabolic differences in such structures by means of localized in vivo MR spectroscopy is therefore challenging, if not impossible. In fact, the spatial resolution of chemical shift imaging (CSI) in humans is typically in the range of centimeters. The feasibility of high spatial resolutions up to 1.4 2 1.4 mm3 was demonstrated by the optimization of 1H-CSI in monkeys180 and the obtained spatial resolution permitts the segregation of gray and white matter in the visual cortex based on the concentration of different metabolites and neurotransmitters like N-acetylaspartate, glutamate, and creatine. NMR microscopy of the honeybee brain: NMR microscopy provides noninvasively distinct soft-tissue contrast in small biological samples. The three-dimensional structure of the honeybee brain in its natural shape in the intact head capsule was visualized.181 In addition to acquiring detailed information about the shapes and volumes of the different brain compartments, the authors were able to show their relative orientations toward each other within the head capsule. Since the brain was lightly fixed but not dehydrated, the NMR experiments exhibited larger volumes and a more natural stereo geometry of the various brain structures compared to confocal laser microscopy experiments on dissected, dehydrated and cleared brains. Canine eye with melanoma: An 8-year-old Beagle dog had exophthalmos of the left eye for the last two past months. On ophthalmoscopy, the intraocular lesion could not be evaluated due to the opacity of the cornea. Ultrasonography revealed that the eyeball was distorted in shape and shifted in position, however, the precise lesion could not be identified. On MRI, the lesion was observed as hyperintense on T1-weighted and hypointense on T2-weighted images, similar to those reported in human melanoma.182 The lesion was histologically diagnosed to be malignant intraocular melanoma. Though this is only a case report, canine ocular melanoma may show the similar characteristic MR images as in human uveal malignant melanoma. The development of NMR diffusion imaging and diffusion tensor imaging (DTI): Diffusion imaging has offered the possibility of studying the porous structures beyond anatomical imaging. Up to now, the DTI method was mainly used to investigate cerebral morphology and study white matter diseases. It has been applied to trabecular bone marrow analysis to obtain structural information on spongy bone tissue.183 The first results show that DTI could represent an important tool in studying the microstructural architecture of the trabecular bone as well as the microarchitecture of porous media. Nucl. Magn. Reson., 2007, 36, 363–396 | 391 This journal is

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NMR of liquid crystals and micellar solutions Maura Monduzzi and Sergio Murgia DOI: 10.1039/b618336k

Chemical species acronyms and abbreviations. AOT: 1,4-bis(2-ethylhexyl) sodium sulfosuccinate; CHOL: cholesterol; CTAB: cetyltrimethylammonium bromide; DHPC: dihexanoyl phosphatidylcholine; DLPC: dilauroyl phosphatidylcholine; DMPC: dimyristoyl phosphatidylcholine; DMPG: dimyristoyl phosphatidylglycerol; DOPC: dioleoyl phosphatidylcholine; DOPE: dioleoyl phosphatidylethanolamine; DPC: dodecylphosphocholine; DPPA: dipalmitoyl phosphatidic acid; DPPC: dipalmitoyl phosphatidylcholine; DPPE: dipalmitoyl phosphatidylethanolamine; DTAB: dodecyltrimethylammonium bromide; LPA: lysophosphatidic acid; LPC: lysophosphatidylcholine; PA: phosphatidic acid; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PEG: polyethylene glycol; PG: phosphatidylglycerol; PL: phospholipid; PLB: phospholamban; POPC: 1-palmitoyl-2-oleoyl-phosphatidylcholine; POPE: 1-palmitoyl-2-oleoylphosphatidylethanolamine; POPG: 1-palmitoyl-2-oleoylphosphatidylglycerol; POPS: 1-palmitoyl-2-oleoyl-phosphatidylserine; PS: phosphatidylserine; SDPS: 1-stearoyl-2-docosaexenoyl- phosphatidylserine; SM: sphingomyelin.

1

Introduction

This chapter presents recent papers (June 2005–May 2006) focusing on the use of NMR techniques to elucidate the microstructure and dynamics of self-assembled systems. As reported in the analogous chapter of last year, here the relevant concepts and acronyms related to liquid crystals (L.C.s) and micellar solutions will be briefly revised. It is well known that self-assembly occurs when molecules having peculiar shape and properties are involved. Molecules that exhibit L.C. phases are called mesogens. Typically, mesogens possess a rigid and anisotropic shape (i.e. longer in one direction than another) and orient depending on their long axis. Disk-like (discotic) mesogens are also known and these orient in the direction of their short axis. In addition to molecules, polymers and colloidal suspensions can also form L.C. phases. Liquid crystals can be divided into thermotropic and lyotropic L.C.s. Thermotropic L.C.s exhibit a phase transition into the L.C. phase as temperature is changed, whereas lyotropic L.C.s exhibit phase transitions as a function of concentration and/or composition. The thermotropic L.C.s that are mainly related to the elongated shape of the molecules and to specific intermolecular interactions may show different long range order according to nematic, smectic A, B and C or cholesteric (in the presence of chiral atoms) organization. The lyotropic L.C.s are based on amphiphilic molecules and need polar or apolar solvents to form different nanostructures. The formation of lyotropic L.C.s, micelles, microemulsions, foams and emulsions is driven by hydrophobic interactions along with weak intermolecular forces. The presence of both polar and apolar solvents is generally needed to obtain microemulsions, foams or emulsions. Stabilization of these systems is driven by a surfactant-based interface. The geometry of the interface University of Cagliari, Department of Chemical Sciences, Italy


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that separates the hydrophobic and hydrophilic domains is related to the supramolecular architecture addressed by surfactant type and shape. It has been shown that such an interface can be exemplified by means of two different contributes: the interfacial curvature and the interfacial topology. While the first is associated to the local geometry, the second describes the global geometry through the degree of interfacial connectivity. As firstly defined by Ninham et al. the local constraint upon the interfacial curvature is specified by the surfactant packing parameter P = v/al. Here v represents the hydrophobic chain volume, a the head group area and l the chain length (taken as 80% of the fully extended chain). This parameter defines the possible nanostructures a surfactant may form. However, the curvature of the polarapolar interface can be modulated through a suitable choice of oils and polar additives (i.e. electrolytes, water soluble polymers, etc.). The interfacial curvature is defined as positive (normal, H 4 0 and P o 1) for oil-in-water (o/w) L1 phases (normal micellar solutions), I1 (discrete cubic L.C.) and H1 (normal hexagonal L.C.). It is defined as negative (reverse, H o 0 and P 4 0) for water-in-oil (w/o) L2 phases (reverse micellar solutions), I2 (reverse discrete cubic L.C.) and H2 (reverse hexagonal L.C.). An average zero curvature H E 0, due to P E 1, is a typical feature of lamellar La L.C. phases and of bicontinuous cubic (V1 and V2) phases that are constituted by connected surfactant bilayers interwoven with a continuous water domain. The following acronyms related to the most common NMR acquisition techniques and methods will be used in the next paragraphs: NOE for Nuclear Overhauser Effect, RDC for residual dipolar coupling, MAS for Magic Angle Spinning, SS NMR for solid-state NMR, SE for spin-echo, CPMG for Carr Purcell Meiboom Gill sequence, PFG for pulsed field gradient, PFGSE for Pulsed Field Gradient SpinEcho sequence and PFGSTE for Pulsed Field Gradient Stimulated Echo sequence. Throughout the chapter 1D and 2D symbols are used to indicate mono- or twodimensional NMR techniques. Moreover, dealing with microstructural characterizations, a variety of other techniques besides NMR methods are often used: typically we have Static Light Scattering (SLS), Dynamic Light Scattering (DLS), X-ray diffraction (Small and Wide Angle, SAXS and WAXRD), Small Angle Neutron Scattering (SANS), cryo-Transmission Electron Microscopy (cryo-TEM), Polarizing Optical Microscopy (POM), Fourier Transform Infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Atomic Force Microscopy (AFM) and Quasi-Elastic Light Scattering (QELS).

