Nuclear Magnetic Resonance: Volume 37 (Specialist Periodical Reports)

Nuclear Magnetic Resonance Volume 37 A Specialist Periodical Report Nuclear Magnetic Resonance Volume 37 A Review of...

Author: G A Webb

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Nuclear Magnetic Resonance Volume 37

A Specialist Periodical Report

Nuclear Magnetic Resonance Volume 37 A Review of the Literature Published between June 2006 and May 2007 Editor G.A. Webb, formerly Department of Chemistry, University of Surrey, Guildford, UK Authors A.E. Aliev, University College London, UK 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 T. Kameda, National Institute of Agrobiological Sciences, Tsukuba, Japan K. Kamien´ska-Trela, Polish Academy of Sciences, Warszawa, Poland C.L. Khetrapal, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Lucknow, India 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 U.R. Prabhu, Indian Institute of Science, Bangalore, India M.J.W. Prior, University of Nottingham, UK K.V. Ramanathan, Indian Institute of Science, Bangalore, India W. Schilf, Polish Academy of Sciences, Warszawa, Poland P.J. Simpson, Imperial College London, UK J. Wo´jcik, Polish Academy of Sciences, Warszawa, Poland T. Yamanobe, Gunma University, Gunma, Japan H. Yasunaga, Kyoto Institute of Technology, Kyoto, Japan

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ISBN 978-0-85404-115-2 ISSN 0305-9804 A catalogue record for this book is available from the British Library r The Royal Society of Chemistry 2008 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 by Henry Ling Ltd, Dorchester, Dorset, UK

Preface G.A Webb DOI: 10.1039/b719474a It is my great pleasure to introduce Volume 37 of the SPR on NMR. Like its predecessors the current volume aims to provide comprehensive coverage of the NMR literature. In the present case, the relevant literature appearing between June 2006 and May 2007. Compared to earlier volumes in the series there are three apparent omissions in this one. The first concerns the chapter on Multiple Resonance which has appeared regularly for many years. It is considered that due to various changes in the extent of coverage in other chapters a separate account of multiple resonance is no longer required. The other two omissions relate to the accounts of Liquid Crystals and Micellar Solutions and that on NMR Imaging. Unfortunately due to personal problems, the reporters for these chapters are unable to fulfil their commissions this year. It is proposed to include a two year coverage of these research areas in Volume 38. There have been two changes in the membership of the reporting team during the past year. T. Kameda has replaced N. Asakawa as a member of the group reporting on Applications of Nuclear Shielding, and the chapter NMR of Proteins and Nucleic Acids is presented by P. J. Simpson. I offer a very warm welcome to these recent additions to the reporting team and offer them, and the more established reporters, my sincere thanks for their support of this series and for a job well done.

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

Nucl. Magn. Reson., 2008, 37, 7–8 | 7 This journal is

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The Royal Society of Chemistry 2008

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

Preface

7

G. A. Webb

NMR books and reviews

21

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

21 21 21 21 21

Theoretical and physical aspects of nuclear shielding

51

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

51 57


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Applications of nuclear shielding

68

Shigeki Kuroki, Tsunenori Kameda and Hidekazu Yasunaga Introduction Shielding of particular nuclear species

68 68

Theoretical aspects of spin–spin couplings Hiroyuki Fukui Introduction Parity-violating effects on the indirect nuclear spin–spin coupling constants of chiral molecules Relativistic calculation of spin–spin couplings Theoretical calculation of spin–spin couplings Spin–spin couplings and conformations

124

Applications of spin–spin coupling

145

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

145 146 148 151 155 157 158 161 163 164 165 166

Nuclear spin relaxation in liquids and gases

180

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

10 | Nucl. Magn. Reson., 2008, 37, 9–20 This journal is

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124 124 126 128 136

180 181 194 197 199

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

208

NMR of proteins and nucleic acids P. J. Simpson Introduction New methodology High-resolution structural studies of biomacromolecules

257

NMR of carbohydrates, lipids and membranes Elizabeth Hounsell Introduction Membrane studies Glycoconjugates Microbial polysaccharides Plants Libraries and metabonomics Drug design and delivery

274

Synthetic macromolecules

293

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

293 293 293 304 305 312

208 209 210 217 221

257 257 264

274 274 278 280 283 285 286


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NMR in living systems

327

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

327 330 331 331 338

Oriented molecules

357

K. V. Ramanathan, Uday R. Prabhu and C. L. Khetrapal Introduction Reviews, theory and general studies New techniques Dynamic NMR studies Chiral, smectic, lyotropic and polymeric systems Relaxation studies Orientational order in liquid crystals Membranes and molecules oriented therein Structure and orientation of small molecules Weak ordering and biomolecular studies

357 357 360 361 363 365 366 367 369 371


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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*)1 ¼ T21 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

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) o carrier frequency in rad s1 oi, o0, o1, o2 as for n i , n 0 , n 1 , n 2 but in rad s1 om modulation angular frequency (in rad s1) or 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 ROESY RPA SCPT SD SECSY SEFT SLITDRESS SOPPA SPI SPT SR TART TOCSY UV WAHUHA ZQ ZQC

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

(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/b617235k

Books Ref. 1

Regular review series Refs. 2–132

Edited books and symposia Refs. 133–305

Reviews in periodicals Refs. 306–600

Reviews and books in foreign languages Chinese Refs. 601–639 Dutch Ref. 640 French Refs. 641–644 German Refs. 645–650 Hungarian Ref. 651 Japanese Refs. 652–715 Polish Ref. 716 Portugal Refs. 717–721 Russian Refs. 722–723 Spanish Refs. 724–725 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw 42, Poland


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636 W. Zhang and S. Wang, ‘Progress of Quality Control Method of Sulfur-Substituted Antisense Oligonucleotides’, Guowai Yixue, Yaoxue Fence, 2005, 32, 132. 637 L. Zhao, L. Cui and C. Li, ‘Detection Methods of Cell Apoptosis’, Hebei Yiyao, 2005, 27, 783. 638 H. Zhu, H. Tang, X. Zhang and M. Liu, ‘NMR Based Metabonomics’, Huaxue Tangbao, 2006, 69, w070/1. 639 Y. Zhu, L. Wei, H. Tian and J. Long, ‘Advances in Acidity Characterization of Solid Acid Catalysts’, Shiyou Huagong, 2006, 35, 607. 640 P. Dubruel, S. Van Vlierberghe and E. Schacht, ‘Boundary Surface Analysis of Biospecific Interactions’, Oppervlaktetechnieken, 2006, 50, 30. 641 D. Auguin and M. Kochoyan, ‘An Introduction to NMR and X-Ray Crystallography Synergies in the Field of Structural Biology’, Spectra Analyse, 2006, 35, 33. 642 J. Bobroff, ‘Impurities and Correlated Systems. Superconducting Cuprate Chains’, Annales de Physique (Paris, France), 2005 (Published 2006), 30, I–v, vii–viii, 1–3, 5–9, 11–43, 45–149. 643 G. Bouvignies, P. Bernado and M. Blackledge, ‘Modeling of Peptide Chain Dynamics of Proteins in Solution by NMR through Dipolar Coupling’, Journal de Phisique IV: Proceedings, Vol. 130 (Neutrons et Biologie), EDP Sciences, 2005. 644 B. Chaudret, ‘Organometallic Chemistry and Nanoparticles’, Actualite Chimique, 2005, 290–291, 33. 645 B. Bluemich, ‘Mobile NMR: How Aged is Polyethylene’, Nachrichten aus der Chemie, 2007, 55, 158. 646 B. Bluemich, A. Buda and K. Kremer, ‘Non-Destructive Testing with Mobile NMR’, Gummi, Fasern, Kunststoffe, 2006, 59, 290. 647 J. Blumel, ‘Solid State NMR Spectroscopy in Catalysis’, Nachrichten aus der Chemie, 2006, 54, 632. 648 T. Engel, ‘Spectra Search Made Easy’, Nachrichten aus der Chemie, 2006, 54, 873. 649 A. Krueger, F. Wuerthner, U. Beifuss, M. O. Senge, T. Mueller, M. Albrecht, T. Bach, C. Tschierske, H. Heydt, J. Hartung, G. Bucher, B. F. Straub, K. Muniz, K. Ditrich, R. Giernoth, M. Oestreich, G. Draeger, T. Lindel, D. Jacquot, J. Pietruszka, R. Breinbauer, M. Es-Sayed, R. Pfau, H. Priebke, N. Sewald, P. Bisel, M. Mueller, E. Weinhold, C. Schalley, P. Schreiner, R. Gschwind, S. Braese and H.-A. Wagenknecht, ‘Organic Chemistry 2006’, Nachrichten aus der Chemie, 2007, 55, 252. 650 I. Reimold-Stahl and M. Reimold, ‘Search for the ChemicalOrigin of Life Selfreplicating Molecule’, CLB Chemie in Labor und Biotechnik, 2006, 57, 58. 651 P. Huszthy, P. Bako, A. Mako and L. Toke, ‘Chiral Crown Ethers’, Magyar Kemiai Folyoirat, Kemiai Kozlemenyek, 2005, 111, 55. 652 T. Akasaka and S. Nagase, ‘Structures of Endohedral Metallofullerenes’, Nippon Kessho Gakkaishi, 2006, 48, 230. 653 T. Asakura and Y. Nakazawa, ‘Determination of Structures of Silk Fibroins from Silkworms and Spiders Using Solid-State NMR’, Kobunshi Ronbunshu, 2006, 63, 707. 654 N. Ayai, M. Kikuchi, K. Yamazaki, S. Yamade, R. Hata, K.-i. Sato, K. Hayashi, T. Kato, J. Fujikami, S.-i. Kabayashi, E. Ueno and K. Fujino, ‘Achievement of HTS Wire Critical Current Exceeding 200 A’, SEI Tekunikaru Rebyu, 2006, 169, 103. 655 K. Chiba-Kamoshida, ‘Measurement of Electrostatic Potential inside Protein Molecule by Neutron Crystallography’,, JAERI Conf., , 2005, 2005-011, Japan Atomic Energy Research Institute. 656 T. Erata and H. Kohno, ‘High-Resolution Solid-State NMR Studies of Cellulose’, Cellulose Commun., 2006, 13, 26. 657 Y. Fukabori and K. Yoshida, ‘Prostate Cancer’, Dokkyo Journal of Medical Sciences, 2005, 32, 197. 658 E. Fukusaki, ‘Possibility and Technical Problem of Metabolomics’, Seibutsu Kogaku Kaishi, 2006, 84, 231. 659 Y. Fukuzawa and H. Iwamoto, ‘Conformational Analysis of Flexible Compounds with Chemical Shift Simulation’, Yuki Gosei Kagaku Kyokaishi, 2005, 63, 1080. 660 K. Furihata and H. Seto, ‘Stereochemical Determination of Chain Compounds. About JResolved-HMBC Method’, Kagaku to Seibutsu, 2006, 44, 710. 661 M. Hattori, ‘New Sensitivity Enhancement Technology for NMR/MRI’, Kagaku Kogyo, 2006, 57, 377. 662 S. Hayashi, ‘Nuclear Magnetic Resonance Study of Proton Diffusion in Inorganic Solids for Fuel Cells’, Shinku, 2006, 49, 12. 663 K. Hori, ‘Observation of Food Lipids by Nuclear Magnetic Resonance (NMR)— Regioisomer Distribution of Acylglycerols and Lipid Alteration for Miso Fermentation’, Foods & Food Ingredients Journal of Japan, 2006, 211, 972. 664 M. Ida, H. Yoshizawa, T. Arai, K. Motoyoshi, A. Yoshihiro, K. Nakamura, T. Oonishi, N. Mizuuchi and K. Maruyama, ‘Proton Magnetic Resonance Spectroscopy (1H-MRS) for Acute Cerebral Ischemia’, Bunshi No Kekkanbyo, 2006, 5, 221.


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665 M. Iijima, H. Sugaya and H. Hiraishi, ‘Hepatoma’, Dokkyo Journal of Medical Sciences, 2005, 32, 229. 666 K. Ishida, Y. Ihara, C. Michioka and K. Yishimura, ‘Magnetic and Superconducting Properties of the Cobaltate Superconductor Probed by Co Nuclear Quadrupole Resonance’, FSST News, 2006, 108, 2. 667 M. Kainosho, ‘A New Horizon of Protein NMR Structure Analysis: The SAIL Method’, Seitai no Kagaku, 2005, 56, 606. 668 M. Kainosho and P. Guntert, ‘SAIL, a Rapid and Accurate NMR Method in HighMolecular-Weight Protein Structure Determination’, Baiotekunoroji Janaru, 2006, 6, 467. 669 Y. Kakahashi, ‘Structure Analysis of One-Dimensional Crystalline Polyethylene Single Crystal Mats’, Kobunshi Kako, 2005, 54, 536. 670 H. Kamei, ‘NMR Imaging of Brain Function’, Kagaku to Kyoiku, 2006, 54, 30. 671 Y. Kamiya, Y. Yamaguchi and K. Kato, ‘NMR Spectroscopy of Glycoconjugate Structural Biology’, in Tosa Kagaku no Shintenkai, eds. T. Naoyuki and I. Yukinari, 2005, pp. 76–83, 1 Plate, Unu-Ti-Esu, Tokyo, Japan. 672 T. Kasuga, T. Akamatsu and H. Osaki, ‘Proton Conducting Hydrogels Derived from Phosphate Glasses’, Mater. Integration, 2006, 20, 41. 673 Y. Kato and Y. Tanokura, ‘Protein Structure and Genomic Science’, Baioimejingu, 2005, 14, 25. 674 J. Kikuchi and K. Akamine, ‘In vivo NMR’, Bunko Kenkyu, 2006, 55, 320. 675 S. Kitagawa, ‘Preparation of Novel Ionic Conductors of Coordination Polymers’, Asahi Garasu Zaidan Josei Kenkyu Seika Hokoku, [computer optical disk], 2005, 01.02/128. 676 T. Kohno, ‘Protein Structural Analysis and Drug Discovery by NMR’, Baiotekunoroji Janaru, 2007, 7, 243. 677 T. Kokubo, S. Ki, F. Sugihara and M. Shirakawa, ‘Gene Expression Analysis in Living Cells Using Magnetic Resonance Imaging’, Baiotekunoroji Janaru, 2006, 6, 605. 678 K. Kumano and S. Iwaya, ‘Pipeline Renewal Technology for Long Life of Pipeline’, Bosei Kanri, 2005, 49, 402. 679 H. Kumeta and F. Inagaki, ‘Progress in NMR Structure Analysis of Protein’, Seikagaku, 2007, 79, 55. 680 H. Kunieda, K. Aramaki and T. Sato, ‘Introduction: Self-Systemization and Latest Structural Measurement Methods of Surfactants and Polymers with Amphoteric Media’, in ‘Kaimen Kasseizai—Ryoshinbosei Kobunshi no Saishin Kino, eds. H. Kunieda and K. Sakamoto, Shi Emu Shi Shuppan, Tokyo, Japan, 2005p. p. 1. 681 H. Maekawa, ‘Recent Advances in Solid State NMR and Its Applications to Ceramics’, Seramikkusu, 2006, 41, 1020. 682 S. Matsukawa, ‘Dynamics Behavior of Water Molecule in Surimi Gels Observed by NMR Spectroscopy’, Suisangaku Shirizu, 2005, 146, 36. 683 N. Matsumori, T. Oishi and M. Murata, ‘Derivatization and Isotope Labeling of Amphotericin B Aiming at Elucidation of the Ion-Channel Structure’, Yuki Gosei Kagaku Kyokaishi, 2006, 64, 502. 684 Y. Matuo, ‘Authenticity Testing for Food Safety. Its Origin and Meaning in Japan’, Seibutsu Shiryo Bunseki, 2006, 29, 211. 685 Y. Miyazaki, ‘NMR Studies on the Solution Property and Function of Ion Exchangers’, J. Ion Exch., 2006, 17, 59. 686 E. H. Morita, ‘Magnetic Resonance Spectroscopy. IV. NMR Spectroscopic Studies on Protein Structure’, Bunko Kenkyu, 2006, 55, 274. 687 T. Nagatsuka, ‘Pyridylamination as an Integrated Operating System of Sugar Chain Analysis’, Tosa Kagaku no Shintenkai, eds. T. Naoyuki and I. Yukinari, Enu-Ti-Esu, Tokyo, Japan, 2005, p. 56. 688 H. Nakagami, ‘Evaluation of Physical Properties and Optimization Method in Formulation Development’, Pharm. Tech. Japan, 2005, 21, 2447. 689 K. Nakamura, Y. Kondoh, A. Wakai, J. Kershow and I. Kanno, ‘Recent Advances in the Tracer for Clinical Magnetic Resonance Imaging’, Magune, 2006, 1, 59. 690 M. Nakano, ‘Preparation and Structural Investigation of Lipid Nanoparticles with Nonlamellar Phases’, Maku, 2006, 31, 202. 691 Y. Noda, S. Iimura and S.-i. Segawa, ‘A Hydrogen-Exchange NMR Study of Structural Fluctuations of Protein’, Bunko Kenkyu, 2006, 55, 379. 692 M. Nomura and Y. Nishimura, ‘The Neural Repressor NRSF/REST Binds to the mSin3 PAH1 Domain by Using Its Short Hydrophobic Helix’, Tanpakushitsu Kakusan Koso, 2006, 51, 913. 693 A. Y. Nosaka and Y. Nosaka, ‘Time Resolved NMR’, Electrochemistry (Tokyo, Japan), 2006, 74, 406. 694 M. Oda, ‘Thermodynamic Analysis of Conformational Change Important to Protein Function’, Netsu Sokutei, 2007, 34, 31. 695 T. Ohno, Y. Kawasaki, Y. Ueda and T. Nakajima, ‘NMR of A-Site Ordered Perovskite LaBaMn2O6’, Kotai Butsuri, 2007, 42, 37.


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696 K. Onitsuka and F. Takei, ‘Helical Conformational Change in Polyisocyanides Induced by External Stimuli’, Jasco Report, 2006, 48, 26. 697 K. Oseto and Y. Mino, ‘MRI Application to Evaluation of Oil and Water Displacement’, Sekiyu Gijutsu Kyokaishi, 2006, 71, 591. 698 K. Saito, ‘Application of NMR Imaging to Solid State Materials’, Nippon Gomu Kyokaishi, 2005, 78, 429. 699 K. Saito, ‘Polymer Deterioration Analysis Using NMR/NMR Imaging Method’, Toso Kogaku, 2006, 41, 33. 700 K. Saito, ‘Structural Analysis of Various Inorganic Oxides Materials Using Recent Solid State NMR Techniques’, Seramikkusu, 2006, 41, 952. 701 T. Sakamoto, ‘NMR Study of RNA Structure’, Bunko Kenkyu, 2006, 55, 173. 702 H. Sato and Y. Kajihara, ‘An Unambiguous Assignment Method and Structural Analysis of Oligosaccharides by 2D Selective-TOCSY-HSQC, Selective-TOCSY-DQFCOSY and Selective-TOCSY-NOESY NMR Spectroscopy’, Bunko Kenkyu, 2006, 55, 397. 703 Y. Sawai, ‘NMR Analytical Approach to Clarify the Molecular Mechanisms of the Antioxidative and Radical-Scavenging Activities of Antioxidants in Tea: Reaction of Polyphenols with Stable Free Radicals’, Yasai Chagyo Kenkyusho Kenkyu Hokoku, 2007, 6, 23. 704 N. Shibata and Y. Okawa, ‘Structure of Fungal Cell Wall Polysaccharides’, Nippon Ishinkin Gakkai Zasshi, 2006, 47, 179. 705 I. Shimada, ‘NMR Study on Larger Protein Complexes’, Seitai no Kagaku, 2005, 56, 614. 706 H. Takahashi, ‘Magnetic Resonance Spectroscopy. III Nuclear Spin Relaxation’, Bunko Kenkyu, 2006, 55, 205. 707 Y. Takano and H. Kawarada, ‘Superconducting Properties of B-Doped Diamond’, Kotai Butsuri, 2006, 41, 457. 708 T. Terauchi and M. Kainosho, ‘Development and Commercialization of a Next-Generation NMR Method for Structural Analyses of Proteins’, Kagaku Kogyo, 2006, 57, 59. 709 T. Tsunoda, H. Chiku, K. Sakaguchi and F. Mizukami, ‘A Protein Refolding Technique Using Zeolites’, Zeoraito, 2006, 23, 64. 710 T. Wakabayashi and K. Murakami, ‘Structural Basis for the Molecular Switching in Regulatory Mechanism of Muscle Contraction Revealed by Electron Cryo-Microscopy and NMR Spectroscopy’, Seitai no Kagaku, 2005, 56, 593. 711 H. Watanabe, M. Ito, N. Atsuta, S. Naganawa, H. Fukutsu and G. Sobue, ‘Magnetic Resonance Imaging in Multiple System Atrophy’, Shinkei Kenkyu no Shinpo, 2006, 50, 397. 712 K. Yamada, ‘Solid-State NMR in Half-Integer Quadrupolar Spins. Oxygen-17 SolidState NMR in Organic Compounds’, Bunko Kenkyu, 2006, 55, 99. 713 K. Yamamoto, ‘High Pressure and Starch’, Koatsuryoku no Kagaku to Gijutsu, 2006, 16, 31. 714 K. Yamauchi, ‘Magnetic Resonance Spectroscopy. V. Practical Solid State NMR’, Bunko Kenkyu, 2006, 55, 350. 715 M. Yanagisawa, ‘Introduction to Surface Analysis on Tribology. (17). Electron Spin Resonance (ESR) and Nuclear Magnetic Resonance (NMR)’, Toraiborojisuto, 2006, 51, 806. 716 J. Gajdus, R. Glosnicka and J. Szaranek, ‘Primary Structure of Salmonella Genus OAntigens’, Wiadomosci Chemiczne, 2006, 60, 621. 717 R. S. Barbieri, C. R. Bellato and A. C. Massabni, ‘Synthesis and Reactivity of Triphenylstilbene-Platinum Complexes: A Bibliographic Revision’, Quim. Nova, 2006, 29, 761. 718 M. L. Barreiros, J. M. David and J. P. David, ‘Utilization of 1H NMR in the Determination of Absolute Configuration of Alcohols’, Quim. Nova, 2005, 28, 1061. 719 F. C. de Macedo, Jr, ‘13C Nuclear Magnetic Resonance Spectroscopy in Studies of Biosynthetic Routes of Natural Products’, Quim. Nova, 2007, 30, 116. 720 V. P. R. Silva, V. Caliman and G. G. Silva, ‘Polymers with Ionic Conductivity: Fundamental Challenges and Technological Potential’, Polimeros: Ciencia e Tecnologia, 2005, 15, 249. 721 S. M. W. Zanin and A. L. L. Lordello, ‘Aporphinoid Alkaloids in Ocotea Species (Lauraceae)’, Quim. Nova, 2007, 30, 92. 722 D. A. Akbaeva, ‘Organometallic and Inorganic Complexes of Transition Metals Containing a P4 Molecule as an Z2-Ligand’, Izvestiya Natsional’noi Akademii Nauk Respubliki Kazakhstan, Seriya Khimicheskaya, 2006, 1, 18. 723 E. Yu. Yushkova, A. M. Ostapkovich and A. G. Lundin, ‘NMR Criterion of Completeness of Curing Processes of Polymer Chains’, Izviestiya Vysshikh Uchebnyhk Zavedenii, Khimiya i Khimicheskaya Tekhnologiya, 2005, 48, 61. 724 E. A. Castro, ‘Theoretical Study of the Molecular and Global Properties of Liquids. Applications’, Rev. Boliv. Quim., 2005, 22, 34. 725 J. Correale, F. Meli and C. Ysrraelit, ‘Neuronal Injury in Multiple Sclerosis’, Medicina (Buenos Aires, Argentina), 2006, 66, 472.


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Theoretical and physical aspects of nuclear shielding Cynthia J. Jamesona and Angel C. de Diosb DOI: 10.1039/b617218k

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Theoretical aspects of nuclear shielding

1.1 General theory The symmetry at the nuclear site determines the number of distinct components of the shielding tensor.1 The symmetry of the nuclear site is related to the symmetry of the whole molecule if the nucleus is located at one of the molecular symmetry axis, center, or plane. Therefore, in many situations, the molecular symmetry has an important bearing on the anisotropy of the shielding tensor. Useful correlations between specific geometrical features of molecules and the shielding tensor are well known. Avnir suggests that a quantitative relation with molecular symmetry can be demonstrated by studying how continuous deviation from exact symmetry around a nucleus affects its shielding.2 He employs the continuous symmetry measures methodology,3 which allows one to quantify the degree of content of a given symmetry, a methodology he has applied to many properties such as hyperpolarizability. The model case he uses for this purpose is a population of distorted SiH4 structures, for which he follows the 29Si shielding anisotropy as a function of the degree of tetrahedral symmetry and of square-planar symmetry. Quantitative correlations between the degree of these symmetries and the NMR shielding parameters emerge. This approach may be very useful for cases where large excursions away from the minimum energy geometry can take place, as when part of the shielding surface is explored in conjunction with broad and shallow potential wells. Due to large contributions from electrons moving at relativistic velocities near the nuclei, the effects of relativity have to be taken into account in theoretical calculations of NMR observables, in particular the nuclear magnetic shielding tensor. The relativistic corrections can be significant even for shielding of light nuclei in molecules containing heavy atoms. The relativistic heavy atom effects on the shielding tensor of the heavy atom itself (HAHA effects) are particularly large. Fully relativistic four-component Dirac-Hartree-Fock methods can be applied to the calculations of nuclear shielding;4 however, four-component methods have not yet been extended to the correlated level for this purpose. Thus, for highly accurate studies of systems containing moderately heavy atoms, four-component theory is not yet competitive to methods based on a non-relativistic reference wave function. Transformed two-component Hamiltonians in which the positronic degrees of freedom have been eliminated from the Dirac equation but spin orbit coupling is still included variationally offer the next lower level of theory. At this level, selfconsistent variationally stable two-component approaches such as the DouglasKroll-Hess to second order (DKH2),5–11 and the zeroth order regular approximation (ZORA)12–16 have been used. The ZORA has been implemented for both HartreeFock and density functional approximations, whereas DKH2 has been implemented only for Hartree-Fock wave functions, until recently.10 It has been shown that for molecules containing elements from the first five rows of the periodic table, a

Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago Illinois 60607-7061, USA b Department of Chemistry, Georgetown University, 37th and O Streets, N. W., Washington DC 20057-2222, USA