2

General articles: reviews, methods, models

Many review articles of general interest for the present topics have been reported. At first, a review on the advances in NMR studies of both thermotropic and lyotropic L.C. systems1 is to be mentioned. The combined use of 2H NMR and computer simulations was proposed to investigate flexible molecules in nematic solutions;2 an overview over NMR studies of structure and dynamics of confined nematic and smectic L.C. was reported;3 NMR methods were outlined to investigate the L.C. state of synthetic macromolecules;4 the use of Xenon NMR as a probe to study different micro- and nanoporous systems such as L.C. was presented in an interesting review;5 a rapid method of performing spatially resolved, restricted diffusion measurements was proposed to enable emulsion droplet sizing.6 A number of reviews deal with NMR in surfactant based systems and lyotropic L.C. phases. In two reviews on NMR studies of surfactants the main features of the NMR techniques and of the pertinent theoretical background were reported;7,8 another review focused on the NMR characterization of bicontinuous cubic and sponge phases.9 A series of review articles, appeared in Current Opinion in Colloid & Interface Science, deal with new trends in NMR10 with emphasis on self-assembled systems of biological interest also. In particular, an article described NMR-detected electrophoretic mobility,11 that is a new method based on the addition of an electric 398 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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field to the NMR diffusion experiment to obtain particle charge determination (or zeta-potential); another article focused on the NMR experiments used to investigate the rheology of complex fluids12 such as nematic L.C. or self-assembled polymers; three articles dealed with the use of NMR diffusometry experiments to probe biological tissue microstructure,13 protein association phenomena,14 and lipid bilayers interactions with membrane proteins.15 Other reviews described NMR of carbohydrates, lipids and membranes,16 PFG NMR studies of lateral diffusion in oriented lipid bilayers,17 1D sensitivity-enhanced 1H NMR spin diffusion experiments for determining membrane protein topology,18 MAS NMR to investigate structure and dynamics of membrane-associated peptides,19 the use of 19F SS NMR methods for studying biomembranes,20 1H and 31P NMR studies to probe membrane structure modulation induced by polyisoprenol recognition sequence peptides,21 NMR studies of membrane peptides and proteins in bicelles,22 transferred cross-saturation NMR experiments to investigate interactions in bead-linked proteoliposomes,23 NMR methods and an overview of other spectroscopic methods to determine orientation/alignment of membrane probes and drugs in lipid bilayers,24 SS NMR studies of the structure, dynamics and assembly of b-sheet membrane peptides and a-helical membrane proteins with antibiotic activities,25 and finally NMR methods to simultaneously monitor temperature and spin lattice measurements in thermosensitive liposomes containing a paramagnetic contrast agent.26 The increasing number of NMR reviews related to improved and novel methods to investigate model membranes and their interactions with drugs as well as reviews focusing on lipid based nanostructures used as drug delivery systems deserves few additional comments. The growing interest in life science has induced new trends in many related fields, particularly in drug delivery formulations. For instance, among other demands, the protection of sensible therapeutic agents such as peptides and oligonucleotides from macrophages and immune response, or molecular recognition to address the drug to specific receptors is of paramount importance in the development of modern drug delivery systems. In addition, the controlled drug release at very long term (months) for patients with low compliance appears as the most difficult challenge. Engineering of nano-sized depot systems is therefore closely related to future pharmacological trends. Essentially, most of the innovative drug delivery formulations are obtained exploiting nanoscience and nanotechnology advances. Depending on the target, a variety of biologically active nanoparticles may be exploited. They embrace microsphere hydrogels based on polysaccharides, emulsions and microemulsions, liposomes, micelles, lipid nanoparticles and colloidal dispersions of L.C.s. In this context, it is clear why NMR techniques, with their unique ability for probing interactions at a molecular level, have become of general interest.

3

Liquid crystals

The articles related to thermotropic and lyotropic L.C. phases and their use as solubilizing media are summarized in this paragraph. Self-assembly features are often investigated using the typical NMR parameters of the 2H quadrupolar nucleus (I = 1), such as the Dnq quadrupolar splittings. Deuterium oxide (2H2O) is used as solvent to investigate lamellar and hexagonal lyotropic L.C. phases; alternatively, perdeuterated and/or selectively deuterated mesogens and surfactants can be used. Topics related to the characterization of the nanostructures and their phase transitions will be mainly considered as well as the effect of solubilization of different molecules such as drugs, proteins and peptides in the anisotropic L.C. matrices or in vesicles that align in the magnetic field. The analysis of the NMR parameters related to the degree of long-range order and also to steric and anisotropic molecular interactions generally enables a detailed characterization of the microstructural features of a solubilizate. However, other techniques are often used to fully characterise these complex fluids. For instance the different types of L.C. phases Nucl. Magn. Reson., 2007, 36, 397–418 | 399 This journal is

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Fig. 1 Optical microscopy: (a) nematic thermotropic L.C., (b) cholesteric thermotropic L.C., (c) DNA oriented in the magnetic field, (d) ferroelectric thermotropic L.C., (e) banana-shaped thermotropic L.C., (f) a w/o emulsion, (g) swollen lamellar lyotropic L.C. and liposomes (maltese crosses), (h) compact lamellar (mosaic texture) lyotropic L.C., (i) hexagonal (fan-like texture) lyotropic L.C.

can be often distinguished on the basis of their different optical properties (such as birefringence). When viewed under a microscope using a polarized light source, a L.C. material, with the exception of cubic L.C. phases, will appear to have a distinct texture. Each ‘patch’ in the texture corresponds to a domain where the LC molecules are oriented in a different direction. Within a domain, however, the molecules are well ordered. Fig. 1 shows some examples of typical textures of both thermotropic and lyotropic L.C. phases observed at the optical microscope. The optical micrograph of a w/o emulsion is also shown in Fig. 1f for comparison with the L.C. obtained under polarized light and under similar magnification conditions. 3.1 Thermotropic liquid crystals Thermotropic phases are those that occur in a certain temperature range. If the temperature is raised too high, thermal motion will destroy the delicate cooperative ordering of the L.C. phase, pushing the material into a conventional isotropic liquid phase. At too low a temperature, most L.C. materials will form a conventional (though anisotropic) crystal. Many thermotropic L.C.s exhibit a variety of phases as temperature is changed. For instance, a particular mesogen may exhibit various smectic and nematic (and finally isotropic) phase behaviour as temperature is increased. Three main classes of thermotropic L.C.s exist: nematic, smectic and cholesteric. One of the most common L.C. phases is the nematic, where the molecules have no positional order, but they do have long-range orientational order. Thus, the molecules flow and their centres of mass positions are randomly distributed as in a liquid, but they all point in the same direction (within each domain). Most 400 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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nematics are uniaxial: they have one axis that is longer and preferred, with the other two being equivalent (can be approximated as cylinders). Some L.C.s are biaxial nematics. This is the case of smectic phases, where the mesogens are grouped into layers thus enforcing their long-range positional order in one direction in addition to the characteristic orientational order. In the smectic A phase, the molecules point perpendicular to the layer planes, whereas in the smectic C phase, the molecules are tilted with respect to the layer planes. Mesogens in a particular layer can also take on a roughly hexagonal close-packed ordering. The chiral nematic phase, otherwise referred as cholesteric phase, exhibits a twisting of the molecules along the director, with the molecular axis perpendicular to the director. In the smectic C* phase, the molecules orient roughly along the director, with a finite tilt angle and a twist relative to other mesogens. The chiral pitch refers to the distance (along the director) over which the mesogens undergo a full 3601 twist (but note that the structure repeats itself every half-pitch, since the positive and negative directions along the director are equivalent). The pitch can be varied by adjusting temperature or by adding other molecules to the L.C. fluids. For many types of L.C.s, the pitch is of the same order as the wavelength of visible light. This causes these systems to exhibit unique optical properties (e.g. Fig. 1), such as selective reflection. These properties are exploited in a number of optical applications. Finally, disk-shaped mesogens can orient themselves in a layer-like fashion known as the discotic nematic phase. If the disks pack into stacks, the phase is called a discotic columnar. The columns themselves may be organized into rectangular or hexagonal arrays. Chiral discotic phases, similar to the chiral nematic phase, are also known. 3.1.1 Phase behaviour. Some articles are related to the synthesis of new mesogens and to the characterization of their thermotropic phase behaviour. Few papers deal with polymer based mesogens. Particularly, 13C NMR was used to investigate the smectic A-Smectic C* transition due to a change of the molecular tilt;27 two tin-containing homopolymers, one L.C. and the other non-mesomorphic, showed two glass transition temperatures;28 13C NMR was used to ascertain that the effect of aromatic moieties on the L.C. behaviour of polyester amides is determined either by hydrogen bond interaction between adjacent chains or inter plane mesogenic interaction between the rigid aromatic groups;29 the thermotropic properties of a series of ionene polymers based on trans-1,2-bis(4-pyridyl)ethylene that contained oxyethylene units in their backbones and organic anions tosylate and triflimide as counterions were investigated via NMR spectroscopy and a number of other experimental techniques;30 1H NMR experiments enabled investigations of the orientation state of disordered nematic polymers.31 Some articles report on cholesteric L.C.s. Particularly, the induction of a cholesteric phase by doping an achiral nematic L.C. with an enantiopure solute was studied through 1H and 13C NMR;32 the L.C. state of a banana-shaped mesogen was characterized via NMR methods;33 2H NMR was used to investigate the formation of ferroelectric L.C.s induced by dopants with axially chiral 2,2 0 -spirobiindan-1,1 0 -dione cores;34 2H NMR and NMR diffusometry techniques were used to investigate the synclinic-anticlinic smectic phase transition of 1-methylheptyl-4 0 (400 -n-decyloxybenzoyloxy)-biphenyl-4-carboxylate ferroelectric mesogen;35 and the distortion of the helicoidal structure of a magneto-aligned ferroelectric phase of a partially deuterated smectogen;36 for the same mesogen 2H 2D exchange NMR technique combined with sample rotation enabled the determination of the fast selfdiffusion constant.37 Finally the phase transitions in 8CB L.C. confined to a controlled-pore glass were characterized via NMR and SAXS measurements.38 3.1.2 Dynamics and solubilization. NMR relaxation and self-diffusion are the most useful methods to investigate dynamics of soft matter at a molecular level. An Nucl. Magn. Reson., 2007, 36, 397–418 | 401 This journal is