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relativistic corrections to the shielding tensor can be successfully described using perturbation theory. In this approach, the relativistic corrections to the diamagnetic and paramagnetic contributions of the non-relativistic theory can partly be obtained by perturbing the non-relativistic reference wave function by the various leadingorder relativistic operators. These relativistic corrections to the shielding tensor can in turn be calculated as higher-order response functions. In addition, new interaction mechanisms may also appear from higher order interactions in the Breit-Pauli Hamiltonian. The advantages of this approach are that both the electron correlation and the gauge-origin problems can be handled via existing techniques that have been developed for non-relativistic calculations. That is, existing methods for calculating response properties with correlated wavefunctions can be used and GIAOs can be used. The formulations and applications of this perturbation approach17–21 have been reviewed in previous volumes of this series. More recently, linear response elimination of small component method has been established which has been shown to give the same final theoretical expressions.22–24 In the present review period, particular attention has been paid to the heavy atom effects on the shielding of the heavy atom itself, using the Breit-Pauli perturbation treatment of relativistic effects described above. Lantto et al. considered small molecular systems of the type XH2, XH3 and XF3, in addition to some charged systems such as XH3 and monatomic ions, all closed-shell systems, for X = group14 and group-15 from Si to Pb, P to Bi,25 while Jaszunski and Ruud considered XH4 molecules, where XQC to Pb.26 The dependence of the HAHA effects on the chemical environment of the heavy atom, the relative magnitudes of the various relativistic correction terms and electron correlations on shielding, and on chemical shifts, are compared. Most of the discussion is based on augmented basis sets. Both Hartree-Fock self consistent field (SCF) and complete active space (CAS) multiconfigurational self consistent field (MCSCF) levels of theory were used, except for the fluorides and the closed shell monatomic ions for which only SCF levels were used. Fully relativistic four-component Dirac-Hartree-Fock shielding tensor calculations were also carried out for comparison. Gauge-including atomic orbitals (GIAO) were used, except that Lantto et al. used common gauge origin (CGO) and coordinate origin at the heavy nucleus for the relativistic corrections.25 No difference had been found between using GIAOs or CGOs for the non-relativistic shieldings at these sizes of basis sets. The important conclusions from these two works 25,26 are as follows: (a) The relativistic corrections to the heavy atom nuclear shieldings are large and scale as very nearly Z3 (3.04, as reported by ref. 26). This has been reported previously in other works. Thus, for the heaviest nuclei the relativistic effects have to be taken into account to obtain a reliable value of the absolute total shielding. (b) In comparison to the four-component calculations, the complete BreitPauli perturbational approach underestimates the relativistic correction for the heaviest nuclei (6th row). (c) All the relativistic correction terms provide significant contributions to the absolute shielding of the heavy atom. (d) The dominant contribution to the HAHA effect on shielding is the FC/SZ-KE contribution, the second order cross term between the Fermi contact (FC) hyperfine Hamiltonian and the relativistically modified electronic spin-Zeeman (SZ-KE) Hamiltonian. This contribution is almost completely produced in the s orbitals of the heavy atom, the values diminishing with the principal quantum number. (e) Whereas the nonrelativistic shielding terms are sensitive to both electron correlation and the chemical surroundings of the heavy atom, the dependence of the FC/SZ-KE relativistic terms on these factors is much smaller. This reflects the predominantly core nature of these relativistic terms and implies small contributions of the FC/SZ-KE relativistic corrections of the HAHA type to chemical shifts between different molecules. (f) For the same reasons, the FC/SZ-KE relativistic corrections of the HAHA type to the anisotropy of the chemical shift tensor are small. (g) However, the spin–orbit effects have several terms and of these, the SO-I terms are sensitive to both electron correlation and chemical surroundings, thus require correlated wavefunctions and 52 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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have significant contributions to HA chemical shifts between different molecules. (h) The SO contributions become more and more important for the anisotropy of the chemical shift tensor of the heavier nuclei. For heavier X, there is an increasing positive relativistic contribution to the shielding anisotropy, e.g., (s||–s>) in axial HA environments. The great majority of shielding calculations reported in the literature these days use gauge-including atomic orbitals (GIAO).27 Alternative approaches for gauge invariant calculations have also been investigated. Of these, the continuous transformation of origin of the current density (CTOCD) approach, based on the continuous set of gauge transformations suggested by Keith and Bader,28,29 has been extensively explored by Lazzeretti and co-workers. In particular, they have done calculations in the scheme where the diamagnetic contribution of the current density is set to zero (CTOCD-DZ). 30–32 In this approach, the point where the current density is calculated is also the origin of the reference system. For this reason, this approach is also called the ipsocentric method of plotting current density maps.33,34 The method is intrinsically independent of the origin of the coordinate system used in the calculations, irrespective of other approximations retained, that is, at any basis set level. In a recent investigation, Lazzeretti and co-workers extend the CTOCD-DZ calculations to density functional theory (DFT) using a variety of functionals, and coupled-cluster-singles-and-doubles linear response theory.35 When the aug-cc-pCVTZ-CTOCD-uc basis sets are used, the fulfillment of the hypervirial relations is almost as good at the correlated level as at the SCF level. That is, the agreement between CTOCD-DZ DFT and common origin or GIAO DFT results is good. They found that the KT3 functional of Keal and Tozer 36 performs on average much better than the popular B3LYP functional. In particular, for the difficult shieldings of multiply-bonded molecules where electron correlation effects are very large, KT3 gives results in close agreement with CCSD calculations. Since precise experimental values of NMR chemical shifts are available for a wide variety of chemical environments, they have become a popular test for density functional theory research. Cohen et al. examined two new methods proposed by Yang and Wu which are based on the Kohn-Sham potential by calculating shieldings in small highly correlated molecules containing main group atoms.37 The first is a method which reproduces an accurate input density (WY) and the second is an implementation of the optimized effective potential (OEP) method.38 They found that these methods give results which are very similar to each other, and when the methods are applied to a hybrid functional (e.g. B3LYP) they obtain good agreement with experiment. Recently, Tozer et al. compared various functionals using the Yang-Wu implementation of the optimized effective potential approach in density functional theory38 in calculations of fourth row transition metal chemical shifts.39 They examined nine transition metal complexes using several GGA functionals and found that expanding the potential in the primary orbital basis leads to reasonably good accuracy, providing a physically appropriate reference potential is used. Further improvement requires the use of a much more extensive potential expansion which is appropriately balanced between the atom types. They also considered hybrid functionals. When the orbital basis is used for the potential expansion, the OEP B3LYP calculations produce significant improvements over conventional B3LYP; mean absolute and rms errors are reduced by a factor of 2. Similar improvements are obtained using the PBE0 functional. In line with the findings of Cohen et al. for chemical shifts in molecules containing main group atoms,37 Tozer et al. find that the use of the uncoupled OEP procedure for calculating transition metal chemical shifts using hybrid functionals do give improvement over conventional calculations using hybrid functionals, but are computationally more complicated. Ramsey considered the possibility of field-dependent nuclear magnetic shielding,40 that is, deviations from linear dependence of the resonance frequencies on the external magnetic field when the field strengths are significantly higher than those in Nucl. Magn. Reson., 2008, 37, 51–67 | 53 This journal is

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conventional high-field spectrometers. There have been attempts to calculate the magnitudes of the field dependent terms in the nuclear magnetic shielding for the 59 Co nucleus, for which Bendall and Doddrell had reported some measurements.41 Manninen and Vaara presented an analytical response theory formulation for the dependence of the nuclear magnetic resonance shielding tensor of molecules on the external magnetic field.42 First-principles calculations for 59Co in Co(acetylacetonate)3 and Co(NH3)63+ were carried out using the Hartree-Fock self-consistent field method as well as density-functional theory. They reported magnetic-field dependence of the 59Co shielding constant of 6 103 ppm/T2 in Co(acetylacetonate)3, which is at the limit of being experimentally observable. Lazzeretti and co-workers developed a general computational scheme for a fourth-rank magnetic hypershielding tensor at a nucleus in a molecule in the presence of an external spatially uniform time-independent magnetic field.43 They calculated the values at the SCF level using a common origin for H2, HF, H2O, NH3, and CH4. For these molecules, all the values are very small, about 20–30 times as small as was calculated for 59Co: 0.3 103 ppm/T2 for C in CH4, and 0.2 103 ppm/T2 for for O in H2O. Parity non-conservation (PNC) contributions to the nuclear magnetic shielding of chiral molecules are small and the treatment of electron correlation as well as basis set size strongly influence the results for H2X2 (X = 17O, 33S, 77Se).44 A systematic four-component relativistic study of the constants of chiral molecules has been presented for the P enantiomers of the series H2X2 (X = 17O, 33S, 77Se, 125Te, 209 Po).45 The PNC contributions are obtained within a linear response approach at the Hartree-Fock level. The magnitude of the parity nonconservation (PNC) contribution to the (isotropic) NMR shielding is found to scale with the charge of the nucleus as Z2.4 in non-relativistic theory, in agreement with previous results. The calculations show that the overall scaling is significantly modified by relativistic effects. The scalar relativistic effect scales as Z4.7 for the selected set of molecules, whereas the spin–orbit effect, of opposite sign, scales better than Z6 and completely dominates the PNC contribution for the heaviest elements.45 This opens up the intriguing possibility of the experimental observation of PNC effects on NMR parameters of molecules containing heavy atoms. 1.2 Ab initio and DFT calculations Calculations of shielding tensors for heavy nuclei in metal complexes in solution are fraught with difficulties. First among these is the problem of taking into account the true solution environment with specific as well as non-specific solvent effects which not only provide absolute and differential contributions to the shielding (which do not subtract out in taking chemical shifts) but also determine the geometry of the (usually charged) complex in solution. The latter is very important since shielding is extremely sensitive to bond distances to the nucleus in question. Continuum methods of including solvent effects, such as COSMO (conductor-like screening model), are not adequate. Second, there is the problem of choosing a reasonable reference substance. There is usually no gas phase sample against which all other complexes could be referenced. Typically one highly symmetric charged complex among the series is picked. Because of the first problem, the choice of reference compound could skew the comparisons with experiment. On the positive side, as basis sets are being developed and extended, the choice of atomic base sets poses more of a computational time vs. size compromise than a real problem. Electron correlation has been found to be important. But these complexes are usually not small enough to permit the use of the CCSD(T) method, so DFT is often used. The question still remains as to whether using hybrid functionals are intrinsically better for transition metal shielding or not. For the lighter transition metal nuclei, there is the question of whether relativistic effects contribute sufficiently to be necessarily included when the other above-mentioned problems still persist. Unfortunately, when various functionals are tested against each other while the first and second 54 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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problems have not been taken care of, comparisons against experimental chemical shifts do not provide a test of functionals at all. Geometry, solvation, and reference problems inevitably confuse the interpretation of the results. The situation is very different from the light main group atoms, where there are comparisons against experimental gas phase data, where the geometries are well determined, and there are the CCSD(T) calculations for a set of benchmark molecules against which other computational methods can be assessed. For 183W a possible gas phase reference is WF6, but so far no one has tried to determine the W chemical shifts against this reference. Relativistic DFT calculations of 183W shielding in polyoxotungstates of different shapes and charges have been reported by Bagno et al.46 The authors adopted the BP86 functional (Becke 88 exchange plus the Perdew 86 correlation),47,48and chose to report chemical shifts with reference to [W6O19]2 which is 58.6 ppm relative to the usual experimental reference, [WO4]2. They used a continuum model (COSMO) to approximate the solvent effects in geometry optimization and NMR calculations, and they included relativistic effects by using zeroorder regular approximation (ZORA) including spin–orbit terms. The linear correlation of the calculated chemical shifts against the experimental chemical shifts was used as an indication of the quality of the results. They found that this depended systematically on the charge density as expressed by the charge to surface area of the complex. Complexes with low ratios of charge to surface area display the best agreement with experiments. At the highest level approach adopted as described above (although they also tested many other levels), the correlation line relative to their chosen reference, [W6O19]2, has slope 0.905 and an intercept which is 7 ppm over a 500 ppm range of chemical shifts, and the mean average error is 35 ppm. In the case of a-[PW11TiO40]5, the six signals are ranked computationally so as to almost reproduce the experimental ordering even though the signals are spaced by as little as 5 ppm. Of course, Bagno et al. have only explored a small section of the 8000 ppm range of 183W chemical shifts. The remaining unsolved problems include the effect of counter ions which were completely neglected here and the true solvent effects, in addition to the truly dynamic structure in solution which is not reflected by having done the calculations in a single geometry fixed at that found by geometry optimization in a continuum description of the medium. The above difficulties apply to complexes of other light transition metal elements. A study of the 89Y chemical shifts calculated using DFT with various functionals has been carried out with a similar goal.49 The authors used three GGA and 6 hybrid functionals. They first considered the [Y(OH2)8]3+ ion which serves as standard reference for 89Y chemical shifts. Geometry optimization in the gas phase was carried out for 18 compounds. Plots of calculated shielding against the experimental chemical shifts lead to the selection of O3LYP (slope of 0.809 across nearly 1300 ppm range) as providing slightly better results than the other functionals. In another example, Bu¨hl carried out a study of the 53Cr shielding in 16 complexes at geometries optimized in the gas phase using the BP86 functional.50 The linear correlation plot of calculated versus experimental chemical shifts across a range of 2100 ppm has a slope (1.2) which differs significantly from 1 when B3LYP functional was used; BPW91 leads to a slope of 1.04. As already discussed above, one of the problems with this approach is that, because the geometry optimization was not carried out in an environment approximately close to the experiments, this result does not necessarily mean that one functional provides a better description of 53Cr shielding than the other. Although several attempts have been made in the calculations of 99Ru chemical shifts to find out whether hybrid functionals work better than generalized gradient functionals, or whether relativistic effects need to be included, the results have not been definitive. As mentioned above, when the important interrelated solvent, geometry, and dynamics have not been properly taken into account, the results can not reliably serve as tests of one type of functional over another. Autsbach and Zheng shed some light on this problem by doing a systematic set of calculations in Nucl. Magn. Reson., 2008, 37, 51–67 | 55 This journal is

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which explicit solvent molecules have been included with the continuum model for a more complete picture.51 Their calculations used ZORA and the BP86 or B3LYP functionals, with TZP quality basis sets for geometry optimization. Compared with experiments are the chemical shifts calculated for 10 complexes relative to [Ru(CN)6]4 as the reference complex, at non-relativistic DFT/BP86 or ZORA with spin–orbit contributions. The combined scalar and spin-orbit relativistic corrections to shielding are roughly between 300 and 600 ppm for most of the complexes. The overall changes in the chemical shifts are not significant when viewed in the 17 000 ppm chemical shift range. The inclusion of relativistic effects does not improve the correlation with experiment. Non-hybrid BP86 functional tends to somewhat underestimate the ligand effects on the 99Ru chemical shifts. For fac-[Ru(CO)3I3], they calculated the 99Ru in the complex in several different solvents. They did geometry optimization of a supermolecule (complex with several solvent molecules) embedded in a polarizable continuum. The calculated shieldings at optimized geometry for several of such environments do reasonably well cover the range of solvent-induced shifts; the latter are found to be better reproduced by the hybrid functional whereas the non-hybrid functional underestimates the solvent effects. 31 P shielding calculations in phosphanes and phosphonium salts used X-ray crystallographic data for ethyltriphenylphosphonium triiodide and the furyl substituted derivatives.52 The values calculated using DFT/B3LYP with TZ2P basis sets shows good agreement with experimental tensor components. The component almost parallel to the P–C(ethyl) bond is found to be most sensitive to the substituents. 25Mg shielding tensors have been calculated at HF, MP2 and DFT/ B3LYP levels for Mg2+ ions in square pyramidal sites in monopyridinated aqua (magnesium) phthalocyanin and in chlorophyll a.53 For the first time, Mg(II) ions in a square-pyramidal geometry have been characterized by solid state NMR. However, the chemical shift tensor is too small to extract from the spectrum which is dominated by the quadrupole coupling. Nevertheless, these are particularly interesting environments for Mg nucleus and the tensor orientations are similar to those for the electric field gradient in the molecular frame. The most shielded component is along the Mg–O bond direction while the other two components lie approximately in the porphyrin or chlorin plane. The 13C shielding tensors in diene complexes of Mo, Ru, Pt and Pd have been measured and calculated.54 The shifts are as large as 70 ppm relative to the free ligand and serve as signatures of the nature of the bonding in these compounds. Pseudopotentials were used for the metal atoms in a DFT/B3LYP calculation. Geometries were taken from X-ray data and then the proton positions were optimized. Fully optimized geometries were also used. Correlations of the shielding components with the components of the experimental chemical shift tensors show excellent agreement with a slope of 0.923 and correlation coefficient 0.9966 when only the H positions were optimized, and equally excellent agreement (slope of 0.994 and correlation coefficient 0.9940) was found by using fully optimized geometry. The calculations of nuclear shielding for species which have low-lying triplet states present a challenge for single reference methods. In this reporting period, the case of o-benzyne is presented as a paradigm for the methodology for an accurate description for such systems using density functional theory.55 Because of near equilibrium triplet instabilities that are associated with its biradical character, the calculated shieldings (and coupling constants) of o-benzyne are extremely sensitive to details of the exchange-correlation functional. The authors show that this sensitivity is greatly reduced if these properties are calculated at the equilibrium of the chosen functional. They calculated the shieldings at both the experimental geometry and the geometry obtained by energy minimization using the same functional. This minimization shortened the triple bond in all cases. In every case, the geometry changes upon DFT energy minimization significantly improve the calculated NMR properties. Among the functionals used, the Keal Tozer KT1 and KT2 functionals gave results which 56 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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are closest to experiment. The nuclear shieldings calculated with CCSD theory at the experimental geometry are also in good agreement with experiment. Prediction of the entire 1H and 13C NMR spectrum of a molecule in isotropic media is becoming a reality, as DFT calculations of shieldings and spin–spin couplings involving 1H and 13C in molecules, of the size of typical natural products, have made such calculations practically accessible. Bagno et al. consider several examples to illustrate this.56,57 The complete spectra of the following natural products were calculated and compared with the experimental spectra: strychnine, corianlactone, daphnipaxim, boletunone B.56 In most cases, the correct ordering of 1 H and especially of 13C signals is found. When experimental spectra are recorded in polar solvents, the modeling of the solvent by means of a reaction field generally leads to substantial improvement. They conclude that such calculations can have considerable utility in the assignment of congested spectra. In addition to the above reports, a large number of DFT/B3LYP-GIAO calculations using moderate basis sets have been performed in the following applications: in hydrogen-bonded systems,58,59 in studies of protonation reactions,60,61 in unequivocal determination of structure of new heterocyclic compounds (identification of which isomer),62–64 to assign E and Z isomers in condensation products of saccharides with heterocyclic oximes,65 to study restricted inversion of sp3 nitrogen,66 in assignment of conformations in piperidine betaine derivatives,67 and in a-acyloxyesters,68 and in assignment of structure to a specific isomer of the protonated iron bis(dicarbollide) ion.69 The same level of 13C and 19F shielding calculations have been used for structural analysis of oligo(perfluoroaryl) compounds,70 and to assist mechanistic studies (using 13C and 19F),71 (using 1H, 2 H, 11B),72 by assigning NMR spectra on the basis of the calculated chemical shifts. The cyclobutylmethyl cations, possible reaction intermediates, are small enough to be studied at a high level of theory.73 This study considered various possible structures and calculated 13C shieldings for each. None of these non-classical structures are observed experimentally, only the classical cyclopentyl cation into which they rearrange is observed. In this latter case, the assignment would have been unequivocal even at the SCF level, the symmetry alone (C2) eliminates the other nonclassical possibilities and the agreement with experimental chemical shifts is good enough at any level of calculation for identification purposes. 1.3 Semi-empirical calculations There are no publications to report.

2

Physical aspects of nuclear shielding

2.1 Anisotropy of the shielding tensor With the possibility of extracting detailed structural information from the shielding tensor and its relationship to the dipolar tensor, optimization of solid state NMR measurements designed to extract this type of information is now crucial. Various optimization schemes for the chemical shift recoupling experiment developed by Tycko et al.74 have been recently examined by Orr and Duer.75 This recent evaluation shows that for improved resolution, a constant-time implementation involving six p pulses over three rotor periods provides the desired result. On the other hand, the larger number of p pulses causes a decrease in the signal-to-noise ratio of the spectra. An alternative optimization scheme then involves adjusting the number of p pulses for each slice of the t1 dimension of the experiment, so that only a minimum number of pulses is employed, thus, providing the highest signal-to-noise ratio. NMR shielding tensors can now be used as a filter for selecting computergenerated crystal structure candidates. Harper and Grant76 have shown that with the methyl pyranosides of the following sugars; galactose, glucose, mannose and Nucl. Magn. Reson., 2008, 37, 51–67 | 57 This journal is

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xylose, it is feasible to employ calculated shielding tensors and their comparison with experiment to eliminate as much as 80% of the structures that are still suggested and accepted by the less restrictive lattice energy criterion. With this new selection criterion, the known correct structures are found in the top five (out of 164 computer-generated structures) best-fit comparisons with NMR data, illustrating that NMR shielding tensor data and calculations can indeed serve as additional selection conditions for crystal structure prediction. The shielding tensor, the magnitudes of its principal components and their orientation, once again proves to be more sensitive than the isotropic value to intraand intermolecular effects as illustrated in the successive deprotonation of Lphosphoserine.77 In this compound, the carboxyl 13C chemical shift tensor shows measurable effects of hydrogen bonding while the 31P shielding tensor displays sensitivity not only to the protonation of the carboxyl group, but also to the ionization state of the phosphate group, and the identity of the counterions in the solid state. Other examples of how chemical shifts and shift tensors could be used to probe the ionization state of various functional groups have been recently reviewed by Gardiennet-Doucet, et al.78 The most shielded component of 31P chemical shift tensor in phosphanes and phosphonium salts has been shown to be sensitive to 2-furyl and 3-furyl substituents.52 The electron-withdrawing furyl groups reduce the length of the P–C(furyl) bond (compared to P–C(phenyl)), which is responsible for the increased magnitude of s33, which in this case, lies perpendicular to the P–C bond. Titanium(IV) phosphinidene complexes possess the shortest TiQP bonds reported, have linear phosphinidene groups and reveal significantly upfield 31P resonances for the phosphinidene sites. Solid state 31P spectra of three such complexes reveal components d|| = 400, 420, and 480 ppm (relative to standard H3PO4 reference) along the TiQP.79 The perpendicular components are more variable, respectively, d> = 430 and 630 ppm, 550 and 476 ppm, and 446, 446 ppm. The effects of para substituents on the 15N chemical shift tensor of N,N-dimethylaniline have been examined by Penner and McCullough.80 As expected, two components, s11 and s33, vary with the electron withdrawing capability of the substituent. The magnitude of these two components increases with the p-electron donating capability of the para substituent. Using single-crystal NMR spectroscopy, detailed investigations of the 17O shielding tensor for the carbonyl group of the central glycine residue of two tripeptides, GGV and AGG, have been accomplished.81 The orientations of the tensors are similar in both cases, with s33 lying normal to the peptide plane and s11 making an angle of 171 with the CQO bond. The difference lies in the magnitude, specifically the tensor span; O = 549 ppm in GGV and 606 ppm in AGG. Calculations indicate that the differences in the magnitudes of the principal components are due to differences in hydrogen bonding. In a related work, measurements at four different magnetic fields, 9.4, 14.1, 16.4 and 18.8 T have allowed the extraction of 17O shielding tensor information in polycrystalline g-glycine.82 In this single amino acid sample, the observed tensor span for the carboxylate oxygen sites is only 400 ppm. The spans of the 25Mg shielding tensor in aqua(magnesium) phthalocyanine and chlorophyll a have been predicted through calculations to be less than 52 ppm.83 This small value of the span can then be neglected in the lineshape analysis of solidstate 25Mg spectra aimed at extracting quadrupolar coupling constants. There have been ample studies of shielding tensors of other heavy nuclei during this reporting period. Rossini and Schurko84 have measured the 45Sc shielding tensors for a variety of compounds: Sc(acac)3, Sc(TMHD)3, Sc(NO3)3 5H2O, Sc(OAc)3, ScCl3 6H2O, ScCl3 3THF, and ScCp3. These solid state measurements have been combined with X-ray crystallography and ab initio calculations. In these compounds, the 45Sc shielding tensor is observed to be affected by the geometry of the coordination environment as well as the nature of the ligands. The authors have also noted that for 45Sc shielding calculations, RHF methods perform better than 58 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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B3LYP. High field measurements have enabled the measurement of 55Mn shielding tensors in Z5-CpMn(CO)3, Mn2(CO)10, and (CO)5MnMPh3 (where M = Ge, Sn, Pb).85 The Cp complex is worth noting as it exhibits a tensor span of 920 ppm for the 55 Mn shielding, while the other compounds have a span of less than 220 ppm. In manganese compounds that exhibit C4v symmetry (as in LMn(CO)5 where L = Cl, Br, I, HgMn(CO)5, CH3), the tensor span could be as large as 1260 ppm.86 This large span is seen with the pentacarbonyl halides while a smaller span, about 180 ppm, is observed for the methyl compound, H3CMn(CO)5. These trends are partially explained by examining the d character of the highest occupied molecular orbital in these systems. Gajda et al.87 have found that the dynamics of L-selenomethionine in the solid state reduces the observed shielding tensor span for 77Se. Calculations for the two distinct sites predict a span of 851 and 730 ppm for the two molecules in the asymmetric unit of crystalline L-selenomethionine, while the observed spans at 297 K are only 548 and 580 ppm, respectively. These experimentally observed tensor spans slightly increase to 615 and 585, respectively, when the measurement is performed at a lower temperature, 183 K. Theoretical and experimental 77Se shielding tensors have been recently reported by Demko et al.88 In this work, it has been demonstrated that as long as the selenium compounds do not contain additional heavy elements, nonrelativistic calculations are able to predict the experimental trends for various organoselenium as well as inorganic selenium compounds. Using the two isotopes of Xe, 129Xe and 131Xe, Forgeron et al.89 have been able to determine both shielding and quadrupolar data for the perxenate anion, XeO64. The 129Xe shielding tensor in this compound is found to be axially symmetric with a span of about 95 ppm. 2.2 Shielding surfaces and rovibrational averaging The dependence of the 13C shielding tensor of Ca on backbone torsion angles in peptides is further explored by Czinki et al.90 To facilitate the utilization of tensor data in the determination of torsion angles f and c, Czinki et al.90 have introduced two new tensor parameters. The first, given the symbol r, describes the magnitude of the anisotropy: r = 21/2 [(s11 s22)2 + (s11 s33)2 + (s22 s33)2]1/2. And the second parameter, t, quantifies the shape of the shielding tensor: t = (1/3) arcsin[(2s11 s22 s33) (2s22 s11 s33) (2s33 s11 s22)/(2r3)]. Using (siso, r, t) as a function of the torsion angles f and c has been illustrated to have the ability to distinguish between the four regions of the Ramachandran surface: b-strand, a-helix, left-handed a-helix, and polyproline II. The shielding surface in this study was performed on the entire Ramachandran surface with 101 grids, using an N-formyl-L-alanine amide as the model peptide, at the B3LYP/TZ2P level. 2.3 Isotope shifts The relationship between deuterium-induced isotope shifts and intramolecular hydrogen bonding continues to be explored in compounds containing nitro- and acetyl groups.91 Correlations between the observed isotope-induced shifts in 13C with the hydrogen bond distance O O are reported. The 2-bond deuteriuminduced isotope shift on 13C, 2DC(OD), is found to increase with decreasing O O distance. And the same is true for the 13C chemical shift of a methyl group, 5 bonds away from the isotopic substitution, 5DC(OD). For the carbonyl carbon which lies 4 bonds away from the substitution site, the correlation is less clear, depending on whether a nitro- group is present or not, and on whether there are additional hydroxy groups. Deuterium-induced isotope shifts on 13C have likewise been utilized to demonstrate that in tetrabutylammonium salts of Schiff bases derived from amino acids, the major tautomer is the NH-form.92 Halogen isotope shift effects are usually smaller than those of deuterium due to the smaller percent change in mass. Recently, in a series of fluorinated cyclopropanes and cyclopropyl ethers, 35Cl/37Cl and 79Br/81Br induced isotope shifts on 19F have Nucl. Magn. Reson., 2008, 37, 51–67 | 59 This journal is