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interesting article reports on the validity of the assumptions related to the mean-field (Maier-Saupe) model about concentration dependence of different solutes, used as probes of L.C. orientational order determination through NMR experiments.39 Some articles deal with dynamic investigations related to intermolecular interactions in different L.C. mesophases. NMR self-diffusion, used to measure the ionic diffusion of lithium L.C. electrolytes, showed diffusion to be determined by two components due to slow exchange between dissociated salt and ion pair.40 A number of papers report on the use of 2H NMR spectroscopy to investigate molecular dynamics;41 the interlayer jump diffusion of smectic A and chiral smectic C L.C. mesophases;42 and to investigate molecular dynamics,43 and nematic like viscosity coefficients44 of ferroelectric L.C. smectogens. Translational self-diffusion anisotropy was investigated in a smectic A phase through 1H NMR diffusometry;45 13C NMR studies were used to investigate orientational order in the chiral smectic C phase of a partially deuterated smectogen;46 the field-induced director alignment for a 4CB mesogen was studied near the smectic A-nematic transition through 2H NMR;47 the magnetic field induced dipolar couplings for a 5CB mesogen was studied in the pretransitional nematic-isotropic phase region via 1H and 13C NMR measurements;48 the role of collective and local molecular fluctuations in the relaxation of proton intrapair dipolar order in nematic 5CB was studied through 1 H NMR;49 in addition the dynamics of 5CB confined into porous glass with average pore diameter of 72 nm was studied above the nematic-isotropic phase transition by field-cycling NMR.50 Other articles report on the dynamics of different molecules encapsulated in L.C. thermotropic mesophases. These studies are often relevant to mimic model membranes behaviour as in the investigation of chiral discrimination of L-and D-N-acyl1-phenyl-D5-2-aminopropanes in a cesium N-dodecanoyl-L-threoninate cholesteric nematic lyomesophase performed by 2H NMR,51 and as in the investigation of the RDCs of small molecules present in a chiral polypeptide L.C. solvent system composed of poly-g-benzyl-L-glutamate in CDCl3.52 Other interesting papers report on the addition of 2–6 wt% of a chiral dopant to a series of nematic copolymers studied through 2H NMR;53 on the structural features of acrolein dissolved in the nematic L.C. I52 studied by 1H and 13C NMR spectroscopy;54 on the conformational analysis of 2,2 0 -bithiophene dissolved in anisotropic, partially oriented mesophases studied by 1H and 13C NMR spectroscopy;55 on the determination of the structure and bond rotational potential of a substituted ethane in nematic L.C. solvent, studied by 1H and 13C NMR;56 on the dipolar and quadrupolar couplings experienced by molecules with large-amplitude torsional motions, partially oriented in the nematic L.C. ZLI 1132 and studied by 2H NMR;57 on the diffusion coefficients of probe ethane molecules confined into long-channel cavities of the hexagonal columnar phase of oriented poly(p-biphenylene) terephthalate, studied by PFGSE 1 H NMR;58 on the orientation and dynamics of benzyl alcohol and benzyl alkyl ethers dissolved in nematic lyotropic L.C.s, formed by tetradecyltrimethyl ammonium chloride-decanol-sodium chloride-water and studied by 2H NMR;59 and on the SS NMR characterization and determination of the orientational order of a novel mesogen, 4-(dodecyloxy)benzoic acid-[((4-(dimethylamino)phenyl)imino)methyl]phenyl ester that can act as a charge-transfer donor.60 3.2 Lyotropic liquid crystals A lyotropic L.C. consists of two or more components that exhibit liquid-crystalline properties in certain concentration ranges. In the lyotropic phases, solvent molecules fill the space around the compounds to provide fluidity to the system. In contrast to thermotropic L.C.s, these lyotropics have another degree of freedom, i.e. the concentration, which enables them to induce a variety of different phases. Since lyotropic L.C.s rely on a subtle balance of intermolecular interactions, it is often more difficult to analyse their structures and properties than those of thermotropic 402 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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L.C.s. Lyotropic liquid-crystalline nanostructures are abundant in living systems. Accordingly, lyotropic L.C.s attract particular attention in the field of biomimetic chemistry. In particular, biological membranes and cell membranes are a form of liquid crystal. Their constituent rod-like molecules (e.g., phospholipids) are organized perpendicularly to the membrane surface, yet the membrane is fluid and elastic. The constituent molecules can flow in-plane quite easily, but tend not to leave the membrane and can flip from one side of the membrane to the other with some difficulty. These L.C. membrane phases can also host important proteins such as receptors freely ‘‘floating’’ inside, or partly outside, the membrane. 2H NMR in studying lyotropic L.C. phase behaviour is of large interest in virtue of the unique performance to easily monitor the occurrence of multiphase systems (i.e. the coexistence of different types of L.C. phases) in the investigations of phase diagrams. Indeed, 2H NMR Dnqs occur in the presence of anisotropic lamellar or hexagonal L.C. phases that align in the magnetic field; isotropic 2H NMR signals are typical of isotropic L.C. phases such as cubic arrangements. 2H2O as solvent and fully or specifically deuterated molecules, particularly in the case of lipids and phospholipids (PLs), can be used. 31P NMR is widely used for studying structural features in PL-based L.C.s. Nowadays NMR self-diffusion measurements have become a routine technique since they provide fundamental information on the dimensions of the organized nanodomains, on their spatial connectivity, i.e. the topology of the long-range ordered structure and on the obstruction effects due to concentration, shape and soft boundaries. A huge number of articles have been reported on the use of PFG NMR methods to probe nanostructures and on improved methods to acquire and to model the NMR self-diffusion experiments. Some articles have been already mentioned in paragraph 2. Beside NMR, SAXS, SANS, POM, DSC and TEM techniques are commonly used in investigating the phase behaviour of amphiphile molecules in binary or multicomponent systems. Here the articles dealing with lyotropic L.C. systems are mentioned according to the following order: ionic and nonionic surfactant-based L.C.s, PL-based L.C. systems and vesicles, bicelles, liposomes and other dispersed L.C. phases used preferentially as solubilizing matrices.

3.2.1 Ionic and Nonionic amphiphiles. Few papers devoted to the study of ionic and nonionic amphiphiles L.C. aggregates have recently appeared. The phase diagram of the ternary system 3-octyloxy-2-hydroxypropyl-trimethylammonium bromide/hexanol/water was investigated at 25 1C:61 lamellar, hexagonal and cubic phases were found in the system and 2H NMR, POM and DSC were used to determine the L.C. structure and to monitor the phase transitions upon water addition; SAXS and 2H NMR were used to confirm the structure of the L.C.s obtained in the ternary system 3-alkoxy-2-hydroxypropyl-trimethylammonium bromide/butanol/water.62 The micellar properties and the phase diagrams (that show micellar, cubic Im3m and hexagonal phases) of PEG 12-acyloxy-stearates were investigated by optical microscopy, SAXS and NMR methods.63 2H NMR was used to investigate the dynamics of the macroscopic sponge (L3)-to-lamellae (La) phase transition that occurs in the C12E5/decane/water system as a consequence of temperature changes:64 it was found that the sponge-to-lamellae transition occurs through a nucleation process followed by domain growth involving bilayer fission at domain boundaries, while the reverse transition implies a succession of uncorrelated bilayer fusion events; the aggregation behaviour of six structurally related 1,4-dialkylpyridinium amphiphiles (Sunfish) in mixtures with DOPE was investigated by means of a combination of techniques (DLS, DSC, NMR, SAXS, etc.), using conditions mimicking key steps of the transfection process;65 the selectively deuterated decylammonium chloride (DACl-d11) in the DACl-d11/water lamellar Nucl. Magn. Reson., 2007, 36, 397–418 | 403 This journal is

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phase was investigated via 2H and 14N NMR spectroscopy to shed light on the molecular headgroup dynamics.66 Lyotropic liquid single crystalline hydrogels (LSCHs) are water-swollen crosslinked amphiphilic polymers that spontaneously form a macroscopically aligned lyotropic L.C. phase. They can be considered as liquid-crystalline elastomers. LSCHs were synthesized via radical polymerization by incorporating an amphiphilic cross-linker molecule with reactive groups in both the hydrophobic and hydrophilic moieties directly into the lamellar liquid-crystalline phase of a rigid rod-like amphiphile that is aligned by a magnetic field:67 the hydrogels were investigated on a macro-, micro- and mesoscopic scale through a number of different techniques as 2H NMR line shape analysis to investigate the director orientation and PFGSTE NMR experiments to prove the existence of defects or pores in the lamellae and to monitor the anisotropy of deuterated water diffusion. The lipid extracts from the Gram-negative bacterium Vibrio sp. DSM14379 was found to form normal micellar and hexagonal phases as revealed by 31P NMR analysis.68

3.2.2 Phospholipids and Solubilization in PL Bilayers. Phospholipids are the main constituents of biological membranes. Thus, it is not surprising that a huge number of investigations deal with PLs-based systems, also in consideration of their importance for drug delivery formulations, as already mentioned in paragraph 2. Several articles deal with PL based L.C.s microstructural characterizations. 2H NMR spectroscopy experiments performed on macroscopically aligned lipid bilayers allowed elucidation of both backbone conformation of selectively deuterated N-palmitoyl-SM and its interaction with PC:69 the average chain order parameters and the relative width of the order parameter distribution were correlated over a range of bilayer compositions; 31P NMR in combination with cryo-TEM was used to investigate the morphology of magnetically aligning DMPC/DHPC aggregates doped with DMPG or CTAB:70 the aggregates are described as intermediates between two-dimensional networks of flattened, highly branched, cylindrical micelles and lamellar sheets perforated by large holes; 31P MAS NMR was used to determine the ionization behaviour of PA and LPA in mixed lipid bilayers;71 a novel MAS CP NMR technique was used to study the conformational response to hydration of DMPC bilayers in the L.C. phase;72 RDCs were used for the analysis of weak, transient binding events between PC bilayers and polyols:73 results designate RDCs as sensitive tool for the analysis of molecular recognition events. A number of investigations deal with mixtures of PL L.C. systems with CHOL, an important constituent of biological membranes, useful to confer the necessary rigidity to the bilayers. The lateral diffusion of SMs of different origin (egg, brain and milk) was determined via PFG NMR measurements in bilayers of SM alone and in the DOPC/SM/CHOL system:74 results indicated that the formation of highly packed bilayers of SM and CHOL is a key element in the domain-forming process, rather than the specific interactions between SM and CHOL; 1H and 13C SS NMR were used to investigate the lipid dynamics in the liquid ordered phase that forms in PL bilayers with over 20% of CHOL;75 a study performed through 31P NMR static powder patterns and 13C MAS NMR along with a number of other techniques, such as DSC, X-ray diffraction and cryo-TEM demonstrated that PC with 16C:1 n-9 acyl chains undergoes polymorphic rearrangements in mixtures with 0.6–0.8 mole fraction of CHOL;76 information about lipid chain order (obtained from 2H NMR), area compressibility modulus and membrane-bending rigidity showed that properties of POPC lipid bilayers are affected to different degrees by the structurally quite similar lanosterol, CHOL and ergosterol;77 the lateral diffusion of CHOL, desmosterol, lanosterol and PL was determined via PFG MAS NMR in DPPCbased membranes to study the influence of the different sterols:78 results revealed a weaker interaction between DPPC and lanosterol compared with the other two sterols; a thorough investigation by variable-temperature multinuclear (1H, 2H, 13C, 404 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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31