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been observed.93 The two-bond shifts on 19F upon 35Cl/37Cl substitution are in the range of 6 to 10 ppb (with the heavier isotopomer being more shielded). These shifts tend to be attenuated by the number of fluorine atoms on the cyclopropyl ring, with the monofluoro compound showing the largest isotope shift. The three-bond shifts are smaller, around 2 ppb, but shows a geometrical dependence, with the cisconformation between Cl and F showing a slightly higher isotope shift. The 79 Br/81Br induced isotope shifts have been observed over two bonds and these are in the 1.5–2.2 ppb range. 2.4 Intermolecular effects on nuclear shielding During this reporting period, Stueber has written an educational review94 on the Embedded Ion Method, an approach that incorporates crystal lattice effects into chemical shift calculations. For liquids and solutions, several assessment studies have been performed on hybrid quantum mechanics/molecular mechanics (QM/ MM) models to consider medium effects on shielding. Input geometries derived from molecular dynamics simulations can be used for quantum mechanical calculations. And in the case of the nevirapine molecule, some improvement can be achieved in predicting the proton chemical shifts.95 An isolated molecule calculation on nevirapine proton chemical shifts yields an R2 correlation of 0.924 with experiment. Upon incorporation of solvent molecules with geometries obtained from simulations, this correlation is improved to 0.997. It should be noted, however, that the slightly poorer correlation seen in the single molecule calculation in nevirapine is due primarily to a single proton site, an N–H proton. Another example of a proton site, at which the calculated chemical shift becomes closer to experiment via QM/ MM is the H-2 proton in 1-butyl-3-methylimidazolium cation.96 In the case of adenine, all of the proton and nitrogen chemical shifts in aqueous solutions require a good description of the intermolecular effects and using hybrid QM/MM models does significantly improve agreement between theory and experiment.97 Kongsted et al.98 have examined the following important ingredients for these hybrid QM/MM models: (1) electron-correlation effects, (2) gauge-origin independence, and (3) a self-consistent reaction field representing the environment. In this recent work,98 shielding calculations are performed at the B3LYP/6311++G(2d,2p) level of theory on liquid water. To approach the experimental values, it is apparent that up to ten water molecules need to be explicitly included in the quantum mechanical calculations. The results are: for 1H, Dsliqvac = 2.53 ppm, for 17O, Dsliqvac = 34.9 ppm, to be compared with the experimental values, 1 H, Dsliqvac = 4.26 and 17O, 36.1 ppm. These calculated values are obtained using a TIP3P potential for water in the molecular dynamics simulations, averaging over 300 configurations. Larger numbers of configurations are cheaper when a smaller number of water molecules are explicitly included. In the case of five water molecules, the convergence in the number of configurations can be investigated, and, in this system, 1500 seem to be required to achieve convergence. Slightly better results for 1H (3.3 ppm) are obtained when an empirical potential that explicitly assigns a dipole polarizability to the water oxygen site, the SPCpol potential, is employed. It is interesting to note that the configurations sampled lead to a range of about 8 ppm for 1H and 50 ppm for 17O. Both are larger than the experimentally observed gas-to-liquid shifts in water. Pennanen et al.99 have similarly used sample configurations from a Car-Parrinello molecular dynamics simulation for shielding calculations in water. In this work, the authors looked closely at the distribution of calculated shieldings. The distribution in the gas phase is found to have two peaks, in which both are close to the ends of the distribution. In contrast, in the liquid phase, the peak in the distribution lies close to the average value, taking a shape close to a Gaussian. These distributions have been attributed to vibrational contributions. A similar trend is seen with the 13C and 17O shieldings in acetone dissolved in water.100 The observed gas-to-aqueous solution shifts are 75.5 ppm (17O) and 18.9 ppm (13C) 60 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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while the range of shifts in the configurations sampled in the molecular dynamics simulations are about 200 ppm for 17O and 25 ppm for 13C. In this work,100 convergence is achieved with 1200 configurations. The average values over 1200 configurations using 2 explicit water molecules and the TIP3P potential are 88.2 ppm (17O) and 17.4 ppm (13C), which compare favorably with the above experimental values. Comparisons are also made against supermolecular calculations at optimized geometries, which yield lower gas-to-solution shifts, 63 ppm (17O) and 13.8 ppm (13C). The 1H NMR chemical shift in water can likewise be perturbed by changes in pH. Murakhtina et al.101 have added HCl in their molecular dynamics simulations to test the effect of solvated ions on water 1H NMR chemical shifts. In this work, the chemical shift distribution has been decomposed into contributions coming from Eigen (H3O+) and Zundel (H5O2+) complexes, protons in the first solvation shell of Cl ions, and the remaining protons in regular water molecules. In the Eigen form, a deshielding of about 7.4 ppm is predicted, while for the Zundel, a value of 5.8 ppm is obtained. These changes, taken and averaged with regular water molecules, are demonstrated to reproduce the experimentally observed shifts (0.7 ppm in 2.7 M HCl and 1.4 ppm in 4.9 M HCl). A spectral decomposition of ring currents derived using the ipsocentric method (CTOCDE-DZ) has been achieved for benzene, cyclooctatetraene, borazine, coronene and corrannulene.102 In both aromatic and antiaromatic systems, this work illustrates that the ring currents are dominated by contributions from the HOMO–LUMO virtual excitations. For borazine, which is considered as a nonaromatic system, localization of electrons on the more electronegative N atoms prevents a global type of circulation. Steiner et al.103 have shown that it is feasible to extend the pseudo-p implementation of the ipsocentric method to relatively large polycyclic aromatic hydrocarbons consisting of up to 438 carbon sites. These large systems are shown to have current densities that bear the characteristic features of an intense global perimeter diatropic ring current and localized benzenoid diatropic ring currents, thus, following the same symmetry rules as those found in smaller monocycles. Pelloni et al.104 have provided general features present in diatropic molecules via stagnation graphs which show both vortices and saddle lines of the current density. For a cyclic CnHn molecule (n = 3–8), stagnation lines are seen to form a cage as these lines branch out from the primary vortex. Extending this methodology to explain five-membered heterocyclic molecules, Pelloni and Lazzereti105 have examined several pentatomic cyclic molecules C4H4X, with X = CH2, NH, O, S, PH, and AsH. Their results show a significant difference between the stagnation graphs of aromatic CnHn molecules and those of the heterocyclic molecules. The heterocyclic molecules contain an axial vortex flowing near the heteroatom. This extends to the outer regions, at which the stagnation line is approximately parallel to the applied magnetic field. Fowler et al.106 have explored aromaticity in a cyclic arrangement of p orbitals that are tangentially s-bonded. The rules are found to be similar to cyclic p systems: (4n) systems correspond to paratropic ring currents while (4n + 2) systems show diatropic currents. The utility of molecular shielding, otherwise known as nuclear independent chemical shifts (NICS), in characterizing transannular p–p interactions has been explored in rigid cyclophanes and their derived carbocations.107 The results suggest that although the out-of-plane component of the NICS tensor computed 1 A˚ from the center of the ring can detect variations in aromaticity, presumably due to transannular p–p interactions, its dependence on substituent effects is not measurable. Experimental and theoretical evidence of intermolecular ring currents have been shown by Ma et al.108 in which the 13C shielding tensors of two compounds, 4,7-di-t-butylacenaphthene and 4,7-di-t-butylacenaphthylene are reported. The main difference between these two crystals is that in the naphthene compound, the CH2 groups lie on top of the naphthalene rings of neighboring molecules. Agreement between calculated and experimental tensors could only be achieved with the naphthene compound if the calculation is done on a trimer of these molecules. Nucl. Magn. Reson., 2008, 37, 51–67 | 61 This journal is

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Shielding effects by a benzene ring are likewise shown to change when there is a cation complex.109 Straka and Vaara110 report on calculated 3He chemical shifts in endohedral helium fullerenes. Lastly, NICS calculations have been utilized in the characterization of inorganic clusters, such as those of boron.111 The 13C NMR chemical shifts of single-walled carbon nanotubes (SWNTs) of the zigzag type (n, 0, where n = 7–17) have been calculated using the gauge-including projector-augmented plane-wave (GIPAW) approach.112 Part of this recent work is an evaluation of shielding computations employing finite capped SWNT fragments into GIAO shielding calculations. Convergence is very slow and differences are still evident between a capped system involving 312 atoms and that of an infinite system. The results of the GIPAW calculations, however, show that the orientation of the shielding tensor is identical to those obtained by employing capped finite SWNTs. In addition, an interesting correlation is noted, the calculated chemical shifts decrease with increasing diameter of the tube. The authors also suggest that for evaluating chemical shifts in SWNTs an internal theoretical reference be used, the calculated chemical shielding in benzene or C60. These studies have already been extended to functionalized SWNTs.113 Functional groups such as –NH, –NCH3, –NCH2OH, and –CH2NHCH2 have been examined, allowing for the prediction of the chemical shifts of the C sites directly bound to any one of these groups. The calculations suggest that chemical shifts can be used to decipher if the functional group has attached to either a parallel or a diagonal C–C bond, as addition to a parallel bond leads to a change in the 13C chemical shift of as much as 44 ppm, while with a diagonal bond, the change is much less. The GIPAW method has also been applied to 51V shielding calculations in AlVO4.114 In this recent work, the calculated tensor components of the three inequivalent V sites are accurate enough that probable errors in previous assignments can be corrected. A plane-wave based approach has likewise been implemented for hydrogen-bonded systems.115 Using periodic boundary conditions, 1H NMR chemical shifts have been computed for crystalline L-alanine, L-tyrosine, L-histidine HCl H2O, and adenine HCl H2O. The results compare favorably with experimental solid-state MAS spectra, a clear improvement upon results obtaining isolated molecules. Using the Gay-Berne model to mimic liquid crystal interactions, Lintuvuori et al.116 have calculated the 129Xe shielding tensors of dissolved Xe gas in liquid crystals. The simulations show that the 129Xe shielding is influenced by the density and orientation dependence of the medium on temperature. When 129Xe is placed inside a chiral environment, such as cryptophane, only the sign of its off-diagonal elements depends on the chirality of the cage. However, when a chiral compound is attached to the cage, then diastereomeric 129Xe chemical shifts can be observed. Using a Xe atom placed inside a full crytophane-A cage surrounded by a chiral potential to represent the substituent, Ruiz et al.117 have been able to show that it is possible to reproduce and assign the diastereomeric 129Xe chemical shifts. By replacing C–C units with O2 molecules, Sears et al.118 have been able to predict 129 Xe NMR line shapes for Xe gas inside model nanochannels doped with paramagnetic centers. The predictions that can be applied for any paramagnetic center are as follows: (1) the skew of the 129Xe shielding tensor changes in the presence of paramagnetic centers. With paramagnetic impurities, the 129Xe nucleus is now more shielded parallel to the channel, (2) unlike in purely diamagnetic channels, the span of the 129Xe shielding tensor increases monotonically with Xe loading, (3) at low Xe loading, the 129Xe nucleus becomes increasingly more shielded parallel to the channel as the temperature is decreased, (4) the span of the 129Xe shielding tensor depends on the concentration of the paramagnetic species. Calculations of paramagnetic shielding tensors have now been implemented into the MAGReSpect program.119 The new implementation has been tested on 1H and 13C chemical shifts in various metallocenes of first-row transition metals. Nitrogen shielding is well known to be very sensitive to polarizing environments. 15 N NMR chemical shifts of various ring substituted benzonitriles have been 62 | Nucl. Magn. Reson., 2008, 37, 51–67 This journal is

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recently studied.120 In this series of compounds, the 15N chemical shift of the cyano group is seen to have a negative correlation with the corresponding cyano 13C chemical shift, indicating that polarization of the CRN bond is perhaps responsible for the observed chemical shift dispersion. Both chemical shifts correlate with Hammett constants although benzonitriles with a hydroxyl substituent are found to be outliers, presumably due to hydrogen bonding between the –OH and CRN groups. An experimental and theoretical characterization of the 15N sites in oxidized flavin reactive sites has been achieved.121 In this enzyme, it is found that the difference in the chemistry between two N sites is clearly reflected in the difference in their shielding tensors. Although the N sites are both ‘‘pyridine-type’’, their chemical shifts are at opposite ends of the known chemical shift range of pyridine nitrogens. A significant reduction in the 15N shielding tensor span and increased shielding signify a decrease in the double-bond character as well as a loss of a nonbonding pair of electrons on N. Shielding can be extremely sensitive to hydrogen bonding. Hydrogen-bond geometries have been determined for polycrystalline 1:1 complexes of Schiff base models of the cofactor pyridoxal-5 0 -phosphate (PLP) with carboxylic acids.122 A combination of chemical shift correlations, H/D isotope effects measurements, and dipolar couplings has enabled this recent characterization. 13C and 15N chemical shielding computations have been utilized likewise for elucidating the hydrogen bonding in imidazole and its 4-nitro derivative.123 Similarly, 13C and 1H NMR chemical shifts have been employed in examining the hydrogen bonding structure in 3-hydroxypyridine betaine hydrochloride monohydrate.124 Lastly, carbonyl 13C chemical shifts have attracted attention in the study of hydrogen bonding in pyrimidinocyclophanes.125 In the presence of ions, changes in both isotropic shielding and tensor span of 17O are found for the carbonyl group in guanine.126 These changes are greater than those observed and predicted for hydrogen bonding. Furthermore, it is shown that the effects of a divalent cation are greater than those of monovalent ions. The greater sensitivity of the 17O shielding to both hydrogen bonding and ion interactions is attributed to the observation that the two components, s11 and s22, are both changing in the same direction. With 13C shielding, the two components are changing in opposite directions, canceling each other and rendering the isotropic value rather insensitive to these interactions. Ion binding is likewise demonstrated to have a significant effect on the 17O shielding tensor of the carbonyl oxygen of the central amino acid in Gly–Gly–Gly.127a As in the case of guanine, the sensitivity of the 17O shielding tensor is due to the two components s11 and s22. Both components become more shielded by about 74–176 ppm in the presence of Ca2+. The corresponding change in the presence of Li+ is about half, 26–96 ppm. In phenyllithium, it has been shown that the 13C chemical shift of the ipso-carbon is also sensitive to the solvation number of lithium.127b The calculated chemical shift for the ipso-carbon site is 177.3 ppm for an unsolvated Li+. The corresponding values when the Li+ ion is solvated are 183.6 ppm, 193.2 ppm, and 196.7 ppm, for one, two, and three dimethyl ethers as solvent molecules, respectively. 1H NMR chemical shifts have been recently employed in examining the self-assembly reactions of cis-protected metal corners.128 In these systems, the chemical shifts of the protons in the 2,2 0 -bypyridine ligand have been demonstrated to be influenced by the N–metal–N bond angle. Zhang et al.129 have shown that the most shielded component of the 1H shielding tensor orients towards the metal when an M H– X bond is formed. Other nuclei involving intermolecular interactions have received interest in this reporting period. 9Be NMR chemical shifts have been reproduced for berrylium encapsulated by a bis-imino/phenol naphthalene ligand.130 Augmented plane wave calculations have likewise been utilized to analyze both 27Al and 23Na NMR chemical shifts in aluminofluoride materials.131 In this work, it has been verified that effects beyond the nearest neighbors are likewise important. In thermotropic Nucl. Magn. Reson., 2008, 37, 51–67 | 63 This journal is

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liquid crystals, the 19F shielding in SF6 displays a slight anisotropy of about 0.5 to 1.4 ppm. This induced anisotropy is due primarily to the polarization of the electron distributions by the liquid crystal environment and not due to a distortion in the molecular structure. 31P serves as a useful probe for studying mononucleotides adsorbed on alumina and calculations suggest that the binding in this specific system occurs via a monodentate, inner-sphere fashion.132 Adding solvent molecules into the computation improves the agreement between calculated and experimental 119Sn chemical shifts in diorganotin(IV) derivatives133 Lastly, the 99Ru chemical shift range for various solvents in fac-[Ru(CO)3I3] have been reproduced by Autschbach and Zheng.51 In this recent work, it is shown that for solvent effects, relativistic effects are not significant, and a model that includes both explicit solvent molecules and a continuum model is enough to reproduce the observed experimental trends.

2.5 Absolute shielding scales Gas phase NMR measurements have provided new zero-density 29Si and 73Ge NMR chemical shifts for SiH4 and GeH4.134 The authors have assumed, since these molecules are small enough, that ab initio calculations may be adequately accurate to use calculated absolute shieldings and the zero-density 29Si and 73Ge NMR chemical shifts as references in establishing absolute shielding scales for 29Si and 73 Ge. The reported chemical shifts extrapolated to zero density are 104.34 ppm (29Si in SiH4 referenced to TMS) and 326.41 (73Ge in GeH4 referenced to Ge(CH3)4). The rotational spectrum and hyperfine structure of AsP have been recently measured, yielding absolute shielding constants for 75As and 31P in this compound.135 For 75As, the following are obtained, siso = 25 ppm and O = 4070 ppm, and for 31P, siso = 150 ppm and O = 3760 ppm.

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Applications of nuclear shielding Shigeki Kuroki,a Tsunenori Kamedab and Hidekazu Yasunagac DOI: 10.1039/b617224p

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 2006 to 31 May 2007. 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 the research made by NMR spectroscopy during the period in the world, 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.

2. Shielding of particular nuclear species The NMR experiments, which are reported in the chapter, for most elements contained in molecules were made in the course of physical, chemical or biological studies during the period. 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). 1H and 13C NMR chemical shifts of cyclic ketone molecules in 17 different solvents, which have 4–7-membered rings, were measured and compared with calculated data, magnetic shielding tensors being taken into account by using DFT coupled gauge-included AO calculations.1 It was found that there is good agreement between the calculated and experimental data, and 1H chemical shifts are affected mainly by polarity-polarisability and basicity of the solvent. The 2-trifluoroacetyl-5-(2 0 -pyridyl)pyrrole was measured by 1H, 13C and 15 N NMR spectroscopy and DFT calculations.2 The results show that it has a bifurcated N–H N and N–H O intramolecular hydrogen bond and the bond causes an increase in the size of the 1J(N,H) coupling constant by about 6 Hz, and the deshielding of the bridge proton by 2 ppm. Cyclopropane was studied by NMR spectroscopy in liquid and gaseous states at 300 K and 1H and 13C absolute nuclear magnetic shieldings of its isolated molecules were determined by using the experimental and calculated data.3 Square planar Rh and Pt complexes were investigated by 1H NMR spectroscopy and DFT calculations.4 It was found that large downfield 1 H NMR chemical shift changes on metal bonding, accompanied by changes in shielding tensor orientations. N1-(anthracen-9-ylmethyl)-3,3-triamine, N1-(anthracen-9-ylmethyl)-4,4-triamine, N1-(anthracen-9-ylmethyl)-N1-ethyl-3,3-triamine, N1-(anthracen-9-ylmethyl)-N1-ethyl-4,4-triamine and dihydromotuporamine-C prefer a hoe geometry.5 A strong shielding effect of the anthracene ring on the chemical shifts associated with the appended polyamine chain was inferred by 1H 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]; Fax: +81-3-5734-2880 b National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba 305-8634, Japan. E-mail: kamedat@affrc.go.jp; Fax: +81-29-838-6213 c Kyoto Institute of Technology, Department of Chemistry & Materials Technology, Kyoto Sakyo-ku Matugasaki Gosyokaido-tyo, 606-8585, Japan. E-mail: [email protected]; Fax: +81-75-724-7562


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NMR spectrum of the free amine of N1-(anthracen-9-ylmethyl)-N1-ethyl-3,3-triamine. This shielding effect was found to be independent over a broad concentration range. The 1H, 13C, 15N and 17O chemical shielding tensors and 2H, 17O and 14N electric field gradient (EFG) in the anhydrous chitosan crystalline structure were investigated taking into account of the most probable interacting molecules with the target molecule in the crystalline phase.6 The 1H, 13C, 15N and 17O NMR parameters and 2H, 17O and 14N nuclear quadrupole resonance (NQR) in the hexameric cluster were evaluated by using the calculated chemical shielding tensors and EFG. The results indicate that both O(3)–H(33) O(5-3) and N–H(22) O(6-4) hydrogen bonds have a major influence on NQR and NMR parameters. The calculation of 1 H NMR chemical shifts for nevirapine (1-cyclopropyl-5,11-dihydro-4-methyl-6Hdipyrido [3,2-b:2 0 ,3 0 -e][1,4] diazepin-6-one) molecule dissolved in DMSO was made using the gauge-including atomic orbital (GIAO) method with the aid of the combination of molecular dynamics simulations and the ONIOM2 method.7 This approach can predict the chemical shifts for the system including acidic proton, where its shielding is greatly influenced by hydrogen bonding of the polar solvent. The usefulness of the combined MD-ONIOM2 method was shown. The interactions between alpha-CD, statistically methylated beta-CD, hydroxypropyl-beta-CD and 2-hydroxypropyl-gamma-CD, and adamantyl, isobornyl, cyclohexyl and phenyl methacrylates were studied by 1H NMR and 1H NOESY spectroscopy.8 1H NMR chemical shift analysis provided quantitative data for very strong methacrylate-CD complexes and 1H NOESY spectra were used to study spatial relationships between host and guest atoms. The 1H NMR chemical shift distribution of aqueous hydrogen chloride solution as a function of acid concentration was studied by combining experimental measurements and ab initio calculations.9 The calculation studies were based on Car-Parrinello molecular dynamics simulations and fully periodic NMR chemical-shift simulations. It was shown that the individual contributions of Eigen and Zundel ions, regular water molecules and the chlorine solvation shell to the NMR line are very distinct and almost independent of the acid concentration. 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, or summation, hydrogen bond acidity for a wide range of solutes.10 It was proposed that their method may be able to estimate the hydrogen bond acidity and especially that of individual protic hydrogens in multifunctional solutes. 1H and 13C chemical shifts for [8] and [10] paracyclophane and of [8] (1,4) naphthalenophane were calculated by the GIAO MO method and converted to chemical shifts for geometries optimised in the corresponding methods combination.11 The calculated chemical shift values were correlated with experimental shifts by linear least squares regressions for 1H and 13C NMR data. The effect of hydrogen bonding, inter- and intramolecular electrostatic interactions on the structure of 1-carboxymethyl-3-hydroxypyridinium chloride monohydrate (3-HO-PBH Cl H2O) was studied by 1H and 13C NMR spectroscopies and the B3LYP/6-31G(d,p) calculations.12 It was obtained that the good linear correlations between experimental 1H and 13C NMR chemical shifts and GIAO/B3LYP/6-31G(d,p) calculated magnetic isotropic shielding tensors (s). The colour-developing complex (CDC) is stabilised by hydrogen-bond formation between two N–H bonds of sulfonylurea (R1SO2NH–CO–NH–R2) and the leuco-dye contained in thermal paper.13 The hydrogen bond donor ability of the colour developer can be evaluated in terms of the a2H parameter and it was shown that 1 H NMR chemical shift values of the N–H protons in the sulfonylurea and HPLC retention times of the sulfonylurea on a silica column have a good correlation with the a2H parameter values. It was reviewed that the role of NMR in determining the three-dimensional structures of conotoxins, which are found in the venom of marine snails of the genus Conus.14 1H and 13C chemical shifts of post-translationally modified amino acids were analysed and they were compared with such the data from common amino acids. This analysis provides a reference source for chemical shifts of post-translationally modified amino acids. Nucl. Magn. Reson., 2008, 37, 68–123 | 69 This journal is

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2.1.2 Deuterium (2H) (I =1). The 2H, 17O and 14N EFG and 1H, 13C, 15N and O chemical shielding tensors in the anhydrous chitosan crystalline structure were investigated as mentioned also at 2.1.1 Hydrogen.15 The 2H, 17O and 14N NQR in the hexameric cluster were evaluated by using the calculated chemical shielding tensors and EFG. The results indicate that the NQR and NMR parameters are influenced by both O(3)–H(33) O(5-3) and N–H(22) O(6-4) hydrogen bonds. The crown and saddle isomers of nonamethoxy-tribenzocyclononene dissolved in lyotropic achiral and chiral liquid crystalline solution based on poly-g-benzyl-glutamate and poly-gbenzyl-L-glutamate (PBG and PBLG) were studied by 2H and 13C NMR spectroscopy.16 The NMR spectra of racemic c-1 in PBLG solution exhibit two sets of lines due to the enantiomers and analysis of the 2H quadrupolar splittings and the 13C residual chemical shift anisotropies shows that the dominant factor determining the chiral discrimination is the difference in the ordering of the two enantiomers in the chiral liquid crystals. The 2H NMR spectra of the s-1 methylene-deuterated in PBLG solution exhibit enantio-discrimination with two quadrupolar doublets. Solid-state 2 H NMR spectra acquired from peptides labeled with 3,3,3-2H3-alanines give information for a more accurate analysis of their helical tilt and rotation pitch angle combining with 15N chemical shift of amide bonds.17 It was found that the 2H NMR line shapes are highly sensitive to small variations in the alignment of the Ca–Cb bond relative to the magnetic field direction and the orientational distribution of helixes relative to the membrane normal. The fast uniaxial rotational diffusion of the M2TMP transmembrane peptide (M2TMP) helical bundle around the membrane normal was characterised via 2H quadrupolar couplings, C–H and N–H dipolar couplings, 13C chemical shift anisotropies and 1H T1r relaxation times.18 The powder-NMR approach for orientation determination was shown to be generally applicable and able to be extended to larger membrane proteins. The two-dimensional 2H NMR experiment was used to measure the 2H quadrupolar and paramagnetic shift anisotropy interactions in powder CuCl2 2D2O as a function of temperature.19 The principal components of the quadrupolar and paramagnetic shift anisotropy tensors and the Euler angles describing the orientations of the tensors in the molecular frame were detected. The paramagnetic shift anisotropy of a deuterium atom measured accurately was used to estimate the distance between deuterium and the nearest copper atom bearing an unpaired electron. The chemical shift, the shielding anisotropy, the asymmetry parameter of shielding, the nuclear quadrupole coupling constant and the asymmetry parameter of the nuclear quadrupole coupling for the O and H/D nuclei hydrogen-bonded water molecules in liquid state were obtained theoretically at 300 K.20 The instantaneous configurations were sampled from a Car-Parrinello molecular dynamics simulation and nuclear coordinates were fed into a quantum chemistry program for the calculation of NMR parameters using density-functional theory with the three-parameter hybrid exchange-correlation functional. It was shown how local changes in the environment affect the NMR parameters in liquid water and that a broken or alternatively extra hydrogen bond induces major changes in the NMR tensors and the effect is more pronounced for H or D than for O. 2H NMR was employed to determine high-resolution 1H chemical shifts in solids reducing the line width due to 2H quadrupole interaction and chemical shift anisotropy by magic angle spinning (MAS) and 1H decoupling.21 The results showed that the sensitivity can be enhanced by applying 1H to 2H crosspolarisation (CP) and by adding spinning-sideband spectra. The second-order quadrupole effects of 2H were also examined. 17

2.1.3 Tritium (3H) (I = 1/2). A review covering and reporting the studies made by using tritium (3H) NMR spectroscopic techniques from 1990 to 2005.22 It is described that the understanding and applications of 3H NMR techniques have markedly expanded in the period, and the determination of 3H labeling position, the conformational and structural information, chemical reactivity and mechanism, the 70 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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determination of specific activity and the insight into biochemical systems were enabled by the techniques. 2.1.4 Lithium (6,7Li) (I = 1, 3/2). LiNH2 and LiH + LiNH2 were studied by in situ 6Li and 1H MAS NMR spectroscopies from ambient temperature to 180 1C to gain insight into the effects of mechanical activation on the hydrogen desorption.23 Up-field chemical shift was observed in 6Li MAS NMR spectra with increased milling time. The results indicate that average local electronic structure around Li nuclei is modified during the mechanical activation. Lithium imidazolium (LiIm) and lithium 2-undecylimidazolium (und-LiIm) were studied by 6,7Li variable temperature MAS NMR experiments at intermediate spinning speeds including 2D exchange spectroscopy to observe possible chemical exchange processes.24 7Li MAS spectra show the presence of the doubly lithiated imidazole ring in pure und-LiIm, and in the LiCH3SO3-und-LiIm mixture. 7Li MAS NMR measurements were performed for the glasses of LiCl–Li2O–P2O5 system in order to obtain the information about the microscopic structure and the ion conduction mechanism of the glasses.25 7Li MAS NMR spectra of the glasses show a broad signal and there is a linear dependence of the chemical shift on LiCl composition. It was concluded that amorphous LiCl aggregate regions are formed within the glasses in the high LiCl composition range, and that the Li+ ions included in the amorphous LiCl aggregates contribute mainly to the fast ion conduction of the glasses. Lithium([12]crown-4)2 di-Me and di-Ph cuprate and lithium(thf)4-[tris(trimethylsilyl)methyl]2 cuprate were studied by solid-state 7Li and 13C MAS NMR spectroscopy with respect to the quadrupolar coupling constants of lithium-7, X(7Li), and the asymmetry parameters of the quadrupolar interactions, Z(7Li), and 6,7Li and 13C chemical shifts.26 The experimental findings were supported by calculations based on charges derived from ab initio 6-31 G* HF computations using the point charge model (PCM) and the program GAMESS. CP studies involving two types of quadrupolar nuclei, 7Li and 23Na, for [(Li2O)x(Na2O)1x]0.3[B2O3]0.7 were complicated by spin state mixing under radio frequency irradiation and MAS.27 23Na–7Li CP/MAS NMR spectra obtained on glasses containing Na+ ions revealed that those lithium species interacting particularly strongly with sodium ions have the same 7Li chemical shift as the entire lithium population. The temperature-dependent static 23 Na–7Li CP experimental results indicated that the Li ions strongly interacting with sodium ions are strongly immobilised. The structure and dynamics of lithium ion transport in monoclinic Li3V2(PO4)3 were studied by high-resolution solid-state 7Li NMR under fast MAS conditions (25 kHz).28 One-dimensional variable-temperature NMR and two-dimensional exchange spectroscopy (EXSY) were also used to probe Li mobility and very fast exchange was observed for the Li hopping processes. Activation energies were determined and correlated to structural properties including interatomic Li distances and Li–O bottleneck sizes. 2.1.5 Sodium (23Na) (I = 3/2). The superconducting and non-superconducting bilayer hydrates NaxCoO2 yH2O (x = apprx. 0.3, y = apprx. 1.3) were investigated by 23Na NMR spectroscopy.29 The central resonance frequencies show various small shifts due to differences in the shielding effect by intercalated H2O molecules. The similar study for double-layer hydrated cobalt oxides NaxCoO2 yH2O (x = apprx. 0.35, y = apprx. 1.3) and dehydrated NaxCoO2 (x = apprx. 0.35) was made by using 23Na NMR spectroscopy.30 Simulations of high-resolution 19F-decoupled 23 Na and 27Al MAS NMR spectra of the aluminofluoride minerals, cryolite, cryolithionite, thomsenolite, weberite, chiolite, prosopite and ralstonite combined with theoretical modeling were made to get accurate values of chemical shift (diso), and quadrupolar interaction parameters (Cq and Z) and to eliminate ambiguities incurred by the complex nuclear interactions.31 These NMR data were correlated with local electronic environments in the minerals, which were calculated using Full Nucl. Magn. Reson., 2008, 37, 68–123 | 71 This journal is