P) SS NMR spectroscopy and X-ray scattering concerning the liquid ordered phase in a PC/CHOL model membrane system was presented;79 dynamic and compositional information were acquired by 1H, 2H and 19F PFG NMR in raftforming bilayers containing DOPC/DPPC/CHOL in excess of water at different molar ratios.80 Many investigations deal with the solubilization into PL based L.C. phases of various types of molecules, mainly drugs and peptides having therapeutic activities. Conformation, location and dynamics of the endogenous cannabinoid ligand anandamide in DPPC multilamellar model membrane system are studied via rotational echo double resonance (REDOR) and 2H NMR experiments;81 the lateral diffusion coefficient of DMPE-N-[methoxy(polyethylene glycol)-2000] (DMPE-PEG 2000) incorporated into magnetically aligned bilayers composed of DMPC, DHPC was measured at different PLs molar ratio through 1H PFGSTE NMR experiments:82 a direct dependence of DMPE-PEG 2000 self-diffusion coefficient on the mole fraction of DMPC was found; CP MAS 13C NMR was used to establish the partial inhibition of Ca2+-ATPase by the (13C-labeled at Leu-44) transmembrane protein PLB when both are incorporated in PC membranes;83 a 13C and 31P NMR investigation was performed on DPPC/POPS/SDPS bilayers in the presence and in the absence of chloropromazine (CPZ), a cationic, amphiphilic phenothiazine:84 results show that CPZ binds preferentially to the PS; diffusion measurements of water, ubiquinone and tethered PL inside cylindrical nanoporous support were accomplished via 1H PFGSTE MAS NMR;85 preliminary data obtained via 2H NMR spectroscopy demonstrated the role of bovine serum albumin in facilitating the diffusion of lipophilic drugs into the membrane bilayer;86 1H and 31P NMR experiments showed that the addition of a polyisoprenol recognition sequence (PIRS) can reverse back to a lamellar structure the hexagonal phase structure induced by polyisoprenols dolichol, dolichylphosphate and undecaprenylphosphate in PL membranes;87 the association of the transmembrane proteins PLB and phospholemman to PL based interfaces was shown to induce lipid clustering using 31 P MAS NMR;88 SS NMR was used to study the topology and the segmental mobility of colicin Ia channel domain in membranes, in the presence of different POPG and KCl concentrations;89 the leucine-enkephaline peptide was studied by NMR spectroscopy and molecular dynamics simulation in DMPC bilayer:90 it was found that this molecule is flexible, switching between specific bent conformations; a strong interaction between PC/PS and PC/PG mixed membranes and the histidinerich amphipatic peptide LAH4 was detected via 31P MAS NMR:91 it was shown that, by using deuterated lipids and 2H NMR, LAH4 preferentially interacts with PS rather than PC, thus effectively disordering the anionic PS lipid fatty acyl chains; a 31 P SS NMR study on two mutants of the b-hairpin antimicrobial peptide protegrin-1 in uniaxially aligned membranes indicated that 31P NMR lineshapes are correlated with the activity of these peptides;92 the structure and alignment of the antimicrobial peptide PGLa in DMPC bilayers was determined through SS 2H NMR;93 2H and 31P SS NMR relaxation experiments were performed to study the interaction mechanism of the antimicrobial peptide KWGAKIKIGAKIKIGAKI-NH2 with POPC and POPC/POPG (both with sn-1 chain perdeuterated as the isotopic labels) bilayers membranes:94 results revealed that the peptide presence induces considerable dynamic changes in the membrane; high-field (900 MHz) SS NMR was used in determining the secondary structure and the orientation of 13C- and 15N-labeled piscidins (amphipatic, cationic, antimicrobial peptides from fish) in hydrated PL bilayers;95 the morphological changes induced by pandinin 1 (an antimicrobial peptide isolated from the venom of the African scorpion) were studied via 31P, 13 C, 1H SS and multidimensional solution-state NMR spectroscopy in model PC lipid membrane to thoroughly investigate the membrane disruption mechanism;96 AFM, CD and 2H and 31P NMR techniques were used to investigate the interaction of the antimicrobial peptide MSI-78 with mechanically aligned DMPC bilayers:97 results were in agreement with a previously published model that suggests the Nucl. Magn. Reson., 2007, 36, 397–418 | 405 This journal is

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location of the peptide at the hydrophobic-hydrophilic interface in the lipid headgroup region; static CP 31P-1H NMR experiments were performed on hydrated DPPC multilamellar bilayers with and without the dipeptide b-Ala-Tyr or the amino acid Glu:98 it was demonstrated that Glu interacts strongly with the PL headgroup while the dipeptide is not located close to the phosphate group; the topological equilibria of the ion channel peptides (Leu-Ser- Ser-Leu-Leu-Ser -Leu)n–CONH2 (n = 2, 3) reconstituted into oriented lipid bilayers were investigated by means of proton-decoupled 15N SS NMR spectroscopy;99 2H SS NMR was used to study the packing and the molecular dynamics of both the human N-ras protein lipid chains and the DMPC membrane matrix where the protein is incorporated;100 the 15Nlabeled Pseudomonas aeruginosa Pf3 phase coating protein was reconstituted into oriented PL bilayers and then analyzed via 15N and 31P SS NMR;101 through synchrotron SAXS and 2H NMR techniques the influence of Gramicidin D on the structure and the phase behaviour of aqueous dispersions of DMPC lipid bilayers in a extensive range of temperatures (from 10 to 60 1C) and pressures (from 0.001 to 4 kbar) were investigated.102

3.2.3 Vesicles, bicelles and L.C. dispersions. Vesicle or liposome and bicelle formulations are mainly based on biocompatible amphiphiles such as natural lipids and PLs or their mixtures. The huge number of papers devoted to these systems reflects the paramount importance they have in both applied and theoretical fields. Indeed, because of their supramolecular architecture, they represent the most common fluid nanocontainers for drug delivery applications and the most common mimicking systems in biological membranes studies. A number of techniques were used to study the morphological behaviour of the lecithin bilayers containing melittin:103 particularly, magnetic alignments of melittinlecithin vesicles were observed via 31P SS NMR; fluorescence, DSC and 15N SS and 2 H and 31P NMR supported the hypothesis that the antimicrobial peptide subtilosin A adopts a partially buried orientation in small unilamellar vesicles of POPC and POPE/POPG (7:3) mixtures;104 the morphological changes induced by the antimicrobial peptide protegrin-1 in DLPC and DOPC vesicles were observed through 1D and 2D 31P exchange NMR;105 the effect of two synthetic cationic antimicrobial peptides with alternating a- and b-amino acid residues (a/b-peptides) on liposomes composed of PE and PG in a 2:1 molar ratio was investigated through freeze fracture electron microscopy, X-ray diffraction and 31P NMR:106 results indicated that the a/b-peptide I induces the formation of a sponge phase, while with the a/b-peptide II, that is more lytic to liposomes than a/b-peptide I, the lamellar phase is retained (although with a drastic reduction of the d-spacing); a 1H and 31P NMR and DSC study of the thermal and morphological behaviour of DPPA, DPPC, DPPE and mixed DPPC/DPPE model membranes, in the multilamellar and unilamellar vesicular forms and in the presence of salicylic acid was reported;107,108 IR and 2H NMR spectroscopy were used to determine the modulation of the membrane orientation and the secondary structure of peptides which mimic the amino acid sequences of the C-terminal domains of the pro-apoptotic protein Bak and the antiapoptotic Bcl-2 when incorporated into different lipid vesicles;109 using EPR and NMR spectroscopy the membrane binding and penetration of a labelled porcine neuropeptide Y in vesicular membranes composed of PC and PS at varying mixing ratios were detected;110 a detailed investigation through fluorescence, Photo-Chemically Induced Dynamic Nuclear Polarization (Photo-CIDNP) and 31P-MAS NMR spectroscopy was performed to study the interaction of a tuberoinfundibular peptide of 39 residues with different kind of mimicking membranes (DOPC micelles and POPC/POPS/CHOL liposomes);111 the influence of temperature (297–340 K), CHOL content (DPPC/CHOL molar ratio 4, 8, 16) and pH (1.9–8.4) on DPPC/ CHOL liposomes membranes obtained by modified reverse-phase method was investigated via EPR, 1H and 31P NMR spectroscopy:112 moreover, the 406 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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incorporation of the 4-dimethyl-2-(carboxypropyl)-2-tridecyl-3-oxazolidynyloksyl into the liposome membrane allowed for the extraction of some parameters and the observation of liposomes structural changes; the effect of microwave irradiation (900 MHz for 5 h) on egg lecithin multilamellar vesicles was studied through DLS, IR, 1H and 31P NMR:113 conformational changes in the acyl chains of the lipids and hydrolysis of carboxylic and phosphoric esters were detected: however, both IR and NMR techniques did not show any appreciable changes in the headgroup part of the lipids; the pH-dependent aggregation properties of mixtures of 1,8-bis(N-octadec-9yl-1-deoxy-D-glucitol-1-ylamino)3,6-dioxaoctane (a sugar-based gemini surfactant) and various amounts of DOPC, DOPE or LPC in water and water at physiological ionic strength were observed via SLS, DLS, cryo-TEM and fluorescence, BPPSTE (Bipolar Pulse Pair Stimulated Echo) and 31P NMR spectroscopy;114 through SS 13C MAS NMR the dynamic effects of the oligopeptide leuprolide in an egg PC/CHOL system were examined;115 the SS DROSS (dipolar recoupling on axis with scaling and shape preservation) NMR technique was used to measure the order parameter in multilamellar DOPC vesicles as a function of temperature, unsaturation content and CHOL addition:116 it was found that the phase formed by DOPC with 30% CHOL is analogous to the liquid ordered phase; the coating of the vesicles forming lipid mixtures composed of DPPC and 1,2-dipalmitoyl-3-trimethylammonium-propane around sulfate-charged polystyrene submicron particles was investigated by thermogravimetric analysis and 1H NMR spectroscopy;117 1H NMR and FT-IR along with other techniques were used to study the vesicular aggregates originated by a single-tailed chiral cationic surfactant in water at temperature higher than 28 1C;118 1 H and 19F NMR spectra were recorded to monitor self-assembly of heptane-1sulfonic acid sodium salt in micellar and lamellar (vesicles) phases when small amounts of the fluorosurfactant 1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H-heneicosafluorotetradecylpyridinium iodine are added;119 through PFG NMR the permeability of ethylene oxide-2-vinylpyridine diblock copolymer vesicles was investigated;120 NMR, TEM and FT-IR were used to characterize vesicles obtained from novel cationic amphiphilic compounds synthesized from vernonia oil, a natural epoxydized triglyceride;121 by 1H NMR titration, p-A isotherm measurements and IR spectroscopy in reflection-adsorption mode, the pK values of the attached amino acid residues in synthesized amino acid-carrying amphiphiles were investigated at the air-water interface and in aqueous vesicles;122 1H NMR, FT-IR and DSC were used to study the effects of cyclodextrins on the formation and colour changes of polymerized 10,12-pentacosadiynoic acid vesicles;123 via 1H NMR, rheology and cryo-TEM techniques, the association between hydrophobically modified PEG and SDS/didodecyldimethylammonium bromide catanionic vesicles were studied;124 DSC and 1H NMR were used to investigate the thermal behaviour of dioctadecyldimethylammonium bromide vesicles dispersions equilibrated at different temperatures (15 and 25 1C).125 Several articles deal with bicelle nanostructures. It is worth recalling that bicelles are unilamellar bilayered micelles composed of a balanced mixture of long and short chain PLs. 2H, 129Xe, 131Xe and optically enhanced 129Xe NMR techniques were used to study the interaction between Xe and DMPC/DHPC bicelles:126 the chemical shift, linewidths and quadrupolar couplings of Xe/bicelles NMR signals were correlated with different regions of the bicellar phase diagram; the threedimensional solution structure of the N-terminal part (1–30) of a mouse Doppel protein was determined in DMPC/DHPC bicelles via 2D 1H NMR spectroscopy;127 the 1H–13C heteronuclear dipolar SS NMR spectroscopy technique (SAMMY) was used to investigate the membrane topological changes in PL bilayer (bicelles) upon addition of the transmembrane segment of PLB, the antimicrobial peptide (KI-GAKI)3 and CHOL;128 the diagrams of binary mixtures of 1,2-di-O-tetradecyl-PC 1,2-di-O-hexyl-PC ether-phospholipids were determined through 2H an 31P wide line NMR:129 by varying the hydration, the temperature and the mole fraction of the long-chain ether-phospholipids, the conditions for which such systems are Nucl. Magn. Reson., 2007, 36, 397–418 | 407 This journal is

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oriented by the magnetic field in the presence of 100 mM KCl were delineated; the partial temperature-composition-hydration diagrams of DMPC/di-caproyl-PC and 1-tetradecanoyl-2-biphenyl-butanoyl-PC/di-caproyl-PC which form bicelle membranes that are, respectively, oriented parallel and perpendicularly to the magnetic field, were determined by 31P NMR:130 it was shown that the 1-tetradecanoyl-2biphenyl-butanoyl-PC/di-caproyl-PC bicelles are a potential tool to study the orientation of hydrophobic helixes in membranes using wide line 15N NMR; 13C NMR relaxation and PFG NMR measurements along with EPR spectroscopy were used to investigate the dynamics of DMPC and the relative sizes of bicelles in different DMPC/DHPC and DMPC/3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonate systems.131 Two other investigations deal with L.C. dispersions that involve polymers and natural lipid mixtures: SAXS and 2H NMR were used to investigate the microstructures of the microphases (lamellar plus isotropic polymer solution) that phaseseparate when the lamellar phase formed by AOT in deuterated water is mixed with poly(dimethylacrylamide) polymers of low molecular weight;132 an investigation on the interaction between oleic acid and model stratum corneum model membranes (a multilamellar dispersion of bovine brain ceramide, CHOL and palmitic acid) was performed via SS 2H NMR as a function of both fatty acid composition and temperature.133

4

Micellar solutions

Micellar systems form as a result of the surfactant self-association whenever a suitable surfactant shape occurs, that is a packing parameter P = v/al not too close to unity. Surfactant molecules in micellar aggregates experience strong intermolecular interactions due to the interplay of both electrostatic and van der Waals forces, hence significant changes of NMR parameters are observed. Moreover, micellar aggregates usually form isotropic liquid systems, thus NMR experiments can be easily performed and modelled. Reliable information, at a molecular level, on critical micelle concentration (c.m.c.), molecular conformations and interactions, counterion binding and hydration, also in mixtures of different amphiphiles, can be generally obtained. 4.1 Micelles in amphiphile-solvent systems Here the investigations on micellar systems formed by single and mixed amphiphiles are presented according to the amphiphile type, e.g. ionic and nonionic, polymer and mixed amphiphiles. 4.1.1 Ionic and nonionic amphiphiles. Only few papers deal with pure ionic and nonionic amphiphiles. 19F chemical shifts and transverse relaxation times were measured as a function of time to investigate micellar kinetics after quick stoppedflow dilution of aqueous solution of sodium perfluorooctanoate:134 possible artefacts of stopped-flow experiments along with differences between NMR and SAXS detection methods were discussed; the effect of glycerol on the micellization of CTAB and Brij 58 surfactants was studied via surface tension, fluorescence quenching and PFG NMR measurements;135 slowly diffusing water molecules (4.33 1010 m2 s1) were observed by NMR and quasi-elastic neutron scattering in SDS micellar solution and in DTAB and in ethoxylated nonylphenol (with different chain length Cn, n = 12, 20, 30, 40) micellar systems:136 the mean slowing down of solvent molecules was checked by gradient compensated stimulated spin-echo pulse sequence; the acid dissociation constant of the hydroxyl group of micellized hexadecyl(2-hydroxyethyl)dimethylammonium bromide was estimated in the range 12.4–12.6 from 1H and 13C NMR chemical shifts analysis of the hydroxyethyl group while varying pH and by monitoring the pH increase on addition of OH;137 31P 408 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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NMR along with a number of other techniques was used to measure the c.m.c. of novel phosphono-bile salts (bile acid analogues) and to investigate the hydrogels derived from trihydroxy bile acid analogues;138 various analytical methods demonstrated that the antiglaucoma ophthalmic agent CS-88 is a self associating compound with a micellar assembly corresponding to a pentamer:139 however, a micellar molecular weight of CS-88 corresponding to a dimer was detected by NMR spectroscopy, thus indicating that self-association of monomers to pentamers is via the formation of dimers.