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Potential Linearised APW (FP LAPW) modeling based on the structures from X-ray diffraction (XRD) data. The structure of RNa2O B2O3 KSiO2 xP2O5 (0.5 o R o 2; 0.86 o K o 3) borosilicate glasses was studied by 23Na, 29Si and 11B MAS NMR and 31P MAS, double quantum-MAS (DQ-MAS) and 31P–11B transfer of populations under double resonance MAS (TRAPDOR MAS) NMR.32 Ab initio calculations of the 31P chemical shielding were carried out to confirm the connectivity between phosphorus and the structural units of the borosilicate glass network. 2.1.6 Potassium (39K) (I = 3/2). Solid-state 39K static and MAS NMR spectra on for potassium salts such as K2CO3 were measured at 21.14 T and it was shown that the chemical shift range for K+ ions in diamagnetic salts is 4100 ppm.33 Inequivalent potassium sites in crystals were resolved through differences in chemical shifts by the measurements and the quadrupolar coupling constants were also obtained from MAS and solid echo experiments on powders. The analysis of static and MAS spectra allows the observation of the various chemical shift and quadrupole coupling tensor components as well as their relative orientations, demonstrating that high-field 39K NMR spectroscopy in the solid state has a substantial sensitivity to the local environment with parameters. It was confirmed by 39K NMR spectroscopy that free potassium is incorporated into geopolymer gels.34 The preferential incorporation of potassium was directly shown by the absence of free potassium in the mixed-alkali geopolymer gel. 2.1.7 Rubidium (87Rb) (I = 3/2). Crystalline and amorphous materials were studied by 87Rb and 27Al NMR spectroscopy with using SPAM and FAM pulses for enhancing the conversion of triple- to single-quantum coherences in the twodimensional multiple quantum MAS (MQMAS) experiments.35 It was concluded that SPAM and FAM pulses are best implemented in phase-modulated whole-echo MQMAS experiments and that the use of SPAM pulses to record echo and antiecho data generally yields lower signal-to-noise ratios. It was studied by 87Rb NMR spectroscopy that the phase segregation in the transition region between long-range ferroelectric (FE) order and glass order in the phase diagram of the deuteron glass system such as Rb1x(ND4)xD2PO4 (x = 0.20–0.32).36 The total FE and glass phase volume fractions as a function of temperature was detected and the behaviour of the system was discussed for different crystal components in the coexistence region of the two phase states. RbH3(SO4)2 single crystals grown using the slow evaporation method were measured by using 87Rb and 1H FT NMR spectroscopy near at the phase transition temperatures. It was found that the change in the splitting of the Rb resonance line at 342 K is associated with a change in the local symmetry at the Rb site.37 The results show that the phase transitions of RbH3(SO4)2 crystals are accompanied by slight rotations of the sulfate group and by slight distortions of the lattice in the neighborhood of the Rb+ ions. On the other hand, RbCuCl3 and CsCuCl3 single crystals obtained by the same method were studied by 87Rb and 133 Cs FT NMR spectroscopy.38 The splitting of the 87Rb resonance lines changes abruptly at 340 K, indicating that the state of 87Rb nuclei depends on the local environments. The RbCuCl3 and CsCuCl3 results were compared with those obtained previously for other ABCl3 (A = Rb or Cs, B = Cd or Mn) perovskite crystals. The monitoring K+ in the brain of an animal was achieved by using partial K+ replacement with Rb+ and 87Rb MRI.39 Multinuclear 87Rb/23Na/1H MRI was performed on phantoms and rats using a twisted projection imaging (TPI) scheme for 87Rb/23Na, and custom-built surface or parallel cosine transmit/receive coils. It was found that the Rb/(Rb + K) ratio in the brain increases overtime in ischemic areas, suggesting an additional index of ischemia progression. Rb+ in brain is detectable by 87Rb MRI and this enables 87Rb MRI to study the behaviour of K+ in ischemia. The K3H(SeO4)2 and Rb3H(SeO4)2 crystals obtained by using a slow evaporation method were studied by 87Rb and 39K NMR spectroscopy and 72 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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stress-strain measurements and it was confirmed that the phase below TC is ferroelastic with twin domains and that the phase above TC is paraelastic with a single domain.40 The ordered state of Na5RbCu4(AsO4)Cl2 which orders antiferromagnetically via a second-order low-entropy phase transition in zero applied magnetic field, was characterised by 87Rb NMR spectroscopy.41 The properties of Rb nuclear site of Na5RbCu4(AsO4)Cl2 and its structural phase transition were discussed. It was investigated that the experimental factors influencing the enhancements achievable for the central NMR transition, mI = 1/2 - mI = 1/2, of spin3/2 and spin-5/2 nuclei in the solid state using hyperbolic secant (HS) pulses for population transfer, such as 87Rb NMR enhancement obtained for RbClO4 using HS pulses.42 2.1.8 Cesium (133Cs) (I = 7/2). The solid–liquid phase transition of glass cells was studied by observing 133Cs NMR peaks arising from these two phases.43 It was found that many cells yield two additional NMR peaks below the melting point. The chemical shifts are thought to be affected by two distinct impurities which may be O2 and unknown one and can dissolve in the liquid alkali metal. Similar effects are seen in 87Rb cells. A quasi-two dimensional Cs2CuBr4, which is characterised as a frustrated spin system on a distorted triangular lattice with easy-plane type anisotropy was studied by 133Cs NMR spectroscopy in the range of magnetic fields up to 15.9 T.44 It was found that the NMR spectrum shows hysteresis and 2 phase coexistence around the transition field. The incorporation and localisation of 133Cs in a plant cellular model and the metabolic response induced were analysed as a function of external K concentration using 133Cs NMR spectroscopy while the final K and Cs concentrations were determined using absorption spectrometry.45 The in vivo 133Cs NMR revealed that intracellular Cs is distributed in two kinds of compartment. 13C and 31P NMR analyses of acid extracts showed that the metabolome impact of the Cs stress is also a function of the K nutrition and suggested that sugar metabolism and glycolytic fluxes are affected in a way depending upon the medium content in K+. 133 Cs NMR measurements on 2D frustrated Heisenberg antiferromagnet Cs2CuCl4 down to 2 K and up to 15 T were reported.46 It was shown that 133Cs NMR is a good probe of the magnetic degrees of freedom in the Heisenberg antiferromagnet. 133Cs and 35Cl NMR and computational molecular dynamics (MD) modeling study of the interaction of Cs+ and Cl with Suwannee River natural organic matter (NOM). The 133Cs NMR results showed that Cs+ is associated with NOM at pH values from 3.4 0.5 (unbuffered Suwannee River NOM solution) to 9.0 0.5 the extent of interaction increases with decreasing CsCl concentration at constant pH. The interaction decreases with increasing pH at constant CsCl concentration due to pH-dependent negative structural charge development on the NOM caused by progressive deprotonation of carboxylic and phenolic groups. 2.2 Group 2 (9Be,

25

Mg,

43

Ca,

87

Sr,

137

Ba)

9

9

2.2.1 Beryllium ( Be) (I = 3/2). Be NMR measurement results for UBe13 with Tc E 0.86 K were reported.47 The EFG tensor at Be(II) site was also calculated using the band-structure calculation based on an FLAPW-LDA method. A well-split 9Be NMR sharp signals were observed indicating the high-quality of the single crystal in UBe13 and the 9EFG and 9Be Knight shift tensors were identified from the fieldangle dependence of 9Be NMR spectra together with the result of the band-structure calculation. The isotropic and anisotropic hyperfine fields were obtained and the anisotropic part can be explained by the spin-dipolar field attributed to the localspin-density at Be 2p orbital, and the 2p orbital perpendicular to the mirror plane contributes to the conduction band. On the other hand, the isotropic part mainly originates from the core polarisation hyperfine field of the Be s shell due to the unpaired Be 2p electrons. The same authors reported the results on field-angle Nucl. Magn. Reson., 2008, 37, 68–123 | 73 This journal is

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dependence of 9Be NMR measurements for a single crystal UBe13.48 NQR parameters such as the nuclear quadrupole frequency (nQ E 84 kHz) and the asymmetry parameter (Z E 0.21) were determined. The incorporation of Be into a naphthalene containing Schiff base ligand was confirmed by 9Be and 1H NMR measurements and calculated 9Be NMR data at the B3LYP/6-311G+(2d,p) DFT level of theory.49 It was indicated that the ligand completely encapsulates the Be cation via tetradentate tetrahedral coordination using both phenol and imine donors. The HLA-DP2 and HLA-DP4 molecules consisting of the a-1 and b-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains were constructed in order to characterise the interaction among HLA-DP2, beryllium and CD4+ T cells. 9Be NMR spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues.50 Be[(R2N)2P(O)F]4(ClO4)2 (R = Me or R = Et) complexes were studied by 9Be, 19F and 31P multinuclear NMR spectroscopy and 9Be NMR spectra of them show sharp quintuplets due to coupling with four equivalent P atoms, indicative of highly symmetric environment for the Be center and consistent with a tetrahedral geometry.51 DFT calculations carried out at the B3LYP level were used to support the interpretations of NMR data for the two complexes prepared. 2.2.2 Magnesium (25Mg) (I = 5/2). 25Mg triple-quantum MAS (3QMAS) NMR technique at 21.8 T was applied to MgSiO3 glass showing successfully the occurrence of multiple Mg sites in MgSiO3, which are distinguished by the degree of polyhedral distortion.52 It was concluded that the highly distorted MgO6 species occur in MgSiO3 glass, in strong contrast with a recent radial distribution study. Alumina and silica Zener pinning particles in sol-gel prepared ZrO2 and MgO were studied by using 25Mg, 17O, 27Al and 29Si NMR spectroscopy after annealing at various temperatures up to 1200 1C.53 Ethylene-vinyl acetate copolymer containing Mg(OH)2 (MDH) and ammonium polyphosphate (APP) and the interactions between MDH and APP were studied by solid-state 25Mg and 31P NMR spectroscopy.54 It was proposed that the formation of magnesium phosphate stabilising phosphorus in the system and the combination of MDH and APP provides a physical and thermal barrier protecting ethylene-vinyl acetate copolymer from combustion. Monopyridinated aqua(magnesium) phthalocyanine (MgPc H2O Py) and chlorophyll a (Chla), in which Mg(II) ion is coordinated by four nitrogen atoms and a water molecule in a square-pyramidal geometry, were studied by solid-state 25 Mg NMR spectroscopy.55 Solid-state 25Mg NMR spectra for 25Mg-enriched (99.1%) MgPc H2O Py were obtained at 11.7 T and for a natural-abundance-25Mg (10.1%) Chla were recorded at 19.6 T. The 25Mg quadrupole parameters were determined and a square-pyramidal geometry of Mg(II) ions was characterised. Extensive quantum mechanical calculations for EFG and chemical shielding tensors were performed at restricted Hartee-Fock (RHF), DFT and second-order MollerPlesset perturbation theory (MP2) levels for both compounds. A new crystal structure for MgPc H2O Py was also reported. 2.2.3 Calcium (43Ca) (I = 7/2). Three calcium silicate glasses containing Al and/ or Na were studied by 43Ca MAS NMR spectroscopy and the spectra obtained were analysed.56 It was indicated that the transition from a charge-compensating role of [AlO4] groups to a network-modifying role near nonbridging oxygen atoms results in an increase of both the isotropic chemical shift and the quadrupolar coupling constant of 43Ca. The 43Ca NMR parameters are shown to be highly sensitive to variations in its chemical environment. High-resolution 43Ca quintet-quantum MAS (5QMAS) NMR spectra at 16.4 T and 43Ca septet-quantum MAS (7QMAS) NMR spectrum at 21.8 T for Ca-containing glasses were obtained.57 The MQMAS NMR spectra present a clear evidence of multiple Ca sites in the amorphous structures and it was suggested that the Ca2+ ions are mainly in 7- and 8-fold coordination sites. 74 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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The same authors studied 43Ca-enriched Ca3.61Mg0.82Al1.38Si2.75O12.0 as the silicate slags by 43Ca MQMAS (M = 3, 5) NMR spectroscopy at 16.4 T.58 2.2.4 Strontium (87Sr) (I = 9/2). Na4Mg6Al4Si4O20F4 was studied by solid-state Sr NMR spectroscopy.59 The 87Sr NMR spectrum of the heat-treated mica shows a strontium environment with a quadrupolar coupling constant of 9.02 MHz and a quadrupolar asymmetry parameter of 1.0, which indicate a highly distorted and asymmetric coordination environment produced by strontium cations without water in the coordination sphere bound deep within the ditrigonal holes. Evidence for at least one additional strontium environment was found via a 1H–87Sr transfer of populations by a double resonance NMR experiment. It was concluded that the strontium cations in the proton-free interlayer are observable by 87Sr NMR and bound through electrostatic interactions as nine coordinate inner-sphere complexes sitting in the ditrigonal holes. 87Sr NMR spectroscopy presented also partially hydrated strontium cations located on the external mica surfaces. 87

2.2.5 Barium (137Ba) (I = 3/2). BaTiO3 and PbTiO3 were studied by 137Ba NMR spectroscopy.60 It was observed that typical changes in the fine structure and the quadrupole coupling tensors in the ferroelectric tetragonal phase which allow information about the structure model for the particles and the critical particle size. 2.3 Group 3 (45Sc,

89

Y,

139

La,

141

Pr,

167

Er,

169

Tm,

171

Yb)

2.3.1 Scandium (45Sc) (I = 7/2). The quasi-one-dimensional Cu2Sc2Ge4O13 was studied by 45Sc NMR spectroscopy at temperatures between 4 and 300 K.61 The temperature-dependent NMR shift exhibits a character of low-dimensional magnetism with a negative broad maximum at Tmax. The NMR shifts and spin lattice relaxation rates clearly indicate activated responses below Tmax, confirming the existence of a spin gap in Cu2Sc2Ge4O13. The experimental NMR data are well fitted to the spin dimer model, yielding a spin gap value of about 275 K and detailed analysis pointed out that the nearly isolated dimer picture is proper for the understanding of its spin gap nature. The endohedral cluster fullerene (Sc3CH in C80) was characterised by 45Sc NMR spectroscopy and other techniques.62 The characterisation provided the experimental evidence for the caging of the five-atom Sc3CH cluster inside the C80 cage isomer with icosahedral symmetry, which was confirmed by DFT calculations showing that a closed shell and large energy gap structure. A pyramidal Sc3CH cluster and the Ih–C80 cage were shown to be the most stable configuration for Sc3CH in C80. ScNi1.54Sn and ScNi1.85Sn were studied by solidstate 45Sc and 119Sn Mo¨ssbauer NMR and it was revealed that there are single tin and scandium sites.63 The spectroscopic data also accounted for the different defect formation. The structure of enriched ScAuSi and ScAuGe synthesised was studied by solid-state 45Sc NMR spectroscopy.64 The ScAuGe and ScAuSi structure have one and two crystallographs, respectively, which were unambiguously distinguished on the basis of 45Sc–29Si magnetic dipole–dipole interactions measured in a site selective fashion. The superstructure of ScAgSn was investigated by solid-state 45Sc and 119Sn and 119Sn Mo¨ssbauer NMR spectroscopies.65 The observation of three crystallographs inequivalent sites by 45Sc 3Q-MAS NMR spectra provided unambiguous proof of the superstructure proposed. Solid-state 45Sc NMR spectroscopy, ab initio calculations and X-ray crystallography were applied to examine the relations between 45Sc NMR interactions and molecular structure and symmetry.66 The powder samples of Sc(acac)3, Sc(TMHD)3, Sc(NO3)3 5H2O, Sc(OAc)3, ScCl3 6H2O, ScCl3 3THF and ScCp3, which provide a variety of scandium coordination environments yielding an array of distinct 45Sc chemical shielding and EFG tensor parameters, were measured by solid-state 45Sc MAS and static NMR spectroscopies. Acquisition of spectra at two distinct magnetic fields allows Nucl. Magn. Reson., 2008, 37, 68–123 | 75 This journal is

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for the observations of scandium chemical shielding anisotropy (CSA). The obtained 45 Sc quadrupolar coupling constants range from 3.9 to 13.1 MHz and they correlate directly with the symmetry of the scandium coordination environment. The results of the ab initio calculations of EFG and chemical shielding tensor parameters are in excellent agreement with the observed parameters. 45Sc NMR isotropic chemical shifts and quadrupole coupling constants of several scandium-containing solid oxides ((ZrO2)0.92(Sc2O3)0.08) were measured in order to clarify their local structure such as the first and second coordination environment (the coordination no).67 The difference in the isotropic shifts between six-coordinated and eight-coordinated scandium is more than 150 ppm, suggesting that this parameter may be useful in studying the scandium coordination in oxide materials. FeSc2S4 and Mn Sc2S4 were studied by 45Sc NMR spectroscopy and the temperature dependences of line shift K (T), linewidth D(T), spin–spin relaxation rate 1/T2 (T) and spin–lattice relaxation rate 1/T1 (T) were determined.68 K(T) of FeSc2S4 exhibits a cusplike maximum, a hallmark of spin frustration. 2.3.2 Yttrium (89Y) (I = 1/2). (Y1xLax)2Ti2O7 was studied by 89Y MAS NMR spectroscopy and spectral analysis of NMR spectra for Y-rich compounds suggested that increasing proportions of La are incorporated onto the pyrochlore A-site randomly, up to the limit of solid solution.69,70 The NMR spectra of the monoclinic phase show four resonances–two broad and two sharp, that is attributed to the four crystallographic distinct ‘A’-type sites within the structure. The local coordination structure around Yttrium ions in yttria stabilised zirconia (YSZ) was investigated by 89 Y MAS NMR and the NMR spectrum shows multiple peaks corresponding to yttrium ions in different coordination numbers.71 The compositional dependence of spectra was observed, yttrium ions of different oxygen coordination number were quantified and the oxygen vacancy concentration around the cations was determined. The local structure change was able to be directly observed by 89Y NMR measurements. Organometallic and coordination compounds containing Y and cyclopentadienyl, alkyl, hydride and aryloxide ligands were usefully characterised by 89Y NMR spectroscopy and optimised with DFT methods.72 The optimised structures were used with the GIAO method to calculate the corresponding 89Y NMR magnetic shielding values (scalc). Agreement between predicted and experimental 89Y NMR shifts is typically within 70 ppm. 89Y NMR calculations were used to provide supporting evidence for the existence of the bulky triallyl complex such as Y[1,3-(SiMe3)2C3H3]3. The yttrium local environment in the series of pyrochlores Y2Ti2xSnxO7 was studied by using 89Y NMR spectroscopy.73 The use of the nonradioactive Y3+ cation provides a sensitive probe for any changes in the local structure and ordering with solid solution compound through 89Y NMR. A significant chemical shift was observed for each Sn substituted into the Y second neighbor coordination environment. The spectral signal intensities of the possible combinations of Sn/Ti neighbors agreed with those predicted statistically assuming a random distribution of Sn4+/Ti4+ on the six-coordinated pyrochlore B site. 2.3.3 Lanthanum (139La) (I = 7/2). LaF3 capped with di-n-octadectyldithiophosphate ligands was studied by solid-state 139La and 19F NMR spectroscopy.74 Solidstate 139La and 19F NMR measurements for bulk and particle LaF3 revealed that the inorganic core of the particle retains the LaF3 structure at the molecular level, while inhomogeneous broadening of the NMR powder patterns arises from distributions of 139La and 19F NMR interactions, confirming a gradual change in the La and F site environments from the particle core to the surface. 139La NMR spectra for Lacontaining metallocenes such as (C5H5)3La, (C5Me4H)3La, [(C5Me5)2La]+ [BPh4] and 15N-enriched [(C5Me4H)2La(THF)]215N2 were obtained by piecewise QCPMG techniques at 9.4 T.75 Simulations of the spectra revealed 139La quadrupolar coupling constants between 44 and 105 MHz. The 139La NMR parameters show 76 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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sensitivity to changes in metallocene structure and preliminary RHF and DFT calculations of 139La EFG and nitrogen chemical shift tensors were used to provide tensor orientations and to rationalise the origin of the NMR parameters in terms of molecular structure and symmetry. La1.2Sr1.8Mn2O7 was studied by 139La NMR spectroscopy to reveal the origin of colossal magnetoresistance (CMR) in manganese oxides.76 It was found that the critical field at which the induced magnetic moment is saturated coincides with the field at which the CMR effect reaches a max. The study indicated that the CMR observed above the Curie temperature in this compound is due to the field-induced ferromagnetism that produces a metallic state via the double exchange interaction. 2.3.4 Praseodymium (141Pr) (I = 5/2). The polarisation from the Pr3+ electron shell in PrF3 to 141Pr nuclear spins as well as the existence of effective channel for magnetisation transfer from 141Pr nuclear spins to nuclear spins of liquid 3He was studied, and the magnetic field dependencies of the Stark energy levels were calculated for high magnetic fields up to 40 T using the set of crystal-field parameters obtained from magnetisation measurements and exchange charges model.77 A direct magnetic coupling between nuclei of the liquid 3He and 141Pr nuclei in the system ‘‘PrF3 powder–liquid 3He’’ was also studied by pulse NMR method. 2.3.5 Erbium (167Er) (I = 7/2). 167Er and 55Mn NMR measurements on ErMn6Sn6 were made at 4.2 K.78 The resonance frequency of the central line in the 167Er NMR spectrum is 955 MHz and the frequency separation between the adjacent lines split by the electric quadrupole interaction is approximate 129 MHz. The hyperfine field analysis shows that the magnetic moments are 8.9 mB for Er and 2.2 mB for Mn at 4.2 K in the ferrimagnetically ordered state. 2.3.6 Thulium (169Tm) (I = 1/2). The angle dependences of magnetisation and hyperfine-enhanced 169Tm NMR for LiTmF4 were studied at 4.2 K.79 The NMR spectra and magnetisation measured are substantially anisotropic and experimental dependences are in good agreement with calculated ones obtained with taking into account the influence of magnetostriction on crystalline field. 2.3.7 Ytterbium (171Yb) (I = 1/2). The potentially diastereomeric {(Me3Si)(Me2MeOSi)CSiMe2CH2CH2SiMe2C(SiMe2OMe)(SiMe3)}K2Yb(THF) gives rise to a single set of NMR signals, suggesting either the presence of only one diastereomer or that exchange between diastereomers is rapid on the NMR time scale. [K][YbSi(SiMe3)3{N(SiMe3)2}2], [K][CH2Si(Me)2N(SiMe3)Yb{N(SiMe3)2}2], [LiYb{N(SiMe3)2}3] and so on were studied by 1H, 13C, 29Si and 171Yb NMR spectroscopy and the nature of the bonding between the carbanionic centers and the Yb and K cations for [K][CH2Si(Me)2N(SiMe3)Yb{N(SiMe3)2}2] was investigated by DFT calculations.80 {(Me3Si)(Me2MeOSi)CSiMe2CH2CH2SiMe2C(SiMe2OMe)(SiMe3)}K2Yb(THF) and [{(Me3Si)2CSiMe2}2O]Yb(THF)2 were studied by 1H, 13C{1H}, 29 Si and 171Yb NMR spectroscopy.81 2.4 Group 4 (47,

49

Ti,

91

Zr)

47, 49

2.4.1 Titanium ( Ti) (I = 5/2, 7/2). Na0.25TiO2 synthesised were investigated by 47, 49Ti and 23Na NMR.82 The gap of the charge-density wave (CDW) formed at magnetic transition temperature due to the Peierls instability below metal–insulator transition temperature was estimated, from the temperature dependences of the susceptibility and the spin–lattice relaxation rate, to be 708 K. The CDW transition temperature was calculated, based on the mean-field theory, to be 402 K, which agrees well with the observed one. TiCl3(Z5-C5H4SiCl3), TiCl3(Z5-C5H4SiMe2F), TiCl3(Z5-C5H4SiMeF2), TiCl3(Z5-C5H4SiF3) and [TiF3(Z5-C5H4SiMe2F) were Nucl. Magn. Reson., 2008, 37, 68–123 | 77 This journal is

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studied by 47, 49Ti NMR and UV-visible spectroscopy and it was showed that the SiMe2F and SiMeF2 substituents have electron-releasing nature, whereas SiCl3 and SiF3 groups have electron-withdrawing properties.83 The hierarchically porous rutile titania obtained from a dense composite of wurtzite ZnO and inverse spinel Zn2TiO4 was studied by solid-state 47,49Ti and 67Zn NMR to know about the local environments around 47,49Ti and 67Zn in both the mixed and pure crystalline materials that are formed during the leaching processes.84 49Ti NMR chemical shifts for a total of 20 titanium complexes and the evaluation of theories in order to identify a reliable approach for the calculation of titanium NMR data were reported.85 NMR data for five titanium fulvene and related complexes were given. The popular B3LYP/631G(d)//B3LYP/6-31G(d) proves to give very good agreement with experimental data over a range from 1400 to 1300 ppm. The linear correlations of lmax of the absorption band and 47,49Ti chemical shift with the number of methyl groups of Z5C5H5nMen)TiCl3 (n = 0–5) were reported.86 It is due to the dependence of both the magnitudes on the HOMO–LUMO energy gap which is influenced by electron donating methyl substituents. Limited DFT calculations were performed to assign HOMO/LUMO orbitals involved. 2.4.2 Zirconium (91Zr) (I = 5/2). The structural and compositional evolution of inorganic-organic silica-based hybrid materials and their conversion to mixed oxides, consisting of host silica and zirconia or hafnia was studied by multinuclear solid-state NMR spectroscopy, FTIR spectroscopy and thermogravimetry.87 91Zr NMR measurements on the sample with the highest zirconium content indicated that a small amount of crystalline zirconia with tetragonal coordination exists upon calcination at 1000 1C and the major zirconia fraction distributed in the silica matrix is in an amorphous state. 2.5 Group 5 (51V,

93

Nb,

181

Ta)

2.5.1 Vanadium ( V) (I = 7/2). 51V NMR chemical shifts calculated from quantum and molecular mechanics (QM/MM)—optimised models of vanadiumdependent chloroperoxidase (VCPO) were presented considering an extensive number of protonation states for the vanadium cofactor (active site of the protein) and a number of probable positional isomers for each of the protonation states.88 A total of 40 models were assessed by comparison to experimental solid-state 51V NMR results recently reported in the literature. The size of the QM region is increased incrementally to observe the convergence behaviour of the 51V NMR chemical shifts. It was found that anisotropic chemical shifts and the nuclear quadrupole tensors appear to be sensitive to changes in the proton environment of the vanadium nuclei. Vanadate speciation in reverse micelles was monitored by 51V NMR spectroscopy, which yields information through chemical shifts and linewidths of spectral features.89 The observed speciation suggested that the relative acidity of a basic vanadate stock solution is slightly reduced in large reverse micelles and speciation reflects the strong interaction of the negative charged oxometalates with the smaller reverse micelle. The speciation of vanadate equilibrium can be used as a parameter to characterise the intramicellar medium. The DFT based calculations of 51V NMR shielding parameters for a transition metal nucleus using periodic boundary conditions were reported.90 The quality of gauge-including projected augmented-wave pseudopotential approach was discussed by comparing experimental and calculated chemical shift tensor eigenvalues for the quadrupolar 51V nucleus in the diamagnetic solid-state AlVO4. The combination of shielding tensor with fast and accurate projector augmented-wave EFG tensor calculations allows to determine the relative orientation of these two tensors. The interior water pool of AOT reverse micelles with a highly charged decavanadate (V10) oligomer was studied by 51V NMR spectroscopy and it showed distinct changes in solute environment.91 When an acidic stock solution of protonated V10 is placed in a reverse micelle, the 51V 51