4.1.2 Polymer amphiphiles. In view of the growing interest of polymer-based amphiphiles for applications of biological interest, many investigations report on biopolymers modifications that may introduce specific groups able to confer a variety of selective functionalities, particularly useful in drug delivery formulations. Unpolymerized and polymerized wormlike micelles obtained upon mixing p-toluidine hydrochloride and sodium 4-(8-methacryloyloxyoctyl)oxybenzene sulfonate were investigated via SLS, DLS, SAXS and 1H NMR methods;140 1H NMR and other techniques were used in studying the properties of N-palmitoylchitosan-based polymer micelles prepared with a novel method;141 1H NMR spectra were acquired in CDCl3 and D2O to demonstrate the existence of hydrophobic poly(sebacic anhydride) (PSA) domains such as the core of micelles formed by PSA-PEG-PSA block copolymers;142 using a combination of 1H NMR, DLS and SLS it was shown that the thermally responsive diblock N-isopropylacrylamide (NIPAM)/N,N-dimethylacrylamide (DMA) and triblock DMA/NIPAM/DMA copolymers are capable of forming micelles reversibly;143 1H NMR along with other methods was used to investigate the micelle formation of poly(4-pyridinemethoxymethyl)styreneblock-polystyrene diblock copolymer controlled by perfluoroalkyl carboxylic acid;144,145 1H NMR, QELS, SLS and fluorescence experiments showed that a series of poly([3-(methacryloylamino)propyl]trimethylammoniumchloride)-block-poly (2-(diethylamino)ethyl methacrylate) diblock copolymers of different block lengths exhibit a reversible micelle formation and dissociation induced by a pH change in aqueous solution;146 the reversible micelles formed by smart amphiphilic block copolymers formed by a switchable hydrophilic-hydrophobic block of poly (N-isopropylacrylamide) and a hydrophilic block of poly(N,N-dimethylacrylamide) of various composition were characterized via 1H NMR, DLS and tensiometry;147 DLS, SLS, TEM, AFM and 1H NMR were used to study the micelles formed during copolymerization of 4-vinylpyridine and divinyilbenzene in cyclohexane using dithyobenzoate-terminated polystyrene as RAFT agent;148 the self-assembled micelle-like spheres originated in water by a polyglycerol dendrimer of generation 4 conjugated with cholesterol were investigated via 1H NMR, DLS and AFM;149 through 1H NMR, TEM and viscosimetry the micellization of polystyrene-graftpoly(ethylene oxide) and its mixtures with polystyrene in ethanol was studied;150 PFG NMR experiments were performed along with laser scanning confocal microscopy in studying micelles formed in aqueous solutions of BuO-(PEO-stat-PPO)block-PLA-OH;151 the structure of the micelles formed by a series of novel hyperbranched multiarm copolyethers PEHO-star-PPO (3-ethyl-3-(hydroxymethyl)oxetane-propylene oxide copolymer) was explored by FTIR and 1H and 13 C NMR;152 cryo-TEM, SEM, AFM and 1H NMR were used to study the cylindrical micelles formed by poly(ferrocenyldimethylsilane-block-methylmethacrylate) (PFDMS-b-PMMA) block copolymers in the block-selective solvent (good only for PMMA) acetone;153 the self-assembly behaviour of poly(methyl vinyl ether)-block-poly(isobutyl vinyl ether) block copolymers in water was investigated via 1H NMR spectroscopy:154 it was shown that polydisperse spherical micelles are formed for asymmetric copolymers containing at least 9 isobutyl vinyl ether units. Nucl. Magn. Reson., 2007, 36, 397–418 | 409 This journal is

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4.1.3 Mixed amphiphiles systems. Mixed micellar systems are very important either for industrial applications or scientific investigations. The industrial interest is mostly related to obtain synergic effects in the formulations. Synergy may be induced typically by mixing amphiphiles of different type, whereas with homologous species ideal behaviour is often observed. Through a combination of PFG NMR, DLS, viscosity and conductivity measurements the microstructure of aggregates formed by SDS and 1-pentanol in mixtures of water and propylene carbonate (a polar aprotic solvent) was determined:155 it was found that propylene carbonate partitions between aqueous bulk and micelles, thus strongly increasing the total interfacial area by acting as a cosurfactant; the self-assembly properties of new amphiphilic diblock copolymers composed of poly(Bu acrylate) as the hydrophobic block and six different (anionic, cationic and nonionic) hydrophilic blocks in aqueous and organic media were studied by NMR and DLS:156 micelle-like aggregates were found in water as well as inverse micelles in organic solvents and it was also shown that mixed micelles form bringing together two populations of micelles made from different copolymers; the effect of the addition of a nonionic surfactant C8E5 to the complex poly(asparagine)-cationic surfactant DTAB was investigated through NOESY NMR:157 a specific interaction of the polypeptide is evidenced in the presence of the cationic surfactant; 1D and 2D NMR along with other techniques was used to investigate the interactions between nonionic surfactants and amphiphilic, random copolymers of a-L-aminoacids containing lysine residues as the hydrophilic moieties;158 the hydrolysis of decyl betainate (DB) and tetra-(ethylene glycol)monon-octanoate (TEO) mixtures was monitored via 1H NMR:159 a moderate synergism was ascertained and it was shown that while DB hydrolysis decreases with increasing TEO molar ratio, the hydrolysis of TEO, not particularly affected by DB presence, can however be accelerated or retarded by coaggregation with stable cationic or anionic surfactant, respectively; the c.m.c. values for different mixed zwitterionic/ anionic and zwitterionic/cationic surfactant systems were investigated through conductivity and NMR spectroscopy:160 strong synergism was ascertained for zwitterionic/anionic surfactant mixtures, whereas only slight deviations from ideal mixing were found for zwitterionic/cationic surfactant mixtures.

4.2 Solubilization, microemulsions and emulsions Micellar systems are ideal systems to solubilize both hydrophilic and hydrophobic moieties. L1 and L2 micellar phases can be swollen by oil and water to form water/ oil/amphiphile ternary or pseudo-ternary systems. These systems can be used for different types of investigations, from structural characterizations of an immobilized peptide or protein, to drug delivery systems, or micellar catalysis. A variety of ternary systems based on water, oil and amphiphile mixtures can form. The solubilization or the dispersion processes may occur spontaneously, thus thermodynamically stable systems are obtained as in the case of microemulsions. Differently, if external work is needed to induce the emulsification process, only kinetically stable systems can form as in the case of foams and emulsions. The crucial factor relies on the decrease of the oil-water interfacial tension (go/w) induced by the amphiphilic molecules located at the polar-apolar interface, according to the usual equation: DG = DA go/w TDS

(1)

where DG is the Gibbs free energy, DA is the interfacial area variation and DS is the configurational entropy associated to the dispersion process, at the defined temperature T. Microemulsions are characterized by nanoaggregates (typical dimensions below 200 nm) and low polydispersity, thus they appear as isotropic solutions. On the contrary, emulsions or other dispersed systems show at least turbidity even in very diluted systems due to the dimensions (order of magnitude around mm) of the 410 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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dispersed phases. Shape, size and stability are addressed by intermolecular forces that modulate the hydration of the polar head groups and the oil penetration which, in turn, determines the elasticity of the interfacial film and thus the stability towards the rupture. Equally important are other parameters such as surface tension, osmotic pressure and the relative densities and viscosities. For instance, the emulsion stability with respect to the typical destabilizing processes, e.g. creaming, sedimentation, flocculation, coalescence and Ostwald ripening, is strongly influenced by the respective densities and viscosities of the dispersed phase and of the dispersing media.

4.2.1 Solubilization media. In this paragraph only the articles related to the use of micellar systems and microemulsions as solubilizing media are reported. The solubilization of styrene in a CTAB based microemulsion was investigated by NMR in comparison with anionic surfactant based microemulsions;161 the different location of tris(2,2 0 -bipyridyl)Co(II) in the Stern layer of SDS micelles and in the hydrophobic core of CTAB micelles was proven by 1H NMR spectroscopy;162 the site of solubilization of anthranilic acid, benzoic acid and their sodium salts and the role they have in producing viscoelasticity in micellar solution of CTAB (10 mM) was investigated by 1H NMR spectroscopy;163 the solubilization of b-cyclodextrin in micelles formed by alkyltrimethylammonium bromide surfactants having different chain length, was investigated through PFGSE NMR;164 FT-IR and 1H NMR were used to study the solubilization of formamide and its aqueous solution by means of AOT in heptane or isooctane reverse micelle, respectively;165 1H NMR data of two deuterated isotopomers of tetraalanine collected in the lyotropic solvent cesium pentadecafluorooctanoate (CsPFO) indicated that the molecule is oriented with the long molecular axis tilted with respect to the surface of the micelles.166 More often solubilization is used to produce drug delivery systems. In other cases, micellar systems constitute a simplified model, alternative to bicelles, liposomes and PL bilayers, for mimicking membrane-like biological interactions. Polymeric prodrugs based on methoxy-PEG, poly(lactic acid) and haloperidol were shown to form micelle-like nanostructures through 1H and 13C NMR, cryo-TEM and DLS;167 a new AOT analogue (3,3-dimethyl-1-butylsulfosuccinate sodium salt) was synthesized and used to prepare reverse micelles capable of encapsulating safely the protein ubiquitin as demonstrated by NMR studies;168 the cationic surfactant CTAB was used to prepare samples of encapsulated anionic proteins dissolved in low viscosity solvent, suitable for NMR analysis;169 DQF-COSY, TOCSY, NOESY and ROESY NMR experiments were used to study the three-dimensional structure of the neuropeptide K in aqueous and DPC micellar environments;170 the binding geometry and the conformational changes of a peripheral membrane protein was investigated in DPC micelles by spin-label NMR spectroscopy;171 the interactions of a-tocopherol as a function of the surfactant molar ratio in solution of dry lecithin reverse micelles dispersed in an apolar medium were investigated through FT-IR, SAXS and 1H NMR spectroscopy;172 the human calcitonin-derived cell-penetrating peptide HCT(9-32) and two HCT(9-32) mutants were studied via high resolution NMR spectroscopy and other techniques in a DPC micellar system;173 1H NMR and quasi-elastic neutron scattering measurements were performed on aqueous solution of DTAB to study the effect of sodium salicylate additives on micellar structure and dynamics;174 the binding and the folding of melittin in the presence of ganglioside GM1 micelles was investigated by 2D NMR methods.175 SDS micellar solutions are often used as simplified model membrane to investigate peptide and protein conformational changes and interactions: for two antimicrobial peptides from bovine lactoferricin the extent of burial of the two tryptophan residues was investigated by fluorescence and NMR spectroscopy;176 a detailed investigation of the interactions between the antimicrobial peptide Novispirin and detergents or lipids was carried out through a number of methods:177 particularly, various NMR Nucl. Magn. Reson., 2007, 36, 397–418 | 411 This journal is