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chemical shifts show that the V10 is deprotonated consistent with a decreased proton concentration in the intramicellar water pool. The results indicated that a proton gradient exists inside the reverse micelles, leaving the interior neutral while the interfacial region is acidic. The effect of water confinement on biological processes and lipid interfaces were studied using vanadium-containing probes observed by 51V NMR spectroscopy.92 The vanadium-containing probe structure, charge and polarity were modified for use in various biological settings. 2.5.2 Niobium (93Nb) (I = 9/2). (1–x)PbMg1/3Nb2/3O3xPb1/2Sc1/2NbO3 (x = 0.6, 0.2) was studied by 93Nb MAS and 3QMAS NMR spectroscopy and deconvolution of the MAS spectra at several temperatures ranging from 245 to 375 K revealed seven narrow peaks, P0, P1, . . . ,P6, and two broad components, D1 and D2, that are assigned to specific local Nb5+ environments defined by the identities of the six nearest B-site cations.93 Site-specific values of the quadrupole product and isotropic chemical shift were obtained by 93Nb MAS and 3QMAS spectra the sample. The 93Nb NMR spectra for PbMg1/3Nb2/3O3 was obtained as a function of temperature (200 K–370 K) at 17.6 T with MAS at 30 kHz.94 The central transition region consists of three overlapping peaks, and deconvolution yielded temperaturedependent distributions of isotropic chemical shift and quadrupole coupling parameters for each peak. The three peaks were assigned to Nb5+ cations with specific configurations of next-nearest B-site neighbors (nBn) in the perovskite structure. The correlation between p–d hybridisation and phase stability in the D022 structure for NbAl3 and NbGa3 was investigated by 93Nb NMR spectroscopy and the quadrupole splittings, Knight shifts and T1 for each individual compound were determined.95 The larger quadrupole interaction and higher anisotropic Knight shift for NbAl3 were observed as compared with NbGa3, indicating the stronger hybridisation effect. The Nb environment in the (PbMg1/3Nb2/3O3)1x(PbTiO3)x (PMN-PT, x = 0, 0.04, 0.1, 0.2, 0.25, 0.3, 0.33, 0.37, 0.4) solid solution was investigated by solid-state 93Nb MAS NMR spectroscopy.96 The results were found to be consistent with a model for the local structure of PMN in which Nb-containing b00 layers and mixed Nb/Mgcontaining b 0 layers alternate along the directions. The variation with x for PMN-PT of the intensities in the components of the 93Nb MAS NMR spectra suggests a model in which exclusively Nb-containing b00 -type layers are preserved up to x = 0.25 with Ti being accommodated only in the mixed b 0 layers. 2.5.3 Tantalum (181Ta) (I = 7/2). Ta-doped photocatalysts prepared by using reactive d.c.-magnetron sputtering, sol-gel or grafting of tantalum on MCM-41 and TiO2 were studied by 181Ta and 29Si CP/MAS NMR spectroscopy.97 Sol-gel and Ta-grafted MCM and TiO2 catalysts exhibit a rather poor activity, which is correlated with the lack of crystallinity of titania. 2.6 Group 6 (53Cr,

95

Mo,

183

W)

2.6.1 Chromium (53Cr) (I = 3/2). 53Cr and 19F NMR spectra were obtained for a heterometallic substituted antiferromagnetic (AF) ring Cr7Cd with an S = 3/2 ground state and compared with the spectra in a homometallic Cr8 AF ring with an S = 0 ground state.98 The experimental values are in excellent agreement with the theoretical values calculated from an effective spin Hamiltonian which includes crystal field effects. 53Cr chemical shifts of CrO42, Cr2O72, CrO3X, CrO2X2(X = F, Cl) and Cr(CO)5L (L = CO, PF3, CHNH2, CMeNMe2) were calculated, using geometries optimised with the gradient-correlated BP86 density functional, at the GIAO-, BPW91- and B3LYP levels.99 53Cr chemical shifts and EFGs were predicted for CrO3, Cr(C6H6)2, Cr(C6H6)CO3 and Cr2(m2-O2CH)4. Nucl. Magn. Reson., 2008, 37, 68–123 | 79 This journal is

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2.6.2 Molybdenum (95Mo) (I = 5/2). Mo(CN)84 was studied by solid-state Mo NMR spectroscopy at 11.75, 17.63 and 21.1 T.100 The sensitivity of the Mo magnetic shielding (s) and EFG tensors to small changes in the local structure of these anions allows the approximately dodecahedral (D2d) and square antiprismatic (D4d) symmetric Mo(CN)84 anions to be distinguished. Quantum chemical calculations of the Mo s and EFG tensors using zeroth-order regular approximation DFT (ZORA DFT) and RHF methods, were carried out and the results are in good agreement with experimental ones. Aqueous molybdate solutions including Mo7O246, b-Mo8O264, Mo36O1128 and MoO22+ were studied by 95Mo and 17O NMR at pH = 7–1 and in 0.3–6 M HClO4.101 The distribution diagram derived from the 95Mo NMR spectra was given for [Mo] = 0.4 M. The 95Mo NMR signals shift to lower frequencies with increasing number and strength of the Mo–O terminal bonds. Photochemical reaction of Mo(CO)6 with Et2SiH2 was investigated by 1H, 29 Si and 95Mo NMR spectroscopy.102 The 95Mo NMR spectrum showed a resonance at d = 3785, characteristic for seven-coordinate molybdenum compounds. 95

2.6.3 Tungsten (183W) (I = 1/2). The 183W nuclear shielding in a variety of tungsten polyoxometalates (POM) (Lindqvist, Anderson, decatungstates, Keggin) was modeled by DFT calculations that take into account relativistic effects by ZORA and solvent effects by the conductor-like screening model (COSMO) continuum method.103 The best results were obtained when both geometry optimisation in solvent and spin–orbit shielding were included. The computed values can aid the assignment of the 183W NMR spectra of polyoxotungstates, as shown by the case of a-[PW11TiO40]5, whose six signals are ranked computationally. The dimerisation of a mono-ruthenium(iii) substituted a-Keggin-type tungstosilicate ([a-SiW11O39RuIII(H2O)]5) to a m-oxo-bridged dimer [{a-SiW11O39Rum}2O]n (m = iii, n = 12; m = iv/iii, n = 11; m = iv, n = 10) and [{SiW11O39RuIV}2O)]10 were studied by 183W NMR spectroscopy showing that the m-oxo bridged dimer structure is maintained in aqueous solution.104 (Bu4N)7H[{PW11O39Zr(m-OH)}2], (Bu4N)8[{PW11O39Zr(m-OH)}2] and (Bu4N)9[{PW11O39Zr}2(m-OH)(m-O)] were studied by 183W and 31P NMR spectroscopy.105 183W NMR revealed the nonequivalence of two subunits of (Bu4N)7H[{PW11O39Zr(m-OH)}2] and their distortion resulting from localisation of the acidic proton on one of the Zr–O–W bridging O atoms. Calculations also revealed that the doubly bridged hydroxo structure is thermodynamically more stable than the singly bridged oxo structure, in marked contrast with analogous Ti- and Nb-monosubstituted polyoxometalates. The stability of the [PW11O39ZrOH]4 structural unit toward at least 100-fold excess of H2O2 in MeCN was confirmed by 183W and 31P NMR spectroscopy. K9NaH4[(b-GeW9Ti3O37)2O3] 40.5H2O was studied by 183W NMR spectroscopy in comparison with K9H5[(a-GeW9Ti3O37)2O3] 16H2O.106 The photocatalytic H2formation for the dehydrogenative oxidation of methanol (CH3OH - H2 + HCHO) with both the compounds was investigated with a help of electronic and ESR spectra and electrochemistry. a1-[P2W17O61]10 and a1-[YbP2W17O61]7 in aqueous solution was investigated by 183W normal and 2D-COSY NMR spectroscopy and their 183W NMR spectra display each 17 lines of equal intensity with a relatively narrow chemical shift distribution.107 The unambiguous assignment of 183 W NMR spectra of polyoxotungstates was achieved with the aid of the correlation of the magnitude of 2JWW coupling constants with the geometry of oxo-bridges in polyoxotungstates. The mechanism of [g-H2SiV2W10O40]4-catalysed epoxidation of alkenes with hydrogen peroxide in acetonitrile/tert-Bu alcohol was investigated.108 The 183W and 51V NMR and CSI-MS spectroscopy showed that the reaction of [g-H2SiV2W10O40]4 with H2O2 leads to the reversible formation of a hydroperoxo species [g-HSiV2W10O39OOH]4. The energy diagram of the epoxidation with DFT supports the reaction mechanism proposed. The structure of [(n-C4H9)4N]3NbW5O19 and [(n-C4H9)4N]3VW5O19 was studied by 183W NMR 80 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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spectroscopy.109 The 183W NMR spectrum of [NbW5O19]3 presents two resonances with relative intensities 4:1 in agreement with the C4v symmetry of the anion. The tetra-n-butylammonium (TBA) salt of the divacant Keggin-type polyoxometalate [TBA]4[g-SiW10O34(H2O)2] was investigated by 183W and 29Si NMR spectroscopy and CSI mass spectrometry and the results showed that its reaction with excess H2O2 leads to fast formation of [TBA]4[g-SiW10O32(O2)2] with retention of a g-Keggin type structure.110 The equilibria and speciation of a-(H2)W(12)O(40)]6 were examined by 1 H and 183W NMR spectroscopy.111 2.7 Group 7 (55Mn,

99

Tc)

2.7.1 Manganese (55Mn) (I = 5/2). The magnetocaloric effect in Nd0.7Sr0.3MnO3 was investigated by 55Mn spin-echo NMR spectroscopy, electron magnetic resonance and polarised Raman scattering measurement.112 It was shown that this effect is a manifestation of a competition between the double exchange mechanism and correlations arising from coupled spin and lattice degrees of freedom which results in a complex ferromagnetic state. The hole-doped transition metal oxides La1xSrxMnO3 (LSMO) and La1xSrxCoO3 (LSCO) (x = 0.3) were investigated by 55Mn and 59 Co NMR spectroscopy at low magnetic field to obtain information on changes in hyperfine couplings and spin dynamics as a function of temperature.113 It was found that the anisotropy effects linked to lattice distortions are more important in LSCO than in LSMO at low temperatures and their structural distortions become important in LSMO above 120 K. Structural, magnetic and 55Mn spin-echo NMR properties of Pr0.6xSr0.4MnO3 (x = 0–0.2) were studied.114 55Mn spin-echo NMR measurements were made at 4.2 K to clarify its microscopic characterisation and several peaks were observed around 380 MHz for Pr deficient samples, suggesting that there are inhomogeneous local magnetic states introduced by the Pr deficiency. Central transition 55Mn NMR spectra of LMn(CO)5 (L = Cl, Br, I, HgMn(CO)5, CH3, PhCH2, Ph3nClnSn (n = 1, 2, 3)) acquired at magnetic field strengths of 11.75, 17.63 and 21.1 T were reported, and the variety of lineshapes obtained demonstrated the sensitivity of solid-state 55Mn NMR to the local bonding environment.115 The width of the solid-state 55Mn NMR spectra of the pentacarbonyl halides is dominated by the chemical shift anisotropies at all of the three applied magnetic fields. DFT calculations of the Mn magnetic shielding tensors reproduced the spectra experimentally obtained and the magnitude of the chemical shift anisotropy was estimated on the basis of Ramsey’s theory of magnetic shielding. It was mentioned that the d-character of the Mn MOs is important for determining the paramagnetic shielding contribution to the principal components of the magnetic shielding tensor. Z5-CpMn(CO)3, Mn2(CO)10 and (CO)5MnMPh3 (M = Ge, Sn, Pb) were measured by 55Mn MAS and MQMAS NMR spectroscopy at 7.05, 11.75 and 21.14 T demonstrating the advantages of the ultrahigh magnetic fields for characterising the chemical shift tensors of several manganese carbonyls.116 The broad chemical shift anisotropy arises from second-order quadrupolar broadening due to the 55Mn quadrupolar coupling constant (64.3 MHz), as well as the anisotropic shielding. Subtle variations in the EFG tensors at the manganese were also observed for crystallographically unique sites. 2.7.2 Technetium (99Tc) (I = 9/2). The H2O exchange process on fac[(CO)3Tc(H2O)3]+ and fac-[(CO)3Mn(H2O)3]+ was studied by 9Tc and 17O NMR spectrometry as a function of the acidity, temperature and pressure.117 The coupling between 99Tc and 17O nuclear spins was observed in the case of the Tc complex. The 99 Tc chemical shifts are strongly dependent on the oxidation state and the ligands within a particular oxidation state and 99Tc chemical shift is a sensitive and useful tool to get information on the formation of Tc complexes. Nucl. Magn. Reson., 2008, 37, 68–123 | 81 This journal is

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2.8 Group 8 (57Fe,

99,101

Ru)

57

2.8.1 Iron( Fe) (I = 1/2). The molecular structure of 1,1 0 -bis(sulfinylamino)ferrocene was determined by X-ray analysis and 57Fe NMR.118 The 57Fe NMR chemical shift (d = +2597.0 ppm) for this compound revealed the strong p-acceptor properties of the NSO groups. 2.8.2 Ruthenium (99, 101Ru) (I = 3/2, 5/2). By using density functional computations of 99Ru chemical shifts, the relativistic effects, the influence of the density functional and the solvent effects on fac-[Ru(CO)3I3] were investigated.119 A combined 101Ru NMR and magnetisation study was performed on the ordered double-perovskite Sr2RuGdO6, and the 101Ru NMR peak revealed the existence of a ferromagnetic phase in the antiferromagnetic matrix at low temperature.120 To determine how Mn substitution initially modifies the magnetic interactions in SrRu1xMnxO3, a polycrystalline SrRu0.9Mn0.1O3 sample was prepared and studied by 55Mn and 99,101Ru NMR.121 2.9 Group 9 (59Co,

103

Rh)

2.9.1 Cobalt( Co) (I = 7/2). The joint use of 119Sn Mo¨ssbauer and 59Co NMR spectroscopies was examined as a quantitative probe of local atom ordering in polycrystalline samples of the Heusler compound Co2TiSn.122 The structures of cobalt(III) tris(2-aminoethanolate) hydrates, i.e., red cubic crystals of the composition fac-[Co(NH2CH2CH2O)3] 5.44H2O (fac-I 5.44H2O) and blue prismatic crystals of the composition mer-[Co(NH2CH2CH2O)3] 3H2O (mer-I 3H2O), were investigated by the 59Co, 13C NMR and X-ray diffraction methods.123 The novel magnetic and electronic properties of SrCo6O11, which exhibits a unique stepwise magnetisation, and its relevant magnetotransport phenomena were investigated by site-selective 59Co NMR at zero and applied magnetic fields.124 Structural modification of (Fe0.5Co0.5)89Zr7B4 and (Fe0.25Co0.75)81Nb7B12 amorphous ribbons subjected to different heat treatments was monitored by 59Co NMR spectroscopy.125 The temperature-dependent 59Co-NMR spectra of Na0.7CoO2 revealed different Co environments below 300 K, and their differentiation increased with decreasing temperature.126 The results of a 59Co NMR study of the skutterudite compound CoSb3 were reported.127 59

2.9.2 Rhodium (103Rh) (I = 1/2). 103Rh NMR spectra for the four new rhodium(III) trimer salts were reported; they indicated that 103Rh NMR chemical shifts spanned more than 200 ppm.128 Two isomeric forms of [Rh(O2Cisoq)(Z2-HSnPh3)(PPh3)(4-Rpy)](O2Cisoq = isoquinoline-1-carboxylate, R = carbomethoxy, acyl, bromo, aldehyde, hydrogen, methoxy, dimethylamino) were analysed by using 1H, 31P and 103Rh NMR.129 The manner of complex formation of Rh(III) sulfate was studied by 17O and 103Rh NMR spectroscopy, and the complexes [Rh2(m-SO4)2(H2O)8]2+, [Rh2(*m-SO4)(H2O)8]4+ and [Rh3(m-SO4)3(m-OH)(H2O)10]2+ were found to be the most stable species in aged solutions.130 103Rh and 17O NMR methods were applied to elucidation of the processes of aquation of Rh(III) complexes in the presence of BaCl2 and Ba(ClO4)2.131 2.10 Group 10 (195Pt) 2.10.1 Platinum (195Pt) (I = 1/2). 195Pt NMR observations were made of a series of novel 4,4 0 -disubstituted organic-organometallic stilbenes—that is, 4 0 -substituted stilbenoid–NCN–pincer platinum(II) complexes [PtCl(NCN-R-4)] (NCN-R-4 = [C6H2(CH2NMe2)2-2,6-R-4] in which R = C2H2C6H4-R 0 -4 0 with R 0 = NMe2, OMe, SiMe3, H, I, CN, NO2).132 A linear correlation was found between both the 195 Pt{1H} NMR chemical shift and the Hammett sr value of the R 0 constituent, 82 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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indicating that the 195Pt NMR chemical shift can be used as a qualitative probe for the electronic properties of the delocalised p-system to which it is connected. The 195 Pt NMR chemical shift tensor of Pt[ S2C2(CF3)2]2 was found to be highly anisotropic and asymmetric.133 This tensor property was considered to be attributable to the non-innocent nature of the ligand. Furthermore, the tensor components and orientation were determined by DFT calculations. Platinum(IV) complexes containing dipeptide and diimine or diamine were subjected to 195Pt NMR observation.134 The 195Pt NMR chemical shifts of [PtCl(dipeptide-N,NO)(bipyridine)]Cl, where –N, NO means dipeptide coordinated as a tridentate chelate, appeared at a higher field when the H attached to the dipeptide carbon atom was replaced with a methyl group. On the other hand, the 195Pt NMR chemical shifts of [PtCl(dipeptideN, NO)(diamine)] appeared at a lower field when the H attached to the diamine nitrogen atom was replaced with a methyl group, in the order of [PtCl(glycylglycineN,NO)(ethylenediamine)]Cl, [PtCl(glycylglycine-N,NO)(N-methyl-ethylenediamine)]Cl and [PtCl(glycylglycine-N,NO)(N,N 0 -dimethyl-ethylenediamine)]Cl. The linear relationships between the 195Pt chemical shift increments induced by substitution of Cl ions with nBr ions in [PtCl6nBrn]2 and [PtCl5nBrn(H2O)] complexes were reported, and the preferential extraction of the [PtX6]2 (X = Cl, Br, or a mixture of the two halides) species over their corresponding aquated [PtX5(H2O)]counterparts by silica-based diethylenetriamine anion exchangers was also demonstrated by means of 195Pt NMR spectroscopy.135 A new approach to calculating the 195Pt chemical shift value by using an artificial neural network algorithm was demonstrated, and this approach was successfully applied to 185 different 195Pt chemical shift values.136 A series of carbon-supported platinum particle electrocatalysts (Pt/CB) with average diameters in the range of roughly 1 to 5 nm was investigated by oxygen reduction reaction (ORR) measurements and 195 Pt electrochemical NMR (EC-NMR) spectroscopy, and characteristic size-dependence of 195Pt NMR spectral features was found.137 Pt(II) and Pt(IV) complexes with histamine were calculated by using more than 20 DFT functionals and various basis sets. Comparison of the theoretical NMR chemical shifts of the Pt(II)(Hist)Cl2 complex with those found experimentally showed that the theoretical 195Pt chemical shifts fitted the experimental values only when the relativistic approach was applied within the ZORA formalism.138 It was reported that 195Pt NMR chemical shifts of complexes of the type [Pt(amine)4]I2—i.e. compounds with different primary amines but not with bulky amines—were observed between 2715 and 2769 ppm in D2O.139 The dependence of 31P, 77Se, 125Te and 195Pt NMR chemical shifts on the nature of the metal, the chalcogen and the aryl group in a series of mononuclear [M(EAr)2(dppe)] [M = Pd, Pt; E = Se, Te; Ar = phenyl, 2-thienyl; dppe = 1,2-bis(diphenylphosphino)ethane] complexes was reported.140 The spectral data of 1H, 13C, 15N and 195Pt NMR for dichloride platinum(II) complexes with 5methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO) were obtained, together with data from thermal and infrared analyses.141 In the processes of synthesis of the novel polymer-bound platinum-based chemotherapeutic agent poly(HPMA)– GGG–AmadQPtQ(1R, 2R)–DACH, AP5346 and its precursors, 195Pt NMR was used to determine the coordination environment of the platinum, and also for identification and purity determination of the platinum chelation of the construct.142 195 Pt 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.143 2.11 Group 11 (63,65Cu,

107,109

Ag)

2.11.1 Copper ( Cu) (I = 3/2, 3/2). It was found that the 63Cu NMR signal of Cu(I) complex with carbonyl became much sharper and showed a larger downfield shift than those of the corresponding acetonitrile complexes. This large downfield shift was explained by a paramagnetic shielding effect induced by the copper-bound 63, 65


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carbonyl.144 65Cu chemical shift and quadrupolar splitting parameters for the polycrystalline octanuclear copper (I) O,O 0 -di-i-propyl- and O,O 0 -di-i-amyldithiophosphate cluster compounds {Cu8[S2P(OR)2]6(m8-S)}, where R = iPr and iAm,145 the O,O 0 -di-n-butyldithiophosphate cluster compound Cu8[S2P(O-n-Bu)2]6(m8-S),146 and O,O 0 -dialkyldithiophosphate cluster compounds with Cu-4, Cu-6 and Cu-8 cores147 were observed at multiple magnetic field strengths (7.05, 9.4 and 14.1 T). The 63Cu, 65Cu and 27Al NMR spectra of Al- and Cu-rich powder samples of Cu1xAl2 were observed in order to clarify the relationship between homogeneity range and chemical bonding in the intermetallic compound.148 The chemical shieldings at the copper nucleus of Nd2CuO4 were determined and compared with the results of NMR measurements.149 The low- and high-temperature phases of lanthanum cuprate LaCu0.81Ni0.19O2.5 + delta were investigated by quantum chemical calculations of the electronic structure and by 139La and 63Cu NMR.150 2.11.2 Silver (107,109Ag) (I = 1/2, 1/2). 109Ag NMR spectroscopic data of Ag(I) complexes of thiourea, selenourea and N,N-dimethyl selenourea were observed and compared with their 1H, 13C and 77Se NMR spectra.151 The structure of a single crystal of disilver(I) monofluorophosphate(V), Ag2PO3F, was determined by X-ray diffraction analysis. The oxygen environment around each of the Ag+ cations was different. Thus, 109Ag MAS NMR analysis of this crystal was carried out, together with 19F and 31P MAS NMR, Raman and IR spectroscopies.152 2.12 Group 12 (67Zn,

111,113

Cd,

199

Hg)

67

2.12.1 Zinc ( Zn) (I = 5/2). During the process of preparation involving the leaching of phases and components from a dense composite of wurtzite ZnO and inverse spinel Zn2TiO4, solid-state 67Zn and 47, 49Ti NMR gave information on local environments around these elements in both the mixed and pure crystalline materials.153 2.12.2 Cadmium (111,113Cd) (I = 1/2, 1/2). 113Cd NMR shifts obtained for bis[bis(tri-tert-butoxysilanethiolato) cadmium(II)] were very close to the shifts reported for cadmium complexes with aliphatic thiols. This indicated that cadmium silanethiolates may serve as useful spectroscopic models and analogs for biologically occurring centers.154 Moreover, the fluxional processes in solutions of bis[bis(tri-tertbutoxysilanethiolato) cadmium(II)] and 3,5-dimethylpyridine were demonstrated by means of 113Cd NMR, together with 1H, 13C and 29Si NMR, and the equilibrium character of the formation of bis(tri-tertbutoxysilanethiolato)(3,5-dimethylpyridine) heteroleptic cadmium complex with sulfur and nitrogen ligands was proved. The single crystal structure of N,N-cyclo-pentamethylenedithiocarbamate (PmDtc) cadmium(II) complex was clarified by X-ray diffraction and its 113Cd CP/MAS NMR spectroscopy was shown, together with the results of 15N CP/MAS spectroscopy.155 The unit cell of the cadmium(II) compound comprised two centrosymmetric isomeric binuclear molecules [Cd2{S2CN(CH2)5}4] that displayed structural inequivalence in both 15N and 113Cd NMR and XRD data. Moreover, the structural states of Cd atoms were characterised by almost axially symmetric 113Cd chemical shift tensors. All experimental 15N resonance lines were assigned to the nitrogen structural sites in both isomeric binuclear molecules. 113Cd NMR was applied to a number of Cd chalcogenide particles.156 A dramatic, size-sensitive broadening of the 113Cd NMR line was observed for the pure CdSe and CdTe particles; this could be explained in terms of a chemical shift distribution arising from multiple Cd environments. 113Cd NMR of CdSeTe alloy and layered particles has provided crucial information, which, in conjunction with results from the application of other techniques (especially optical characterisation), has made it possible to develop a detailed picture of the composition and structure of these materials. 113Cd NMR chemical shifts of 84 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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Cd(II) complexes containing trithioether to hexathioether ligands were observed in the range of 225 to 731 ppm.157 Upfield chemical shifts in these NMR spectra were seen whenever (a) the number of thioether sulfur donors in the complex was decreased; (b) a thioether sulfur donor was replaced by a secondary nitrogen donor; or (c) the size of the macrocycle ring increased without a change in the nature or number of the donor atoms. Changes in the identity of non-coordinating anions such as perchlorate or hexafluorophosphate had little effect upon the 113Cd NMR chemical shift in solution. 2.12.3 Mercury (199Hg) (I = 1/2). The reaction of Hg[N(SiMe3)3]2 with the 3,3 0 disubstituted binaphthols proceeds via an intramolecular electrophilic aromatic substitution reaction. Several intermediates in this process were detected by 1H and 199Hg NMR spectroscopy.158 119Sn and 199Hg NMR studies were carried out for metallic tin and mercury embedded in synthetic opals and porous glasses.159 199Hg solid state NMR spectroscopy of the composite powder material constituted by polyaniline powder containing mercury droplets closely linked into the PANI matrix was reported; the results indicated that the incorporated mercury was in metallic form, and they proved that there was a redox reaction between polyaniline (leucoemeraldine form) and an aqueous solution of Hg(I).160 The principal components of the 77Se and 199Hg shielding tensors for mercury (II) complexes of selones (L) with the general formulae [L2HgCl2], [L3HgCl]Cl and [L4Hg]Cl2 were determined from solid-state NMR spectra.161 Correlations between the ligand environment around the Hg(II) ion and 199Hg NMR chemical shifts were shown.162 2.13 Group 13 (10,11B,

27

Al,

71

Ga,

115

In,

203,205

Tl)

10

10,11

2.13.1 Boron ( B) (I = 3, 3/2). B NMR experiments on borate glasses were reported.163 The structure of a hyaluronan derivative, in which the n-propyl carborane was linked to hyaluronan via an ester linkage, as a carrier of carboranes for tumor targeting in boron neutron capture therapy was determined by means of FT-IR and 1H, 13C and 10B NMR analysis.164 The structure of boric acid complexes formed in aqueous solution with a number of bidentate O-containing ligands was investigated by means of ab initio calculation, 11B NMR and 11B and 10B isotope fractionations.165 DFT calculation of the 11B NMR chemical shift was applied to assign the structure of protonated iron(II) bis(dicarbollide) to a staggered isomer with a cisoid conformation of the carborane ligands.166 DFT calculation of the 11B quadrupole coupling constant was carried out to investigate the influence of carbon doping in the single-walled boron-nitride tube.167 11B MQMAS NMR was performed to analyze the structure of 50PbO–xB2O3–(50x)P2O5 glasses with x = 0–25 mol% B2O3; the spectra of glasses with x = 15, 20 and 25 mol% B2O3 revealed the presence of two BO4 sites in these glasses.168 The ability of the water-soluble polymer incorporating 2,3-dihydroxy propyl attached to a polyethylenimine backbone to bind to boric acid was investigated by 11B NMR spectroscopy.169 Because the boric acid interacted with the polymeric 2,3-dihydroxy propyls by forming borate monoester and borate diesters, the borate ion concentration was able to be measured from the 11B NMR chemical shift of the boric acid/borate peak. The gas-phase structure of 6,9-CSB8H12 and 6,9-CNB8H13 was determined by electron diffraction and ab initio calculations.170 11B NMR calculations were used to confirm the accuracy of each structure. The behaviour of the electrolyte anion, tetrafluoroborate (BF4), in an electric double-layer capacitor was studied by solid state 11B NMR using two activated carbons of medium and large surface area.171 The MAS and MQ-MAS 11B NMR spectra reflected the states of the BF4 anion in the activated carbons at various stages. The 11B NMR spectra of the complex of [7,10-b-H-7-CO-7,7-(PPh3)2isonido-7,8,9-ReC2B7H9], which has a highly asymmetric structure with two inequivalent PPh3 ligands and a single CO ligand, were reported.172 The 11B NMR spectra indicated seven distinct boron vertices. The 11B NMR resonances spanned an Nucl. Magn. Reson., 2008, 37, 68–123 | 85 This journal is

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enormous chemical shift range (Dd = 113), and this appeared to be a direct consequence of deshielding of the boron vertex directly opposite the quadrilateral ReCCB aperture. 31P–11B transfer of populations under double resonance MAS (TRAPDOR MAS) NMR was applied to the structural analysis of RNa2O–B2O3– KSiO2–xP2O5 (0.5 o R o 2; 0.86 o K o 3) borosilicate glasses to determine the phosphate speciation in the glasses and their connectivity with the borosilicate network.173 11B, 1H, 13C, 31P, 119Sn, 31P and 119Sn NMR spectroscopies were applied to the structural characterisation of bimetallic zwitterionic complexes with an ambident stanna-closo-dodecaborate ligand: [1-{M(CO)5}-2,7,8-(m-H)3-{Fe(triphos)}-SnB11H11](M = Cr, Mo, W).174 The molecular structures of the four heterodecaboranes arachno-6,9-C2B8H14, arachno-6,9-N2B8H12, arachno-6,9Se2B8H10 and arachno-6,9-C2B8H14 were determined by ab initio MO theory or electron diffraction. The accuracy of all four of these structures was confirmed by the agreement of the 11B chemical shifts calculated at the GIAO-MP2 level with the experimental values.175 An 11B MAS NMR study of surface-sorbed boron on minerals was carried out.176 On the basis of the chemical shifts and quadrupole coupling constants of the 11B NMR spectra, the signal was readily resolved for both trigonal (B(3)) and tetrahedral (B(4)) boron exchanged onto boehmite. The results demonstrated the ability of this method to a) effectively probe the local structure of the sorption sites at total B concentrations in the samples as small as 0.03 wt% and b) provide insight into the mechanisms of sorption. The overall rate of K2Cl6Ptcatalysed hydrolysis of AB complex was calculated by the use of in situ 11B NMR spectroscopy to be third-order.177 11B NMR observation of sodium borosilicate glasses containing different amounts of BaO revealed that there was no direct interaction between Ba2+ ions and boron structural units.178 11B MAS NMR was used for the structural investigation of sodium diborate glasses containing PbOBi2O3 and TeO2.179 The residues of heat treatment of a mixture containing an ammoniumpolyphosphate-based compound and zinc borate were investigated by X-ray diffraction and by 31P and 11B NMR.180 The phase transitions of CuB2O4 were investigated by 11B NMR under an applied magnetic field along the a-axis.181 The mechanism of hydrogen release from solid-state ammonia borane was investigated via in situ solidstate 11B and 11B{1H} MAS-NMR techniques in external fields of 7.1 and 18.8 T at a decomposition temperature.182 The temporal evolution of the coordination environments of boron atoms in simple and complex borosilicate glasses following temperature jumps near the glass-transition temperature was studied by using 11B MAS NMR spectroscopy.183 11B NMR spectroscopy was applied to a study of the crystalline and amorphous states of copper metaborate, as well as of the transition from the amorphous to crystalline states.184 The rates of hydroboration reactions of 1-octene with HBBr2 SMe2 and HBCl2 SMe2, in CH2Cl2 as a solvent, were monitored by 11B NMR spectroscopy.185 Superconductivity was discovered in boron-doped diamonds by means of 11B NMR on heteroepitaxially grown films.186,187 The effect of probe molecules with different proton affinities on the coordination of boron atoms in dehydrated zeolite H-[B]ZSM-5 was investigated by 1 H and 11B MAS NMR spectroscopy.188 The structure of lead borate glasses was investigated by 217Pb and 11B NMR, and the 11B spectra showed the familiar dependence of N-4 on composition.189 11B MAS NMR analysis was conducted to examine the structural changes in the glass system of BaO–B2O3–SiO2 as a function of BaO content.190 The mechanism of the Fries rearrangement of aryl formates promoted by boron trichloride was investigated by monitoring both the substrate and the Lewis acid by 1H, 2H and 11B NMR and by DFT NMR chemical shift calculations.191 Rhodium-catalysed hydroboration of 1-octene and trans-4-octene with sulfur- and nitrogen analogs of catecholborane were demonstrated by in situ 11B NMR spectroscopy.192 The 11B MAS spectrum of a novel mesoporous BCN material at 11.7 T showed severe signal overlap as a result of second-order quadrupolar broadening. In contrast, the resolution improved significantly at


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21.8 T and three distinct peaks were observed, indicating the presence of three sites in the material.193 2.13.2 Aluminum (27Al) (I = 5/2). The 27Al NMR spectra of 9Al2O3–2B2O3 observed by the method of dubbed chemical shift-quadrupolar projection-reconstruction of one-dimensional spectra (CQ-PRODI) in different magnetic fields were shown, and the dependence of magnetic field on the chemical shift and second-order quadrupolar effect were investigated.194 27Al MAS NMR was used to study diluted alkali earth metal-doped lanthanum manganite solid solutions in the lanthanum aluminate ((1 y)LaAlO3–yLa0.67A0.33MnO3 (A = Ca, Sr, Ba) with y = 0, 2, 3 and 5 mol%. An MAS NMR line corresponding to aluminum at sites different from the octahedral site in pure LaAlO3 was observed only in solutions doped with Ba. 3Q MAS NMR revealed that the broadening of this line was governed mainly by quadrupole coupling and made it possible to calculate the isotropic chemical shift.195 29 Si, 31P, 19F and 27Al MAS NMR were applied to 4.5SiO2–3Al2O3–1.5P2O5– (5-z)CaO–zCaF2 glasses with z = 0–3 to elucidate the effect of fluoride content on the glass structure.196 The 27Al MAS-NMR showed a large broad central peak around 50 ppm that was assigned to four-coordinated Al linked via oxygen to P. Nominal Li1+xAlxGe2x(PO4)3 (0 r x r 1.2) lithium fast-ion conductors were prepared as polycrystalline powders and characterised by Rietveld analysis of laboratory X-ray powder diffraction patterns (LXRPD), AEM, and 7Li, 31P and 27 Al MAS NMR analysis.197 Experimentally observed spectra of 19F-decoupled 23 Na and 27Al MAS NMR for the aluminofluoride minerals cryolite, cryolithionite, thomsenolite, weberite, chiolite, prosopite and ralstonite were theoretically simulated to determine the accurate values of chemical shift and quadrupolar interaction parameters, thereby eliminating ambiguities resulting from the complex nuclear interactions.198 23Na and 27Al NMR satellite transition spectroscopy and 3Q MAS spectra of the ternary NaF–CaF2–AlF3 system were observed and the quadrupolar frequency, asymmetry parameter and isotropic chemical shift were extracted from the spectrum reconstructions.199 27Al NMR and Raman spectra of alkaline aluminate solutions with various M 0 OH solutions (M 0 + = Na+, K+, Li+) were recorded and analysed. A single peak was observed on the 27Al NMR spectrum of each solution.200 The chemical shift of this peak shifted significantly upfield with increasing [M 0 OH]T in solutions with [Al(III)]T o 0.8 M. This variation showed a strong dependence on the cation of the solution and practically disappears in systems with [Al(III)]T Z 0.8 M. Detailed structural studies of vanadia supported on SiO2 and modified SiO2 (Si0.8M0.2O2+d where M = Al3+, Zr4+, Y3+) were carried out using different techniques such as powder XRD, IR spectroscopy, and 29Si, 51V and 27 Al MAS NMR spectroscopy.201 The process of recrystallisation of mesoporous SBA-15 into microporous ZSM-5 was analysed by using FTIR, SEM, X-ray diffraction and 27Al MAS NMR.202 The process of heat-treatment of anodic aluminum oxide materials containing a two-dimensional array was observed by XRD and 27Al MAS NMR. The results indicated the progressive development of local and long-range order in the heated structures and the reaction sequence of amorphous Al2O3 -y-Al2O3 - a-Al2O3 (corundum).203 Moreover, 27Al NMR showed the co-existence of aluminum in four-, five- and six-coordinated sites through most of the heating sequence until the stable (6-coordinated) corundum phase was established. The nature of acid sites in Al-SBA-15 materials with various Si to Al ratios was studied by various NMR techniques including 27Al, 29Si, 1H and 31 P MAS, and also by some double-resonance methods such as 1H/27Al transfer of population in double resonance (TRAPDOR).204 XRD and 27Al NMR results indicated that Al was successfully incorporated into the framework of SBA-15 materials by a post-synthesis method. The bridging hydroxyl groups (SiOHAl) associated with Brønsted acid sites were invisible in the 1H MAS or 1H/27Al TRAPDOR spectra of the dehydrated Al-SBA-15 materials. The nonequilibrium Nucl. Magn. Reson., 2008, 37, 68–123 | 87 This journal is

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cation arrangement in high-energy milled MgAl2O4, ZnFe2O4 and NiFe2O4 was studied by XPS and by 57Fe Mo¨ssbauer spectroscopy and 27Al MAS-NMR.205 27Al SATRAS and MQ-MAS spectra were recorded for eight crystalline compounds from the CaF2–AlF3 and BaF2–AlF3 binary and BaF2–CaF2–AlF3 ternary systems and for four glasses with different CaF2/BaF2/AlF3 contents, and precise determination of the NMR parameters for each spectrum was carried out.206 The local structural environments in a commercial photopolymerisable resin-modified glass ionomer were investigated by using a variety of NMR techniques, and the amount of Ala leached out from glass particles was determined by solid-state 27Al NMR spectra.207 The structural difference between natural and synthetic alunite samples [ideally AAl3(SO4)2(OH)6, A = H3O+, D3O+, Na+ and K+] was clarified by using a variety of NMR techniques, and the numbers of structural defects and Al vacancies were determined on the basis of 27Al NMR spectroscopy.208 Characterisations of alumina and silica Zener pinning particles in sol-gel-prepared crystalline ZrO2 and MgO were carried out by 29Si and 27Al MAS NMR.209 27Al, 23Na and 19F NMR chemical shifts were reported in Na3AIF6–FeO and Na3AIF6–Fe2O3 systems for different iron oxide contents.210 1D 1H MAS NMR, 27Al - 1H CP MAS NMR, as well as 2D 27Al 3QMAS NMR, 27Al - 1H heteronuclear correlation (HETCOR) and high-resolution 3QMAS/HETCOR NMR techniques were applied to KAlSi3O8, NaAlSi3O8 and NaAlSiO4 glasses.211 27Al NMR measurement of a single crystal of YMn4Al3 at 8 T was carried out, and the two sets of NMR peaks observed were assigned to the respective Al sites on the basis of the differences in NMR shift, linewidth and relaxation rates.212 2.13.3 Gallium (71Ga) (I = 3/2). To observe the high-resolution spectra of quadrupolar nuclei with half-integer nuclear spin displaying significant second-order linebroadening, the technique of chemical shift—quadrupolar projection-reconstruction of one-dimensional spectra (CQ-PRODI) was used to analyze 71Ga in bGa2O3, and the different magnetic field dependences of the chemical shift and second-order quadrupolar effect were investigated.213 31P and 71Ga NMR experiments were applied to gallium orthophosphate solutions prepared from the system acid–GaPO4–H2O, where acid = H3PO4, H2SO4, or H3PO4–H2SO4, in order to determine the effect of the concentration of acids and their composition, as well as of the concentration of gallophosphate.214 Three main three signals were observed in the 71Ga NMR spectra. A relatively narrow peak at around 0 ppm was due to nonbonded hexaqua-gallium species, whereas resonances at 12 to 14 ppm and broader signals at 24 to 36 ppm were attributed to gallium in direct interaction with sulfate and phosphate species, respectively. The chemical shift changes observed in the 71Ga nuclear magnetic resonance spectrum of polycrystalline 15Nlabeled gallium nitride originated from crystal structure defects on the nearest neighbor atomic-level.215 15N and 71Ga NMR experiments revealed that these structural defects were caused by nitrogen-deficiency of the material. Measurement of the isotropic chemical shift and EFG of 69Ga and 71Ga were performed at 9.4 T on a-Ga2O3, b-Ga2O3, LiGaO2, NaGaO2, KGaO2, Ga2(SO4)3 and LaGaO3 by static, high-speed MAS, satellite transition (ST) spectroscopy and rotor-assisted population transfer (RAPT).216 2.13.4 Indium (115In) (I = 9/2). The pressure-induced magnetic ordering phase in YbInCu4 was investigated by using dc magnetisation, X-ray diffraction and 115In NMR.217 NMR measurements of 115In in Yb0.9Y0.1InCu4 were performed at 4.2 K up to 30 T with a hybrid magnet. An FT spectrum at a constant magnetic field was obtained by summing a set of FT spectra while shifting the transient frequency.218 2.13.5 Thallium (203,205Tl) (I = 1/2, 1/2). A 205Tl NMR experiment was used to characterize cation binding to Na, K-ATPase, in native membranes at room 88 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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temperature by solid-state NMR spectroscopy using the K+ congener 205Tl.219 The NMR signals from occluded Tl+ and nonspecifically bound Tl+ could be detected and distinguished. 2.14 Group 14 (13C,

29

Si,

73

Ge,

117,119

Sn,

207

Pb)

13

2.14.1 Carbon ( C) (I = 1/2). A review was given on the crystal structure determined using NMR chemical shifts. To solve crystal structures by NMR, the following computational requirements must be fulfilled: (i) the energy of a unit cell including the influence of the lattice must be calculated, (II) extremely fast methods are necessary to calculate the chemical shifts and (iii) the derivations of the chemical shifts must be evaluated with respect to the atomic coordinates.220 NMR methodologies were discussed that they were successfully applied for the characterisation of phenolic antioxidants, such as phenolic acids and flavonoids in plant extracts, without any previous separation and isolation of the individual components.221 The 2.89 A˚ intradimer separation for cofacial [TCNE]22 (TCNE = tetracyanoethylene) dimers is twice that of conventional C–C bonds but B0.6 A˚ shorter than the sum of the van der Waals radii. Experimental and computational studies best characterize the intradimer bonding as a 2-electron-4-center (2e–4c) C–C bonding interaction (or bond). This nonconventional bonding exhibits unique spectroscopic properties (lower energy electronic absorption, nCC, shifted nCN and dCCN vibrational absorptions and characteristic 13C NMR chemical shifts) and is diamagnetic.222 This work shows how two expert systems, LSD and SISTEMAT, can be used together to solve structure elucidation problems that were selected from recent literature articles. The LSD system is a structure generator that mainly relies on homo- and heteronuclear 2D NMR data. It lacks the knowledge of chemical shift values and of natural product chemistry. Conversely, the SISTEMAT data base contains about 20 000 natural compounds and refers to both their 13C NMR chemical shifts and their botanical origin.223 Well-resolved, fully visible 13C NMR signals of membrane proteins were successfully recorded either at ambient or at lower temperatures when they were embedded in lipid bilayers constituting a 2D crystal lattice, as manifested from site-directed 13C NMR studies on [3-13C]Ala and(or) [1-13C]Val-labeled bacteriorhodopsin (bR) from purple membrane, instead of uniformly labeled preparations.224 Gold-based drugs were successfully used for the treatment of rheumatoid arthritis. When administered, they undergo ligand exchange reactions in the body with biofluids, cells and proteins. NMR spectroscopy is a very useful technique for probing these ligand exchange reactions under physiological conditions. The strength of the binding ligands can be established by studying the chemical shift changes in 13C and 31P NMR.225 Conotoxins are small conformationally constrained peptides found in the venom of marine snails of the genus Conus. They are usually cysteine rich and frequently contain a high degree of post-translational modifications such as C-terminal amidation, hydroxylation, carboxylation, bromination, epimerisation and glycosylation. Here, the authors review the role of NMR in determining the three-dimensional structures of conotoxins and also provide a compilation and analysing of 1H and 13C chemical shifts of post-translationally modified amino acids and compare them with data from common amino acids.226 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.227 A review with 15 references discussing dependence of 13C chemical shifts of bis-arenechromium compounds on the structure and electrochemical properties of the complexes and theoretical calculations of the chemical shifts. Chemical shifts of 13C nuclei in 1:1 arenechromium complexes do not correlate with carbon–chromium bond lengths and depend also on redox potentials and charge distribution patterns. Results of Nucl. Magn. Reson., 2008, 37, 68–123 | 89 This journal is

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DFT GIAO calculations for (Z6-benzene)(Z6-naphthalene) chromium (2) and (Z6-benzene)(Z6-biphenylene)chromium agree well with experimental data.228 2.14.2 Silicon (29Si)(I = 1/2). Reaction of 9-bromo-9,10-dihydro-9-silaphenanthrene (6) with lithium diisopropylamide (LDA) in THF at room temperature afforded kinetically stabilised 9-silaphenanthrene 1a bearing an efficient steric protection group, 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl (Tbt). 9-Silaphenanthrene 1a was isolated as pale yellow crystals, and the structure of 1a was completely determined by spectroscopic and X-ray crystallography analyses. The 1H and 13C NMR chemical shifts corresponding to the 9-silaphenanthrene ring of 1a were observed in a typical aromatic region, while the central silicon atom showed the characteristic signal at 86.9 ppm in the 29Si NMR in C6D6.229 The dynamics of poly(dimethylsilane) (PDMS) in the mesophase was investigated by DSC and solidstate 29Si NMR.230 solid-state 27Al and 29Si NMR spectra and X-ray diffraction (XRD) patterns were obtained for a-SiAlON powders prepared by combustion synthesis, according to which the phase transformation and structure evolution of aSiAlON were studied.231 The 1H, 13C, 15N and 29Si NMR, IR and UV spectra of N(1-silatranylmethyl) and N-(trimethoxysilylmethyl) derivatives of nitrogen heterocycles were studied. The dependence and interrelation of the chemical shifts of 29Si and 15N nuclei of the silatranyl group in the spectra of N-(1-silatranylmethyl)substituted nitrogen heterocycles were determined by the nature of the heterocyclic system.232 The covalent linkages formed during functionalisation of MCM-41 mesoporous molecular sieves with five chloroalkylsilanes ((EtO)3Si(CH2Cl), (MeO)3Si(CH2CH2CH2Cl), Cl3Si(CH2CH2CH3), Cl2Si(CH3)(CH2Cl) and Cl2Si(CH3)2) were investigated using high-resolution solid-state NMR spectroscopy and DFT calculations. Structural information was obtained from 1H–13C and 1H–29Si heteronuclear (HETCOR) NMR spectra, in which high resolution in the 1H dimension was obtained by using fast MAS. Subsequently, DFT calculations of 29Si, 13C and 1H chemical shifts were performed using Gaussian 03 at the B3LYP/6-311++G(2d,2p) level.233 Two novel indium silicates, K5In3Si7O21 (1) and K4In2Si8O21 (2), were synthesised by a flux-growth method and characterised by single-crystal x-ray diffraction. The solid-state 29Si MAS NMR spectrum of compd. 1 was recorded; it shows the influence of the In atoms in the second coordination sphere of the Si on the chemical shift.234 Different compositions in the Lu2Si2O7–Sc2Si2O7 system were synthesised following the ceramic method. 29Si MAS NMR spectra show a decrease of the 29Si chemical shift with increasing Sc content.235 29Si, 27Al, 31P and 19F MAS NMR spectroscopy was used to study the effect of fluoride content on the structure of 4.5SiO2–3Al2O3–1.5P2O5–(5-z)CaO–zCaF2 glasses.236 Experimental techniques for the measurement of 29Si NMR spectra (mainly for solutions) were briefly discussed, followed from considerations of the nuclear-spin relaxation mechanisms with emphasis on the 29Si nucleus. Chemical shifts d 29Si and indirect nuclear spin– spin coupling constants nJ(29Si, x), the most prominent NMR parameters, were discussed in more detail.237 Five elastomeric bis(dimethylsilyl)-m-carborane-siloxane polymers with Me, Ph and 2-cyanoethyl ligands were characterised by 1H, 11B, 13C and 29Si NMR (NMR) spectroscopy.238 NMRPredict (Version 2 Enhanced, released June 2006) is a useful and straightforward stand-alone product to facilitate the prediction and interpretation of NMR spectra. Given a chemical structure, it can accurately predict 1H, 13C, 19F, 15N, 31P, 11B and 29Si chemical shifts, based on calculations or comparison to library spectra.239 New gas-phase NMR measurements of the shielding constants of 29Si, 73Ge and 1H nuclei in SiH4 and GeH4 were reported.240 The thermal transformation of Ba exchanged zeolite X to celsian was studied by 27Al and 29Si MAS NMR spectroscopy.241 The structures of one synthetic and two natural chlorites of the clinochlore type were explored using X-ray diffraction, MAS NMR and Mo¨ssbauer spectroscopy. It was also reported that unit-cell parameters, Mo¨ssbauer isomer shifts, 29Si NMR chemical shifts as well as 90 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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Al isotropic shifts and quadrupolar coupling parameters.242 A multinuclear solidstate NMR investigation of the structure of the amorphous alteration products (socalled gels) that form during the acquire alteration of silicate glasses used for radioactive waste containment was reported. Two series of gels were obtained, in acidic and in basic solutions, and were analysed using 1H, 29Si and 27Al MAS NMR spectroscopy.243 A series of synthetic sodium-rich saponites and trioctahedral Na, K and Ba mica solid solutions were investigated by 29Si MAS-NMR spectroscopy.244 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.245 MnAPSO-34 molecular sieve was synthesised with triethylamine as the template, characterised with XRD, XRF, 31P, 27Al and 29Si NMR and FT-IR techniques and compared with SAPO-34.246 A hybrid inorganic/organic, anhydride proton-conducting polymer electrolyte (MePEG3SiO3)n was prepared. Structural characterisation of this MePEG3 polymer through 29Si NMR spectroscopy and gelpermeation chromatography indicates that our MePEG3 polymer is composed of several different structures giving a distribution of molecular weights and silicon resonances.247 2.14.3 Germanium (73Ge) (I = 9/2). New gas-phase NMR measurements of the shielding constants of 29Si, 73Ge and 1H nuclei in SiH4 and GeH4 were reported.240 2.14.4 Tin (117, 119 Sn) (I = 1/2, 1/2). Three new resins were synthesised by radical co-polymerisation of triorganotin-4-vinylbenzoates (substituent at tin = Me, Bu or Ph) with styrene and 1,4-divinylbenzene. The products prepared were characterised by FT-IR and NMR spectroscopy both in the solid state and as swollen samples, showing a predominantly tetracoordinated tin atom. The reaction mechanism and the effects of Lewis acidity of the different groups linked to tin were investigated by 1H and 119Sn HR-MAS NMR.248 Gudat recently reported using 31P as a relay nucleus to correlate 1H and 183W in the absence of a direct coupling utilising double INEPT and INEPT/HMQC transfers assisted by gradient selection of the desired coherence pathways. It was presented that the extension of these techniques to 119Sn which exhibits much greater chemical shift dispersion than 31P and (in general) larger coupling constants, as well as the necessary experimental modifications and strategies to implement these techniques.249 In the last years, several studies were performed in the ternary system Sn–B–O as a simplified variant of the Sn-based amorphous composite oxide (TCO), a material in use as negative electrode of Li-ion rechargeable batteries. The authors report on thermo analytical aspects (DTA-TG and temperature-resolved in situ powder diffraction), DFT calculations, IR spectroscopy, Mo¨ssbauer spectroscopic results and solid-state NMR studies on b-SnB4O7. The latter method allows to make a general differentiation of Sn2+ and Sn4+ in Sn–O systems from well-separated 117, 119Sn chemical shifts.250 X-ray pure samples of the stannides RECuSn (RE = Sc, Y, La, Lu) were prepared by arc-melting of the elements and subsequent annealing. The noncubic local symmetry at the tin site is reflected by a small nuclear electrical quadrupolar splitting in the 119Sn Mo¨ssbauer spectra and a moderate chemical shift anisotropy in 119 Sn solid state NMR.251 The monostannides 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 localisation function.252 Reactions of RSnCl3 (R = Et and Bu) with internally functionalised oximes in 1:1 and 1:2 stoichiometric ratios in anhydride benzene afforded nonionic fibrous complexes RSnCl3 nHON:C(R 0 )Ar [R = Et and Bu; R 0 = H, Me n = 1 and 2 (1–8); R 0 = only Me (9–11); Ar = 2-pyridyl, 2-furyl]. Except for 1:1 furyl derivative, Nucl. Magn. Reson., 2008, 37, 68–123 | 91 This journal is

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the value of 119Sn chemical shifts for all these derivatives in the 119Sn NMR spectra suggests hexacoordination around Sn atom.253 The reaction between SnCl2 and the Li salt [[{Pr2P(BH3)}(Me3Si)CCH2]Li(THF)2]2 yields the cyclic dialkylstannylene [{Pr2P(BH3)}(Me3Si)CCH2]2Sn (6) as a 1:1 mixture of rac and meso diastereomers. Fractional crystallisation from n-hexane gives samples of pure rac-6 and meso-6 which were studied by X-ray crystallography, UV/visible, IR and multi-element NMR spectroscopy. Multi-element and variable-temperature NMR spectroscopy suggests that these contacts persist in solution, resulting in unusual 119Sn chemical shifts of 587 and 787 ppm for the rac and meso diastereomers, respectively, significantly upfield in comparison to other dialkylstannylenes.254 Novel 4-acylpyrazolon-5-ato-dihalotin(IV) complexes, [Q2SnX2], (X = F, Cl, Br or I); HQ = HQCHPh2 (1,2-dihydro-3-methyl-1-phenyl-4-(2,2-diphenylacetyl)pyrazol-5-one), HQBn (1,2-dihydro-3-methyl-1-phenyl-4-(2-phenylacetyl)pyrazol-5-one) or HQCF3,py (4-(2,2,2-trifluoroacetyl)-1,2-dihydro-3-methyl-1-(pyridin-2-yl)pyrazol5-one) were synthesised and characterised by spectroscopic (IR, 1H, 13C, 19F and 119 Sn NMR, electrospray ionisation mass spectrometry (ESI-MS)), analytical and structural methods (X-ray and density functional theory).255 The nuclear shielding and spin–spin coupling constants of 119Sn in stannane, tetramethylstannane, methyltin halides Me4nSnXn (X = Cl, Br, I; n = 1–3), tin halides, and some stannyl cations were investigated computationally by DFT methods and Slater allelectron basis sets, including relativistic effects by means of the ZORA method up to spin-orbit coupling.256 2.14.5 Lead (207Pb) (I = 1/2). Solid-state 207Pb NMR studies were conducted on mixed lead halides PbFCl, PbFBr and PbFI.257 Ethylenediamine (en) solutions of K4Pb9 react with toluene solutions of ML4 (M = Pt, Pd, L = PPh3; M = Ni, L2 = COD) and 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (2,2,2crypt) to give M@Pb122- cluster anions (M = Pt, Pd, Ni) as the [K(2,2,2-crypt)]+ salts in low (Ni) to good (Pt) yields. The ions have near perfect Ih point symmetry and were characterised by X-ray diffraction, 207Pb NMR and LDI-TOF mass spectrometry studies.258 solid-state 207Pb NMR studies were 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.259 The central problem in the physics of relaxors is the nature of the polar clusters. Whereas relaxors are homogeneous at high enough temperature, polar regions immersed in a neutral matrix are formed below a certain temperature Tb. This should lead to a two component system. Here it was presented direct microscopic evidence for the two component nature of relaxors. The chemical shift perturbed 207Pb NMR spectra of these systems consist of an isotropic component corresponding to a spherical glassy matrix which does not respond to an applied electric field, and an anisotropic component, corresponding to frozen out polar clusters which order in a strong enough electric field, forming a ferroelectric phase.260 2.15 Group15 (14,15N,