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techniques were used to solve the peptide structure in SDS and lauryltrimethylammonium bromide micellar systems; the helical conformation of cell-penetrating peptides in SDS micelles was investigated by NMR using Mn2+ as a paramagnetic probe;178 the lipid composition of integral purple membrane in SDS or Triton X-100 micellar solutions was investigated by 1H and 31P NMR.179 In other articles solubilization is compared in SDS and DPC micelles or in mixed micellar systems: the structure of human lactoferricin in DPC and SDS aqueous solution and in a membrane mimetic solvent (4:4:1 methanol-d3-CDCl3–H2O) was determined by conventional 2D NMR methods;180 a structural investigation of a glycoprotein involved in the fusion domain of HIV was performed in SDS, DPC and SDS/DPC micelles using NMR for some labelled peptides;181 the structures of indolicin, a I3-residue antimicrobial peptide-amide, were determined by NMR spectroscopy in 50% d3-trifluoroethanol and in the absence and in the presence of SDS and d38-DPC micelles;182 a porphyrin derivative was studied in different micellar environments (e.g. SDS, Triton X-100, etc.) as a function of pH by 1H NMR;183 the bound structure of an antimicrobial peptide in different PL-based vesicles and in SDS and DPC micelles was solved by 2D 1H NMR;184 the cationic antimicrobial peptide polyphemusin I and its synthetic variant were investigated in DPC micelles and in other PL vesicles by 1H NMR;185 the three-dimensional structure of the antimicrobial peptide Curvacin A was studied in DPC micelles by NMR spectroscopy;186 three amphipatic helical segments were ascertained for the epidermal growth factor receptor, a member of the receptor tyrosine kinase family, in DPC micelles using various NMR methods;187 the structural model and the interactions with d38-DPC micelles of the complex between the peptide corresponding to the BH3 region of the pro-apoptotic protein BID and the anti-apoptotic protein BCL-w were studied by different NMR methods;188 the anti-cancer drug adriamycin was found to be located into the inner core of micelles formed by novel biomimetic surfactants based on CHOL and poly(2-(methacryloyloxy)ethyl phosphorylcholine) as demonstrated by NMR, AFM, and fluorescence excitation spectra.189

4.2.2 Microemulsions. To form a microemulsion a subtle interplay of intermolecular forces (van der Waals, electrostatic, hydration, polarizability, specific ion effects, etc.) should occur and modulate the amphiphilic polar–apolar interface. From a phenomenological viewpoint, the decrease of the interfacial tension is always of utmost importance. A variety of microstructures from discrete to bicontinuous nanoaggregates, exactly as in the lyotropic L.C. phases can be found. To clarify microstructural features and transitions in microemulsion systems NMR techniques have provided a wide and unique insight of knowledge. For instance, the transition of the dispersed phase from a disconnected to an interconnected domain, generally referred as percolative threshold, can be nicely proven by NMR relaxation and diffusion experiments. The occurrence of different nanostructures within the same monophasic region is mainly due to composition dependent modifications. Composition changes perturb the delicate balance among the various intermolecular forces thus inducing changes in the spontaneous curvature of the amphiphilic interface. Some recent investigations on microemulsion systems focus either on sophisticated modelling of the NMR experiments, or on the analysis of NMR parameters in order to improve predictive theories. Examples of modelling can be found in two articles. The spontaneous curvature was shown to increase as the oil chain length is increased in two ternary microemulsions based on C12E5 nonionic surfactant and decane or hexadecane as oil, as demonstrated by NMR, SAXS and DLS techniques;190 a microstructural transition from branched micelles to w/o droplets with increasing the oil content was observed in the microemulsions formed by 2H2O, the n-octane oil, the nonionic surfactant octyl-b-D-glucoside and 1-octanol as demonstrated by NMR self-diffusion 412 | Nucl. Magn. Reson., 2007, 36, 397–418 This journal is

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measurements and by SAXS technique used to characterize the swelling of the lamellar phase occurring in the four-component system.191 Two articles on lecithin (LCT) based microemulsion systems have been reported: the phase transitions induced by water dilution in LCT based microemulsions were investigated by NMR, conductivity and DSC techniques;192 a PFG NMR study showed anomalous diffusion in LCT based microemulsion as a result of either an increase of LCT concentration or the addition of a polycation.193 Two interesting articles report on the use of microemulsion for drug delivery applications: 1H NMR measurements confirmed the entrapment of chloroamphenicol in o/w microemulsions composed of span20/80, tween20/80, n-butanol, water, isopropyl-palmitate/isopropyl-myristate that can be used as ocular drug delivery systems;194 NMR self-diffusion measurements were used to characterize the w/o or the bicontinuous microstructure of different microemulsions formed by ethyloleate, polyoxyethylene 20 sorbitan monooleate, sorbitan monolaurate, water, and butanol used for the preparation of nanoparticles composed of the protein ovalbumin and ethyl-2-cyanoacrylate.195 4.2.3 Emulsions. The increasing demand for reproducibility in the performance of emulsions of industrial interest brought about important developments of NMRbased experiments aimed to gain information on the formation, microstructural features and stability of these systems. For instance, NMR self-diffusion measurements have become routine tasks to droplet sizing. Here, besides reviews, methods and articles of general interest reported in paragraph 2, few other articles are presented. The effects of droplet size and emulsifiers on the oxidative stability of polyunsaturated triacyl glycerides (PU TGA) in o/w emulsions was studied using 1H NMR relaxation:196 the smaller the droplet size the lower the amount of residual oxygen, a fact that implies a higher oxidative stability of the PU TGAs; the stability of o/w emulsions based on Triton X-100 significantly increased with increasing surfactant concentration and the oil chain length from octane to tetradecane as determined through freeze fracture TEM, laser diffraction particle sizing and PFG NMR measurements:197 particularly, three different types of diffusion—namely, restricted diffusion of the oil in the droplets, and free and restricted diffusion of the droplets themselves—were ascertained; the rate of nitroxide-mediate polymerization of styrene and divinylbenzene in o/w miniemulsions increased with decreasing droplet size and was significantly higher than in bulk;198 a transition from a bicontinuous microemulsion, at the hydrophyle-lipophile balance temperature, to o/w nanodroplets upon cooling was monitored through multicomponent 1H PFGSE NMR techniques and the results were compared with theoretical predictions;199 1H PFGSE NMR measurements were used to characterize droplet size and the influence of viscosity, temperature and dilution in several w/o emulsions based on different heavy crude oils,200 and to analyze intercompartment exchange and the inner compartment droplet size distribution of a w/o/w multiple emulsion.201

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