31

P)

14,15

2.15.1 Nitrogen ( N) (I = 1, 1/2). The polarisable continuum model (PCM) was employed to describe the system in the condensed phase. The performance of DFT and PCM in describing high order nonlinear mixed elec. and magnetic effects in condensed phase were described. In this paper the effect of 10 solvents with a wide range of dielectrical constants on 4 amino acids was considered. NMR shielding values (ppm), isotropic and anisotropic effects, energy interaction between solute and solvent, and the effect of hydrogen bond on shielding were described.261 The measurement of amide nitrogen 14N quadrupolar coupling by two-dimensional 14 N/13C correlation experiment was presented with a natural abundant polypeptide. Directly bonded 14N/13C pairs are correlated through J and residual dipolar coupling under MAS using a HMQC-type pulse sequence. The 14N quadrupolar 92 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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coupling was measured from the isotropic second-order quadrupolar shift obtained by comparing the 14N peak positions with the 15N chemical shifts.262 The high resolution offered by 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. Clearly, the 14N quadrupole coupling parameters (Cq, Zq) for ammonium ions appear highly sensitive toward crystal structure and therefore appreciably more informative for the characterisation of ammonium salts in comparison to the isotropic 14N (or 15N) chemical shifts.263 Chemical shifts of nuclei in or attached to a protein backbone are exquisitely sensitive to their local environment. A computer program, SPARTA, was described that uses this correlation with local structure to predict protein backbone chemical shifts, given an input three-dimensional structure, by searching a newly generated database for triplets of adjacent residues that provide the best match in f/c/w1 torsion angles and sequence similarity to the query triplet of interest. The database contains 15N, 1HN, 1Ha, 13Ca, 13Cb and 13C 0 chemical shifts for 200 proteins for which a high resolution X-ray (r2.4 A˚) structure is available.264 Temperature coefficients (Dd/DT) of amide chemical shifts of N-acetylglucosamine residues were measured in a range of oligosaccharides of the important vertebrate polysaccharide hyaluronan.265 First principles calculations of the 1H and 15N NMR solvent shift of adenine in acquire solution was presented. The calculations are based on snapshots sampled from a molecular dynamics simulation, which were obtained via a hybrid quantum-mechanical/mechanical modeling approach, using an all-atom force field (TIP3P).266 The 1H and 15N NMR spectra of several 15N-labeled pyridoxal-5 0 phosphate model systems were measured at low temperature in various aprotic and protic solvents of different polarity, i.e., dichloromethane-d2, acetonitrile-d3 tetrahydrofuran-d8, Freon mixture CDF3/CDClF2 and methanol.267 Membrane protein orientation has traditionally been determined by NMR using mechanically or magnetically aligned samples. Here a new NMR approach that abolishes the need for preparing. macroscopically aligned membranes was shown. It was then shown that 15N chemical shift anisotropy and N–H dipolar coupling measured on these powder samples can be analysed to yield precise tilt angles and rotation angles of the helixes.268 By use of 15N NMR spectroscopy, the pKa values of the aldimines 15N(pyridoxyl-5 0 -phosphate-idine)-methylamine, N-(pyridoxyl-5 0 -phosphate-15Nidine)-methylamine and 15N-(pyridoxyl-idine)-methylamine were measured. The 15 N chemical shifts indicate that the corresponding deprotonation occurs partially in the pyridine and partially in the phenolic site, which compete for the remaining proton.269 The 15N chemical shifts of 13 N-methylpiperidine-derived mono-, bi- and tricycloaliph. tertiary amines, their methiodides and their N-epimeric pairs of N-oxides were measured, and the contributions of specific structural parameters to the chemical shifts were determined by multilinear regression analysis.270 According to the 1H, 13C and 15N NMR spectroscopic data and DFT calculations, bifurcated N–H N and N–H O intramolecular hydrogen bond was shown to be present in 2-trifluoroacetyl-5-(2 0 -pyridyl)pyrrole.271 It was presented that a novel series of hydrogen-bonded, polycrystal 1:1 comp1exes of Schiff base models of the cofactor pyridoxal-5 0 -phosphate (PLP) with carboxylic acids that mimic the cofactor in a variety of enzyme active sites. These systems contain an intramolecular OHN hydrogen bond characterised by a fast proton tautomerism as well as a strong intermolecular OHN hydrogen bond between the pyridine ring of the cofactor and the carboxylic acid. In particular, the aldenamine and aldimine Schiff bases N-(pyridoxylidene)tolylamine and N-(pyridoxylidene)methylamine, as well as their adducts, were synthesised and studied using 15N CP and 1H NMR techniques under static and/or MAS conditions.272 Achatin-I (Gly1-D-Phe2–Ala3–Asp4), known as a neuropeptide containing. a D-amino acid, binds to the surface of a zwitterionic phosphatidylcholine (PC) membrane only when the peptide N-terminal amino group is in the ionised state, NH3+). Interestingly, when the side chain b-carboxyl group in Nucl. Magn. Reson., 2008, 37, 68–123 | 93 This journal is

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Asp4 is deionised at acidic pH, the 15N signal of the N-terminal NH3+ exhibits no significant chemical shift change upon membrane binding of achatin-I.273 Rhodopsin is the visual pigment of the vertebrate rod photoreceptor cell and is the only member of the G protein coupled receptor family for which a crystal structure is available. Towards the study of dynamics in rhodopsin, NMR spectroscopic investigations of a,.vepsiln.–15N-tryptophan labeled rhodopsin in detergent micelles and reconstituted in phospholipids were reported. 1H,15N chemical shift assignment was achieved for indole side chains of Trp351.30 and Trp1754.65.274 The 1H, 13C and 15N NMR chemical shifts of seven 2-alkylnitrosoamino-4-nitropyridines and seven 2-alkylnitrosoamino-4-nitropyridine N-oxides were assigned.275 The authors present a series of heteronuclear NMR experiments for the direct observation and characterisation of lysine NH3 groups in proteins. In the context of the HoxD9 homeodomain bound specifically to DNA, it is possible to directly observe three cross-peaks, arising from lysine NH3 groups, with 15N chemical shifts around E33 ppm at pH 5.8 and 35 1C.276 Monocyclic iminoaziridines and exo-endo diastereomers of spirocyclic iminoaziridines that are derived from norbornane are prepared in batches of up to 10 g to foster applications as building blocks in syntheses. The ranges of 15N NMR chemical shifts span more than 60 ppm. Neither the b- nor the g-effects of substituents on both types of nitrogen follow a uniform increment pattern.277 Tetrazine-based organic species are interesting intermediates for organic synthesis and represent a source of new materials bearing specific properties with potential applications in biological and material science. 1H, 13C, 15N NMR measurements carried out in solution. and in the solid-state were used to characterize a series of 3,6-disubstituted 1,2,4,5-tetrazine/dihydrotetrazine new derivatives.278 2,3-Dimethylquinoxaline (DMQ) and dimethylglyoxime (DMGH2) form a 1:1 hydrogen-bonded complex in the solid state, which is completely dissociated in methanol solution. The changes in solid-state 15N chemical shifts are more significant: the hydrogen bond imparting a low frequency shift of ca. 19 ppm.279 The 1 H, 13C and 15N NMR spectra of the reduction product of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt with sodium sulfite were measured and analysed. The observed 15N chemical shifts were compared with the predicted ones using the ACD/NNMR 9.01 program.280 Au(III), Co(III) and Rh(III) chloride complexes with pyridine (py), 2,2 0 -bipyridine (bpy) and 1,10-phenanthroline(phen) [M1LCl3], trans-[M2L4Cl2]+, mer-[M2L3Cl3], [M1(LL)Cl2]+, cis-[M2(LL)2Cl2]+, where M1 = Au; M2 = Co, Rh; L = py; LL = bpy, phen, were studied by 1 H–13C HMBC and 1H–15N HMQC/HSQC. The 1H, 13C and 15N coordination shifts (the latter from E78 to E107 ppm) were discussed in relation to the type of metal, electron configuration, coordination sphere geometry and the type of ligand.281 High resolution 15N NMR probing of the solid-solid phase transition of 15 N-labeled ammonia borane (NH3BH3) at 225 K was reported. Both the 15N isotropic chemical shift (diso) and the spin–lattice relaxation rate (T11) exhibited strong anomalies around 225 K.282 15N chemical shifts in an extensive series of para, meta, as well as ortho-substituted benzonitriles, X–C6H4–CN, were measured in deuteriochloroform solutions, using three different methods of referencing.283 A method for assigning solid-state NMR spectra of membrane proteins aligned in phospholipid bicelles that makes use of isotropic chem. shift frequencies and assignments was demonstrated. The resonance assignments are based on comparisons of 15N chemical shift differences in spectra obtained from samples with their bilayer normals aligned perpendicular and parallel to the direction of the applied magnetic field.284 In order to characterize the folding mechanism of Im7, the conformational properties of the protein unfolded in 6 M urea in detail using heteronuclear NMR were studied.285 Signal assignment and secondary structural analysis of uniformly [13C, 15N] labeled H+-ATP synthase subunit c from E. coli (79 residues) in the solid state were carried out by two- and three-dimensional solid-state NMR under MAS.286 Three spiro[pyrrolidine-2,3 0 -oxindoles], 1,1 0 ,2,2 0 ,5 0 ,6 0 ,7 0 ,7 0 aoctahydro-2-oxo-1 0 -phenyl-spiro[3H-indole-3,3 0 -[3H]-pyrrolizine]-2 0 -carboxylic acid 94 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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Me ester (1), 1,1 0 ,2,2 0 ,5 0 ,6 0 ,7 0 ,7 0 a-octahydro-2-oxo-1 0 -nitro-2 0 -phenyl-spiro[3H-indole-3, 3 0 -[3H]-pyrrolizine] (2) and 1,1 0 ,2,2 0 ,5 0 ,6 0 ,7 0 ,7 0 a-octahydro-2-oxo-1 0 -nitro2 0 -(400 -chlorophenyl)-spiro[3H-indole-3,3 0 -[3H]-pyrrolizine] (3) were synthesised and their 1H, 13C and 15N spectra assigned.287 Amide one-bond 15N–1H scalar couplings of 15N– and [15N, 2H]-isotopically enriched ubiquitin were measured with the Quant. J approach by monitoring NMR signal intensity modulation. In contrast, the dynamic frequency shift whose main contribution to 1J(15N–1H) arises from 15N chemical shielding anisotropy/NH dipole cross-correlation, is not eliminated by refocusing spin evolution under this interaction.288 Flavins are central to the reactivity of a wide variety of enzymes and electron transport proteins. There is great interest in understanding the basis for the different reactivities displayed by flavins in different protein contexts. It was found that the 15N chemical shift principal values promise to be valuable tools for understanding electronic differences that underlie variations in flavin reactivity, as well as the reactivities of other heterocyclic cofactors.289 1H, 13C and 15N NMR measurements (1D and 2D including 1H–15N gs-HMBC) were carried out on 3-amino-1,2,4-benzotriazine and a series of N-oxides and complete assignments established.290 Solid-state NMR was applied for the first time to the photoreceptor phytochrome. The two stable states, Pr and Pfr, of the 59-kDa N-terminal module of the cyanobacterial phytochrome Cph1 from Synechocystis sp. PCC 6803 containing a uniformly 15N-labeled phycocyanobilin (PCB) cofactor were explored by 15N CP MAS NMR.291 Fully automated structure determination of proteins in solution (FLYA) yields, without human intervention, three-dimensional protein structures starting from a set of multidimensional NMR spectra. Integrating existing and new software, automated peak picking over all spectra is followed by peak list filtering, the generation of an ensemble of initial chem. shift assignments, the determination of consensus chem. shift assignments for all 1H, 13C and 15N nuclei, the assignment of NOESY cross-peaks, the generation of distance restraints, and the calculation of the three-dimensional structure by torsion angle dynamics.292 NMRPredict (Version 2 Enhanced, released June 2006) is a useful and straightforward stand-alone product to facilitate the prediction and interpretation of NMR spectra. Given a chemical structure, it can accurately predict 1H, 13C, 19F, 15N, 31P, 11B and 29Si chemical shifts, based on calculations or comparison to library spectra. It can also be used to search for compounds or mixtures that exhibit a particular set of resonances.20 1H, 13C and 15N NMR chemical shifts and couplings nJ(H, C) in DMSO-d6 at 30 1C were determined for 1,2-diaryl-(4E)-arylidene-2-imidazolin-5-one derivatives 1–27. Their chemical shift assignments were based on PFG DQF 1H,1H COSY, PFG 1H,13C HMQC as well as PFG 1H, 13C and 1H,15N HMBC experiments.293 The synthesis and assignment of 15N and 13C NMR signals of the isoxazole ring in para-substituted 3-Ph derivatives were reported. DFT calculations of 15N and 13C chemical shifts were presented and compared to observed values.294 The individual components of the backbone 15N CSA tensor, s11, s22, s33 and the orientation of s11 relative to the NH bond described by the angle b were determined for uniformly labeled 15N, 13C ubiquitin from partial alignment in phospholipid bicelles, Pf1 phage and poly(ethylene glycol) by measuring the residue-specific residual dipolar couplings and chemical shift deviations.295 Basicity constants for a series of 3,7-diazabicyclo[3.3.1]nonane derivatives in acetonitrile with a variation over 13 orders of magnitude were determined using a spectrophotometric titration technique. An excellent correlation between basicity and calculated proton affinities obtained at PCM-B3LYP/ 6-31+G(d)//B3LYP/6-31G(d) level was found. The results were discussed in terms of substituent effects and compared to 15N NMR chemical shifts.296 The structure of the membrane protein MerF was determined in magnetically aligned phospholipid bicelles by solid-state NMR spectroscopy. PISEMA, SAMMY and other doubleresonance experiments were applied to uniformly and selectively 15N-labeled samples to resolve and assign the backbone amide resonances and to measure the associated 15N chemical shift and 1H–15N heteronuclear dipolar coupling Nucl. Magn. Reson., 2008, 37, 68–123 | 95 This journal is

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frequencies as orientation constraints for structure calculations.297 Spin-state selective off-resonance decoupling (SITAR) was applied to the amide proton-to-nitrogento-alpha-carbon correlation (HNCA) triple-resonance experiment by measuring the 15 N chemical shift during the acquisition simultaneously with the 1H chemical shift.298 Torsion angle restraints are frequently used in the determination and refinement of protein structures by NMR. It was described that a program, called SHIFTOR, that is able to accurately predict a large number of protein torsion angles (f, c, o, w1) using only 1H, 13C and 15N chemical shift assignments as input.299 2Hydroxymethyl-pyridine with phenacyl bromide gives 3-hydroxy-3-phenyl-pyrido[2,1-c][1,4]dihydrooxazinium bromide (1). Its structure in crystal was determined by X-ray diffraction and confirmed by FTIR spectra and B3LYP calculations. In DMSO and D2O solutions, this compound exists in equilibrium mixture. with Nphenacyl-2-hydroxymethyl-pyridinium bromide (2). The equilibrium mixture was proved by FTIR, 1H, 13C and 15N NMR spectra.300 Combined use of 2D NMR correlation methods (1H–13C and 1H–15N 2D HMBC) and the DFT-GIAO chemical shift calculations allows unequivocal determination of structure for novel quinoxaline.301 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. The line widths and quality of the resulting 15NH dipole–15N chemical shift spectra demonstrate that there are no insurmountable obstacles to the study of large membrane proteins in magnetically aligned media.302 A cancer candidate, compound I, is a weak base with two heterocyclic basic nitrogens and five hydrogen-bonding functional groups, and is sparingly soluble in water rendering it unsuitable for pharmaceutical development. The findings in this study provided insight into the structural characteristics of complexes involving heterocyclic bases and carboxylic acids, and demonstrated that X-ray crystallography and solid-state 15N NMR are truly complementary in elucidating hydrogen bonding interactions and the degree of proton transfer of these complexes.303

It was applied that a combination of 15N relaxation and CSA/dipolar crosscorrelation measurements at five magnetic fields (9.4, 11.7, 14.1, 16.4 and 18.8 T) to determine the 15N chemical shielding tensors for backbone amides in protein G in solution relaxation measurements.304 Appropriate compounds were synthesised to 96 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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create models for the 1 0 ,4 0 -imino tautomer of the 4 0 -aminopyrimidine ring of thiamin diphosphate recently found to exist on the pathway of enzymic reactions requiring this cofactor. Both the UV spectroscopic values and the 15N chemical shift for the 1,4-iminopyrimidine tautomer should serve as useful guides to the assignment of enzyme-bound signals.305 Amide 15N chemical shift anisotropy (CSA) tensors provide quantitative insight into protein structure and dynamics. Experimental determinations of 15N CSA tensors in biological relevant molecules have typically been performed by NMR relaxation studies in solution, goniometric anal. of singlecrystal spectra, or slow MAS NMR experiments of microcrystalline samples. The measurements of 15N CSA tensor magnitudes in a protein of known structure by three-dimensional MAS solid-state NMR was reported.306 Three N-substituted pyrazoles and three N-substituted indazoles [1-(4-nitrophenyl)-3,5-dimethylpyrazole (1), 1-(2,4-dinitrophenyl)-3,5-dimethylpyrazole (2), 1-tosylpyrazole (3), 1-p-chlorobenzoylindazole (4), 1-tosylindazole (5) and 2-(2-hydroxy-2-phenylethyl)-indazole (6)] were studied by NMR spectroscopy in solution (1H, 13C, 15N) and in the solid state (13C, 15N). The chemical shifts were compared with GIAO/DFT calculated absolute shieldings.307 15N NMR spectra of twelve neat ionic liquids derived from 1,3-disubstituted imidazolium salts were measured, and effects of nitrogen atoms substitution, type of anions and influence of solvents used for dilution of neat ionic liquids were studied.308 To understand the structure and activity relationship of human LL-37, a series of peptide fragments was designed. Because LL-37 acts on bacterial membranes, three-dimensional structures of its fragments were determined in micelles by NMR, including structural refinement by natural abundance 15N and 13 C chemical shifts.309 To elucidate the catalytic advantage of the low-barrier hydrogen bond (LBHB), it was analyzed that the hydrogen bonding network of the catalytic triad (His57–Asp102–Ser195) of serine protease trypsin, one of the best examples of the LBHB reaction mechanism. The 15N and 13C chemical shifts are consistent with the experiments. This largely downfield chemical shift is originated from the strong electrostatic interaction, not a covalent-like bonding character between His57 and Asp102.310 A variety of dipyrromethanes and dipyrromethenes were prepared, and their 15N NMR chemical shifts were measured by two-dimensional correlation to 1H NMR signals.311 Tautomerism in 6-mercaptopurine (6mpH), 2,6-dimercaptopurine (2,6dmp) and 6-mercaptopurine-9-riboside (6mp9rb) was studied in the solution with 2D NMR methods-1H–13C HMBC and 1 H-15N HMQC. The 15N NMR signals were assigned and the distribution of mobile protons proposed on the basis of d13C, d15N chemical shifts and JHC, JHN coupling constants, determined with HECADE.312 The guanidinium-denatured state of the N-domain of phosphoglycerate kinase (PGK) was characterised using solution NMR. Rather than behaving as a homogenous ensemble of random coils, chemical shift changes for the majority of backbone amide resonances indicate that the denatured ensemble undergoes two definable equilibrium transitions upon titration with guanidinium, in addition to the major refolding event. 13C and 15N chemical shift changes indicate that both intermediary states have distinct helical character.313 The tautomeric equilibrium in a Schiff base, N-(3,5-dibromosalicylidene)-methylamine 1, a model for the hydrogen bonded structure of the cofactor pyridoxal-5 0 phosphate PLP which is located in the active site of the enzyme, was measured by means of 1H and 15N NMR and deuterium isotope effects on 15N chemical shifts at variable temperature and in different organic solvents.314 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, 195 Pt and 15N NMR.315 Nine new and three earlier known 4-halogen (Cl and Br) substituted pyridine N-oxides were prepared and their 1H, 13C and 15N NMR chemical shifts assigned based on PFG 1H, X (X = 13C and 15N) HMQC and HMBC experiments as well as the comparison with our earlier results for substituted pyridine N-oxide derivatives.316 Eight members of a new family of fullerene Nucl. Magn. Reson., 2008, 37, 68–123 | 97 This journal is

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derivatives, [60]fulleropyrrolidine-N-oxides, were synthesised and characterised. Conclusive evidence for the formation of an N-oxide moiety was provided by the synthesis, oxidation and NMR characterisation of a novel [60]fulleropyrrolidine containing a 15N isotope, showing an 85 ppm downfield heteroatom chemical shift.317 A 15N NMR study of arylamidoximes were performed at natural isotopic abundance in acetone-d6 and CDCl3 solutions.318 N-Nitroso- (5) and N-nitraminotetrazoles (6) were synthesised from the corresponding 5-aminotetrazoles (3) either by the direct nitration with acetic anhydride/HNO3 or by dehydration of the corresponding nitrates (4) with concentrated sulfuric acid. The N-nitroso- (5) and N-nitraminotetrazoles (6) were fully characterised by vibrational (IR, Raman) and multinuclear NMR spectroscopy (14N/15N, 1H, 13C), mass spectrometry and elemental analysis. A detailed discussion of the 15N chemical shifts and 1H–15N coupling constants was given.319 According to the 1H, 13C and 15N NMR spectroscopic data and ab initio calculations, 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 deshielding of the proton and nitrogen by 5–6 and 15 ppm, respectively, and the lengthening of the N–H link by 0.025 A˚.320 Cytochrome P 450’s (P 450’s) catalyze the oxidative metabolism of most drugs and toxins. Although extensive studies have proven that some P 450’s demonstrate both homotropic and heterotropic cooperativity toward a number of substrates, the mechanistic and molecular details of P 450 allostery are still not well-established. UV/Vis and heteronuclear NMR spectroscopic techniques were used to study the mechanism and thermodinamics of the binding of two 9-aminophenanthrene (9-AP) and testosterone (TST) molecules to the erythromycin-metabolising bacterial P 450eryF.321 Solid-state NMR measurements on the peptide Vpu(1–40), comprising residues 1–40 of the 81-residue type 1 integral membrane protein Vpu encoded by the HIV-1 genome was reported. On the basis of a combination of 13C and 15N NMR chemical shifts under MAS, effects of local mobility on NMR signal intensities, sitespecific MAS NMR line widths and NMR-detected hydrogen-deuterium exchange, they develop a model for the structure and dynamics of the Vpu(1–40) monomer in phospholipid bilayer membranes.322 2.15.2 Phosphorus (31P)(I = 1/2). There is a review, which is a brief account on the application of a novel methodology to the quality control and authentication of extra-virgin olive oil. This methodology is based on the derivatisation of the labile hydrogens of functional groups, such as hydroxyl and carboxyl groups, of olive oil constituents with the phosphorus reagent 2-chloro-4,4,5,5-tetramethyldioxaphospholane, and the use of the 31P chemical shifts to identify the phosphitylated compounds.323 Phosphonic acid capped SnO2 particles with diamines less than 5 nm were synthesised and characterised with multinuclear solution and solid-state MAS NMR. The 31P resonances of derivatised SnO2 particles display isotropic chemical shifts that are more shielded compared to the native phosphonic acids.324 Mononuclear [M(EAr)2(dppe)] [M = Pd, Pt; E = Se, Te; Ar = Ph, 2-thienyl; dppe = 1,2-bis(diphenylphosphino)ethane] complexes were prepared in good yields by the reactions of [MCl2(dppe)] and corresponding ArE-with a special emphasis on the aryltellurolato Pd and Pt complexes for which the existing structural information is virtually nonexistent. The trends in the 31P, 77Se, 125Te and 195Pt chemical shifts expectedly depend on the nature of metal, chalcogen and aryl group.325 The solution structure of cupiennin 1a, a 35 residue, basic antibacterial peptide isolated from the venom of the spider Cupiennius salei, was determined by NMR spectroscopy. Solidstate 31P and 2H NMR was used to study the effects of cupiennin 1a on the dynamic properties of lipid membranes, using zwitterionic chain deuterated dimyristoylphosphatidylcholine (d54-DMPC) and anionic dimyristoylphosphatidylglycerol (DMPG) multilamellar vesicles.326 DFT was applied to study the conformational 98 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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dependence of 31P chemical shift tensors in B-DNA.327 High field electrical switching studies on xAg2O–(50x)P2O5–50V2O5 glasses were carried out as a function of sample thickness, composition and temperature. 31P MAS-NMR chemical shift show presence of [POO3/2]0 and [POO2/2O] groups.328 Trehalose preserves lipid bilayers during dehydration and rehydration by replacing water to form hydrogen bonds between its own OH groups and lipid headgroups. The lipid conformation and dynamics between trehalose-protected lyophilised membranes and hydrated membranes were compared, to assess the suitability of the trehalose-containing membrane as a matrix for membrane protein structure determination. 31P spectra indicate that the lipid headgroup of trehalose-protected dry POPC membrane (TREPOPC) have an effective phase transition temperature that is E50 K higher than that of the hydrated POPC membrane.329 The structure and dynamics of the Dickerson DNA dodecamer [5 0 d(CGCGAATTCGCG)2] in solution were investigated by joint simulated annealing refinement against NMR and large-angle X-ray scattering data (extending from 0.25 to 3 A˚1). The NMR data comprise an extensive set of heteroand homonuclear residual dipolar coupling and 31P chemical shift anisotropy restraints in two alignment media, supplemented by NOE and 3J coupling data.330 Three new dental monomers containing methacrylamidoethyl phosphonic acids were synthesised. The structures of the synthesised monomers were determined with electrospray mass spectrometry (ESMS), Fourier transform IR and 31P NMR.331 The speciation in the phosphitomolybdate system, H+–MoO42–(HP)O32, was determined from combined potentiometric and 31P NMR measurements in 0.600 M Na(Cl) medium at 298(1) K.332 Addition of R 0 2PCl to anilines substituted with di- or trimethylcyclopentadienyl unit at ortho-position affords ortho-phenylene-bridged Me2Cp or Me3Cp/phosophinoamide ligands, 2-(RMe2C5H2)C6H4NHPR2 0 (R = Me or H; R 0 = Ph, Me2CH, or cyclohexyl). The metric parameters determined on the X-ray crystallography studies and the chemical shifts of the 31P NMR signal indicate that the phosphorus atom coordinates to the Ti in the dichloro-complexes.333 The size of phosphate-glass (Pglass) particles dispersed in a polyamide-6 (PA 6) matrix by melt blending was characterised by solid-state 1H–31P NMR (NMR). The 31P spectrum associated with the polyamide 1H revealed that the phosphate sites near the polyamide matrix are chemically altered but differently than previously observed in Pglass-polyethylene hybrids, where no such contact was proven.334 The 1st experimental evidence for the formation of ordered threedimensional structures in solutions of organometallic complexes in a thin film of supported ionic liquid was obtained. Catalysts were prepared by immobilisation of [Pd(DPPF)(CF3CO2)2] and CF3SO3H in a thin film of the imidazolium salts 1-alkyl3-methylimidazolium triflate (alkyl = Et, Bu, hexyl) or molten 1-hexyl-2,3-dimethylimidazolium triflate supported on silica, and were characterised by BET surface area, pore vol., and by 1H and 31P{1H} NMR chemical shift and MAS data.335 a-H abstraction and a-H migration reactions yield Ti(IV) complexes bearing terminal phosphinidene ligands. via an a-H migration reaction, the phosphinidene (N B N)Ti:P[Trip](CH2tBu) (1, N B N = tBunacnac- = [Ar]NC(tBu)CHC(tBu)N[Ar], Ar = 2,6-iPr2C6H3, Trip = 2,4,6-iPr3C6H2) was prepared by the addition of the primary phosphide LiPH[Trip] to the nucleophilic alkylidene triflato complex (N B N)Ti:CHtBu(OTf) in 61% yield. These Ti(IV) phosphinidene complexes possess the shortest Ti:P bonds reported, have linear phosphinidene groups, and reveal significant upfield shift of P resonances for the phosphinidene in solution. 31P NMR spectroscopy. Solid state 31P NMR spectroscopic data also corroborate with all three complexes possessing considerably shielded chemical shifts for the linear and terminal phosphinidene functionality.336 NMR Predict (Version 2 Enhanced, released June 2006) is a useful and straightforward stand-alone product to facilitate the prediction and interpretation of NMR spectra. Given a chemical structure, it can accurately predict 1H, 13C, 19F, 15N, 31P, 11B and 29Si chemical shifts, based on calculations or comparison to library spectra.20 The condensation reactions of N2Ox (x = 2, 3) donor-type aminopodand and dibenzo-diaza-crown ethers with Nucl. Magn. Reson., 2008, 37, 68–123 | 99 This journal is

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hexachlorocyclotriphosphazatriene, N3P3Cl6, produce two kinds of partially substituted novel phosphazene derivatives, namely, spiro-bino-spiro- and spiro-crypta phosphazenes. The relationship between the exocyclic NPN (a 0 ) and endocyclic (a) bond angles for spiro-crypta phosphazenes and exocyclic OPN (a 0 ) bond angles for spiro-ansa-spiro- and spiro-bino-spiro-phosphazenes with 31P NMR chemical shifts of NPN and OPN phosphorus atoms, respectively, were investigated.337 A new NMR chemical shift standard and pH indicator, (difluorotrimethylsilanylmethyl)phosphonic acid (DFTMP), was described, and the utility of this reagent was demonstrated for in situ determination of pH in complex biofluids. Advantages of this reagent over previously described pH-sensitive components include (1) lack of metal binding affinity, (2) minimal disturbance of endogenous spectral regions and (3) the potential to function as a multinuclear pH indicator and chemical shift reference point for 19F, 1H and 31P nuclei.338 A novel cycloadduct of 1-boryl-3,4dimethylphosphole was prepared by reaction of 3,4-dimethylphospholyl anion with monobromoborane-methylsulfide complex (CH3)2S BH2Br at 60 1C. It was characterised as a six-membered trimer by spectroscopic means, and its structure confirmed by an X-ray crystal analysis and quantum chemical calculations. In particular, the changes of the 31P NMR chemical shifts upon oligomerisation were examined.339 The novel platinum and palladium complexes with phosphorin, [Pt(dmppn)2X2] (X = Cl, 1; Br, 2; I, 3) and [Pd(dmppn)2X2] (X = Cl, 4; Br, 5), were prepared using 4,5-dimethyl-2-phenylphosphorin (dmppn) with M(cod)X2 or M(PhCN)2X2 (M = Pt, Pd). The chemical shifts for these complexes were observed by 31P{1H} NMRspectroscopy in the solution and they showed significant upfield shifts over 30 ppm relative to that of the free ligand.340 The effects of deprotonation on the 13C and 31P chemical shielding tensors of L-O-phosphoserine were revealed by using solid-state NMR spectroscopy and ab initio calculations.341 The backbone states of B-DNA influence its helical parameters, groove dimensions and overall curvature. Using routine NMR experiments on a nonlabeled B-DNA oligomer and analysing high-resolution X-ray structures, it was investigated the relationship between interproton distances and backbone conformational states. The three H2 0 i-H6/8i + 1, H200 i H6/8i + 1 and H6/8i H6/8i + 1 sequential distances were found cross-correlated and linearly coupled to e–z values in X-ray structures and 31P chemical shifts (dP) in NMR that reflect the interconversion between the backbone BI (e–z o01) and BII (e–z 401) states.342 The electronic properties of 2furyl and 3-furyl substituents attached to phosphines and phosphonium salts were studied by IR spectroscopy and experimental and computational 31P NMR spectroscopy.343 The acidity of mesoporous MoOx/ZrO2 and WOx/ZrO2 materials was studied in detail by multinuclear solid-state NMR techniques as well as DFT quantum chem. calculations. The 1H MAS NMR experiments clearly revealed two different types of strong Brønsted acid sites on both MoOx/ZrO2 and WOx/ZrO2 mesoporous materials, which were able to prontonate adsorbed pyrine-d5 (resulting in 1H NMR signals at chemical shifts in the range 16–19 ppm) as well as adsorbed trimethylphosphine (giving rise to 31P NMR signal at E0 ppm).344 Tachyplesin I is a cyclic b-sheet antimicrobial peptide isolated from the hemocytes of Tachypleus tridentatus. The lamellar phase 31P chemical shift spectra observed at various concentrations of the peptide in bilayers suggest that the peptide may function neither via fragmentation of bilayers nor by promoting nonlamellar structures.345 Polycrystalline tetranuclear Cu4[S2P(O-i-Pr)2]4, hexanuclear Cu6[S2P(OC2H5)2]6 and octanuclear Cu8[S2P(O-i-Bu)2]6(S) complexes were synthesised and analysed by solid-state 31P CP/MAS and 65Cu static NMR spectroscopy.346 To study the Ru– M interactions and their effects on 31P NMR, complexes [Ru(CO)3(Ph2Ppy)2] (py = pyridine) (1) and [Ru(CO)3(Ph2Ppy)2MCl2] (M = Zn (2); M = Cd (3); M = Hg (4)) were calculated by the DFT-PBE0 method.347 The rhodium(III) complex mer,cis[RhCl3(PPh2py-P,N)(PPh2py-P)] (1) (PPh2py = di-Ph(2-pyridyl)phosphine) was prepared from RhCl3 3H2O and PPh2py and converted to the trans,cis[RhCl2(PPh2py-P,N)2]PF6 (2) in acetone solution by treatment with Ag+ and 100 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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PF6. All complexes were characterised by MS, UV-Vis, IR and 1H and 31P{1H} NMR spectroscopy and the Ru(III) complex was characterised by EPR spectroscopy as well.348 Six triaryl phosphorothionates substituted in the para position of the aromatic rings, (4-XC6H4O)3P(S) (X = OMe, Me, H, Cl, CN, NO2), were synthesised and studied by 31P NMR, X-ray diffraction techniques and ab initio calculations at a RHF/6-31G** level of theory, to find the main structural factors associated with the d31P in these compounds.349 The reaction of PCl3 with SnCl2 in THF solution, followed by treatment with dpp-BIAN (dpp = 2,6-i-Pr2C6H3), affords the phosphenium complex [(dpp-BIAN)P][SnCl5 THF]. The 31P chemical shift (d 232.5) and the metrical parameters from a single-crystal X-ray diffraction study indicate that the oxidation state of phosphorus in this compound is +3.350 Crowded triarylphosphines possessing ferrocenyl groups [(4-ferrocenyl-2,6-diisopropylphenyl)n(2,4,6-triisopropylphenyl)3nP (5a, n = 1; 5b, n = 2; 5c, n = 3)] were synthesised by the reaction of the corresponding arylcopper(I) reagents with the diarylchlorophosphines. Structures of the triarylphosphines were studied by 1H, 13C and 31P NMR spectroscopies, and the characteristic patterns of the proton signals of the 2,6-iso-Pr groups and upfield 31P chemical shifts suggest structural similarities of the triarylphosphine moiety to the previously reported tris(2,4,6-triisopropylphenyl)phosphine (2).351 The first quantum chemical investigation of the solid- and solution-state 31P NMR chemical shifts in models for phosphoryl transfer enzyme reaction intermediates and in polymeric inorganic phosphates was reported.352 2.16 Group 16 (17O,

33

S,

77

Se,

125

Te)

2.16.1 Oxygen ( O) (I = 5/2). An 17O-enriched version of the titanosilicate glass, KTS2 (K2O TiO2 2SiO2), was analysed by 17O MAS, off-MAS and 3QQCPMG MAS experiments.353 The complete set of NMR parameters for 17O enriched phenylphosphinic acid C6H5HP O(*OH) was calculated from first principles by using the Gauge Including Projected Augmented Wave (GIPAW) approach.354 A computational investigation was carried out to characterize the 17O, 15 N and 13C chemical shielding tensors in crystalline acetaminophen.355 The gas-toaqueous solution shifts of the 17O and 13C NMR isotropic shielding constants for the carbonyl chromophore in formaldehyde and acetone were studied.356 It was reported that the determination of the 17O NMR tensors for the keto carbonyl oxygen (O6) of guanine in two 17O-enriched guanosine derivatives: [6-17O]guanosine (G1) and 2 0 ,3 0 ,5 0 -O-triacetyl-[6-17O]guanosine (G2).357 The relationship between the 13C and 17 O NMR chemical shifts and the dihedral energies (non-bonding interactions) of 1,4-dioxaspiro[4.4]nonane, 1,4-dioxa- and 6,10-dioxaspiro[4.5]decane, 1,4-dioxaand 6,11-dioxaspiro[4.6]undecane, 1,5-dioxaspiro[5.5]undecane, 1,5-dioxa and 7,12-dioxaspiro[5.6]dodecane and 1,6-dioxaspiro[6.6]tridecane were analysed.358 High-resolution 17O/1H double resonance NMR spectra were obtained for two zeolites, one with a low Si/Al ratio (zeolite HY) and one with a high Si/Al ratio (HZSM-5), to investigate their local structure and Brønsted acidity.359An experimental investigation of the carboxyl oxygen NMR parameters for four distinct sites in L-valine and L-isoleucine was reported.360 A novel method for studying membrane proteins in a native lipid bilayer environment by solid-state NMR spectroscopy was described and tested. It was demonstrated that the utility of this method by a solidstate 19.6 T 17O NMR study of reversible binding effects of mono- and divalent ions on the chemical shift properties of the Leu10 carbonyl oxygen of transmembrane pore-forming peptide gramicidin A (gA).361 The high NMR spectral resolution attained via MAS on single crystals enabled to detect new aspects of mechanism of phase transitions in hydrogen-bonded ferroelectrolytes and antiferroelectrolytes. Results were summarised for anomalous changes in the temperature dependence of the isotropic part of the NMR chemical shifts for 13C and 17O in squaric acid (SQA), and for 31P from NH4H2PO4, KD2PO4 and RbH2PO4, and more recently on 15N in NH4H2AsO4 and NH4H2PO4.362 In this contribution the authors presented a 17


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comprehensive approach to study hydrogen bonding in biological and biomimetic systems through solid-state 17O and 17O–1H NMR combined with d. functional theory calculations of 17O and 1H NMR parameters.363 Li+ and Ca2+ binding to the carbonyl oxygen sites of a model peptide system was studied by solid-state 17O NMR spectroscopy. 17O chemical shift (CS) and quadrupole coupling (QC) tensors were determined in four Gly–(Gly–17O)–Gly polymorphs by a combination of stationary and fast MAS methods at high magnetic field, 19.6 T.364 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 number 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 six-coordinated Ge, has remained unresolved. It was reported that the high-resolution 17O results, including 3QMAS NMR, on a series of crystalline model compounds that allow the definition of ranges of chemical shifts corresponding to oxygens bonded to various coordinations of Ge. High-field 23Na MAS NMR shows systematic decreases in mean Na–O bond distance and/or coordination number with increasing alkali content that can be compared with published results for hightemperature liquids.365 A solid-state 17O NMR 1H-decoupled double angle rotation (DOR) study of monosodium L-glutamate monohydrate (L-MSG) was reported.366 Effects of temperature and some aqueous solutions of electrolytes consisting of ions in natural water on the chem. shifts of NMR of water (17O NMR) were measured.367 The natural abundance 17O NMR chemical shift data for 3,5-diarylisoxazoles (1a–k) and 3,5-diarylisoxazolines (2a–j) in acetonitrile at 75 1C were reported.368 ZORA was 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.369 A phosphine 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.370 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 were measured.371 It was investigated that the performance for nuclear magnetic const. calculations for a selective set of d. functional methods (B3LYP, PBE0, BLYP, PBEPBE, OLYP and OPBE). The testing set includes the 13C, 15N, 17O and 19 F magnetic shieldings and chemical shifts of 23 molecules with 64 comparisons altogether.372 The 17O chemical shifts of substituted benzyl ethers and a set of organotin(IV) derivatives containing O,C,O-chelating ligands were studied. Measured 17O chemical shifts were correlated with the additivity substituent increments for carbon atoms in the alkyl groups, and intramolecular Sn–O distance was obtained by X-ray diffraction techniques in the solid state.373 17O NMR spectra of title compounds were measured at natural abundance in acetonitrile solutions. Intercarbonyl dihedral angles were established by molecular mechanics, which show invariance except in one case.374 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, was reported.375 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.376 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, were synthesised. 17O NMR longitudinal and transverse relaxation


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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.377 2.16.2 Sulfur (33S) (I = 3/2). It was reported that the first 33S chemical shift anisotropy (CSA) data as obtained from a combined determination of 33S CSA and quadrupole coupling parameters utilising the observation of both the 33S (I = 3/2) central and satellite transitions in a natural abundance 33S MAS NMR study. Two tetrathiometallates (NH4)2MoS4 and (NH4)2WS4 were characterised.378 With the development of high-magnetic field spectrometers, solid-state 33S NMR is now clearly feasible but remains complex, especially considering the low sensitivity of 33S NMR. This communication briefly explores the potential of 33S NMR in the field of cement chemistry.379 33S NMR parameters (chemical shifts and linewidths) in 2substituted sodium ethanesulfonates, XCH2CH2SO3Na (X = H, CH3, OH, SH, NH2, Cl, Br, NH3+) depend upon the electronic properties of substituents. To explain experimental results and obtain additional information on the origin of the observed substituent effect (SE), sulfur isotropic absolute shielding constants were calculated at DFT level of theory (B3LYP/6-311++G(2d,p)) by GIAO method.380 2.16.3 Selenium (77Se)(I = 1/2). Plain rules founded in a theoretical background were presented that can be used to determine the structure of selenium compounds on the basis of d(Se) data and to predict d(Se) data from a given structure with satisfactory accuracy.381 Simple synthetic routes for several analogs of the antiinflammatory organoselenium drug, ebselen, were described. The compounds were characterised by 1H, 13C and 77Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies.382 Mononuclear [M(EAr)2(dppe)] [M = Pd, Pt; E = Se, Te; Ar = Ph, 2-thienyl; dppe = 1, 2bis(diphenylphosphino)ethane] complexes were prepared in good yields by the reactions of [MCl2(dppe)] and corresponding ArE- with a special emphasis on the aryltellurolato Pd and Pt complexes for which the existing structural information is virtually nonexistent. The NMR spectroscopic information indicates the formation of only cis-[M(EAr)2(dppe)] complexes in solution. The trends in the 31P, 77Se, 125Te and 195Pt chemical shifts expectedly depend on the nature of metal, chalcogen and aryl group.325 In this paper, the synthesis and characterisation of thiones and selones having N,N-disubstituted imidazole were described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by 77Se NMR spectroscopy and the 77 Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution.383 A comprehensive investigation of selenium chemical shift tensors was presented. Experimentally determined chemical shift tensors were obtained from solid-state 77Se NMR spectra for several organic, organometallic, or inorganic selenium-containing compounds.384 [2 + 2] Cycloadditional reactions of thiocarbamoyl isoselenocyanate, Me2NC(S)NCSe (formed in situ from Me2NC(S)Cl and KSeCN), with aromatic imines RCH:NPh (R = Ph, 4-MeC6H4, 4-ClC6H4, 4-Me2CHC6H4) afforded the corresponding substituted 1,3-selenazetidines (I; same R, 3a–d, respectively.) under reflux conditions. The authors could confirm the structure using significant difference of chemical shifts between selenazetidines and selenoureas including cyclic selenoureas in 77Se NMR spectra.385 1-Mesityl-1,3-dihydro-imidazole-2-selone, (seimMes)H, may be obtained from 1-mesitylimidazole via deprotonation with BuLi with subsequent reaction with elemental selenium and protonation by HCl(aq). Selones and diselenides undergo fast fluxional exchange in the mixtures, e.g., (seimMe)H/(seimMe)2, averaging their 77Se chemical shifts; the exchange rate was established to be E25 000 s1.386 1,3-Bis(ferrocenylchalcogeno)propanes, FcE(CH2)3E 0 Fc (E, E 0 = Se, Te) and 1,2-bis(ferrocenylseleno)ethane, FcSe(CH2)2SeFc Nucl. Magn. Reson., 2008, 37, 68–123 | 103 This journal is

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were prepared, characterised and included in a spectroscopic and electrochemical study of a series of compounds containing two ferrocenes linked by a chalcogencontaining bridge. 77Se and 125Te NMR spectroscopic measurements reveal that the 77 Se chemical shift of Fc2Se2 is anomalously high, which correlates with the long wavelength of its lowest energy electronic absorption.387 The orientational effect of p-YC6H4 (Ar) on d(Se) was elucidated for ArSeR, based on experimental and theoretical investigations. The effect was examined in the cases in which Se-CR in ArSeR is either in the Ar plane (pl) or is perpendicular to the plane (pd). 9-(Arylselanyl)anthracenes (1) and 1-(arylselanyl)anthraquionones (2) were employed to establish the effect in pl and pd, respectively.388 To investigate if [(GS)2AsSe] is formed in rabbit blood, the authors added arsenite and selenite and analysed blood aliquots using arsenic and selenium X-ray absorption spectroscopy. The characteristic arsenic and selenium X-ray absorption spectra of [(GS)2AsSe] were detected within 2 min. after addition and comprised 95% of the blood selenium 30 min after addition. To elucidate if erythrocytes are involved in the biosynthesis of [(GS)2AsSe] in blood, arsenite and 77Se-selenite were added to rabbit erythrocyte lysate and the obtained solution was analysed by 77Se NMR spectroscopy (273 K). This resulted in a 77Se NMR signal with a chemical shift identical to that of synthetic [(GS)2AsSe] added to lysate.389 2.16.4 Tellurium (125Te)(I = 1/2). Mononuclear [M(EAr)2(dppe)] [M = Pd, Pt; E = Se, Te; Ar = Ph, 2-thienyl; dppe = 1,2-bis(diphenylphosphino)ethane] complexes were prepared in good yields by the reactions of [MCl2(dppe)] and corresponding ArE with a special emphasis on the aryltellurolato Pd and Pt complexes for which the existing structural information is virtually nonexistent. The NMR spectroscopic information indicates the formation of only cis-[M(EAr)2(dppe)] complexes in solution. The trends in the 31P, 77Se, 125Te and 195Pt chemical shifts expectedly depend on the nature of metal, chalcogen and aryl group. Each trend can be considered independently of other factors.325 1,3-Bis(ferrocenylchalcogeno)propanes, FcE(CH2)3E 0 Fc (E, E 0 = Se, 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.169 2.17 Group 17 (19F,

35,37

Cl)

19

2.17.1 Fluorine ( F)(I = 1/2). The structures of acetic acid (AA), trifluoroacetic acid (TFA) and their aqueous mixtures over the entire range of acid mole fraction xA were investigated by using large-angle X-ray scattering (LAXS) and NMR techniques. 1H, 13C and 19F NMR chemical shifts of acetic acid and TFA molecules for acetic acid–water and TFA–water mixtures indicate strong relationships between a structural change of the mixtures and the acid mole fraction.390 Metalloregulators of the MerR family activate transcription upon metal binding by underwinding the operator–promoter DNA to permit open complex formation by pre-bound RNA polymerase. To observe directly MerR’s ligand-induced behaviour the authors prepared 2-fluorotyrosine-substituted MerR and found similar, minor changes in 19 F chemical shifts of tyrosine residues in the free protein exposed to Hg(II), Cd(II) or Zn(II).391 The introduction of CF3 reporter groups close to the paramagnetic center in macrocyclic lanthanide(iii) complexes allows faster acquisition of 19F magnetic resonance data, and amplifies chemical shift non-equivalence, as exemplified by the definition of ratiometric chemical shift probes for pH and, in principle, enzyme activity.392 The coordination compounds [Mg(XeF2)2][AsF6]2, [Mg(XeF2)4][AsF6]2, [Ca(XeF2)2.5][AsF6]2, [Ba(XeF2)3][AsF6]2 and [Ba(XeF2)5][AsF6]2 were characterised 104 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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by solid-state 19F and 129Xe MAS NMR spectroscopy.393 2-Nitro-a-[(2,2,2-trifluoroethoxy)methyl]-imidazole-1-ethanol (TF-MISO) was investigated as a potential noninvasive marker of tissue oxygen levels in tumors using 19F magnetic resonance spectroscopy (MRS) and 19F chemical shift imaging.394 19F MAS NMR spectra were obtained and chemical shifts measured for 37 molecules in the gas phase and adsorbed on the surfaces of six common materials: octadecyl- and octyl-functionalised chromatographic silicas, Kieselgel 100 silica, Brockmann neutral alumina, Norit activated charcoal and 3-(1-piperidino)propyl functionalised silica.395 Riboflavin synthase from Escherichia coli is a homotrimer of 23.4 kDa subunits and catalyzes the formation of one molecule each of riboflavin and 5-amino-6-ribitylamino-2, 4(1H,3H)-pyrimidinedione by the transfer of a 4-carbon moiety between two molecules of the substrate, 6,7-dimethyl-8-ribityllumazine. The mutation of the amino acid residue C48 forming part of activity cavity of the enzyme causes significant 19F NMR chemical shift modulation of trifluoromethyl derivatives of 6,7-dimethyl-8-ribityllumazine in complex with the protein, while substitution of A43 results in smaller chemical shift changes.396 The adsorption of fluorobenzene (C6H5F) and hexafluorobenzene (C6F6) onto the surface of neutral alumina was investigated by reflectance IR spectroscopy, near-IR spectroscopy and measurement of 19F NMR chemical shift values.397 Two novel series of polyfluorinated amino acids (PFAs) were designed and synthesised according to a very short and scalable synthetic sequence. The enzymic reactions were monitored by 19F NMR spectroscopy, using the 3-FABS (three fluorine atoms for biochemical screening) technique.398 1H and 19F NMR spectra were recorded for D2O solutions of sodium perfluoroheptanoate with defined concentrations up to 200 mM, in the absence and presence of b-cyclodextrin (15 mM).399 The fluorine magnetic resonance spectra, with 13C satellites at natural abundance, of oriented fluorinated molecules paradibromotetrafluorobenzene and para-diiodotetrafluorobenzene in three nematic liquid crystals were analysed. The analyses of the 19F spectra and 19F–13C satellites spectra yielded the 13C (12C) isotope effects on the 19F chemical shifts and provided evidence of the indirect contributions to some 19F–13C dipole–dipole coupling constants.400 Analysis of the 19F chemical shifts of trifluoromethylpyrazole regioisomers has shown that while chemical shift is in general a reliable predictor of regiochemical in this series, there is a narrow chemical shift range in which the two isomers overlap and the regiochemical cannot be assigned with certainty. It was examined that the usage of 19F–15N correlation spectroscopy as a method to provide a second unambiguous confirmation of regiochemical of 3- and 5-trifluoromethylpyrazole regioisomers.401 The carbon and fluorine chemical shifts of mixtures of carbon dioxide and Krytox, a carboxylic acid end-capped perfluorinated polyether used as stabilizer for the dispersion polymerisation of Me methacrylate, were studied using high-pressure, high-resolution NMR.402 19F NMR is a powerful tool for monitoring protein conformational changes and interactions; however, the inability to site-specifically introduce fluorine labels into proteins of biological interest severely limits its applicability. Using methods for genetically directing incorporation of unnatural amino acids, trifluoromethyl-L-phenylalanine (tfm-Phe) was inserted into proteins in vivo at TAG nonsense codons with high translational efficiency and fidelity. The binding of substrates, inhibitors and cofactors, as well as reactions in enzymes, were studied by selective introduction of tfm-Phe and subsequent monitoring of the 19F NMR chemical shifts.403 19F NMR was used to study topological features of the SH3 domain of Fyn tyrosine kinase for both the free protein and a complex formed with a binding peptide.404 In the Hall-Heroult process for the industrial production of aluminum, iron oxide impurities are known to lower the current efficiency as well as the metal quality. Iron can be present in the di- or trivalent form. The nature of dissolved Fe(III) and Fe(II) species and the reactions taking place in cryolitic melts were investigated by high-tempetature NMR spectroscopy. The evolution of 27Al, 23Na and 19F NMR chemical shifts were reported in the Na3AlF6–FeO and Na3AlF6–Fe2O3 systems for different iron oxide contents.405 Nucl. Magn. Reson., 2008, 37, 68–123 | 105 This journal is

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The reagent Me3Si(C6F5) was used for the preparation of a series of perfluorinated, pentafluorophenyl-substituted 3,6-dihydro-2H-1,4-oxazines (2–8), which, otherwise, would be very difficult to synthesize. The structures of the oligo(perfluoroaryl) compounds were confirmed by 19F- and 13C-NMR, MS and/or X-ray crystallography.406 The intermolecular dipole–dipole cross-relaxation was measured between 19F nuclei of sodium perfluorooctanoate in micelles and 1H nuclei of the water solvent. Both intermolecular cross-relaxation and aggregation-induced 19F chemical shift changes indicate no direct water contact to fluorines except for those closest to the head group.407 High magnetic field and high spinning frequency one- and twodimensional one-pulse MAS 19F NMR spectra of b-ZrF4 and CeF4 were recorded and reconstructed allowing the accurate determination of the 19F chemical shift tensor parameters for the seven different crystallographical fluorine sites of each compound.408 The IR and Raman spectra of 2-chloro-2,2-difluoroacetamide (ClF2CC(O)NH2) were recorded and analysed with the complement of results derived from computational chemical calculations. Thus, delocalisation effects and stabilisation energies were computed for ClF2CC(O)NH2 and a complete assignment was also proposed. 13C, 19F and 1H NMR chemical shifts and coupling constants were also measured for this substance.409 27Al and 23Na NMR satellite transition spectroscopy and 3Q MAS spectra were recorded for three compounds from the ternary NaF–CaF2–AlF3 system. High-speed 19F NMR MAS spectra were recorded and reconstructed for the same compounds, leading to the determination of 18 isotropic chemical shifts.410 The volatile fluorofullerene products of high-temp. reactions of C60 with the ternary manganese(III, IV) fluorides KMnF4, KMnF5, A2MnF6 (A+ = Li+, K+, Cs+) and K3MnF6 were monitored as a function of reaction temperature, reaction time and stoichiometric ratio by in situ Knudsen-cell mass spectrometry. Quantum chemical calculations at the DFTlevel combined with 1D and 2D 19F NMR, FTIR and FT-Raman spectroscopy indicate that the C60F8 isomer previously reported to be 1,2,3,8,9,12,15,16-C60F8 is actually 1,2,3,6,9,12,15,18-C60F8, making it the first high-temperature fluorofullerene with non-contiguous fluorine atoms.411 Norfloxacin and levofloxacin, two fluoroquinolones of different bulk, rigidity and hydrophobicity taken as model ligands, were docked to one apo and two holo crystallographical structures of bovine b-lactoglobulin (BLG) using different computational approaches. Changes in chemical shift and dynamic parameters were observed between the 19F NMR spectra of the complex and of the ligand.412 In copper(2+) complexes of tripodal ligands, the protonation state of the phenol moiety and its position (axial vs. equatorial) are easily assessed by 19F NMR.413 NMRPredict (Version 2 Enhanced, released June 2006) is a useful and straightforward stand-alone product to facilitate the prediction and interpretation of NMR spectra. Given a chemical structure, it can accurately predict 1H, 13C, 19F, 15N, 31P, 11B and 29Si chemical shifts, based on calculations or comparison to library spectra.20 A new NMR chemical shift standard and pH indicator, (difluorotrimethylsilanylmethyl)phosphonic acid (DFTMP), was described, and the utility of this reagent was demonstrated for in situ determination of pH in complex biofluids. Advantages of this reagent over previously described pH-sensitive components include (1) lack of metal binding affinity, (2) minimal disturbance of endogenous spectral regions and (3) the potential to function as a multinuclear pH indicator and chemical shift reference point for 19F, 1H and 31P nuclei.120 2-Fluoro-4-nitrophenol-b-D-galactopyranoside (OFPNPG) belongs to a novel class of NMR active molecules. (fluoroaryl-b-D-galactopyranosides), which are highly responsive to the action of b-galactosidase (b-gal). OFPNPG has a single 19 F peak (55 ppm relative to aq. sodium trifluoroacetate). Upon cleavage by b-gal, the pH sensitive aglycon 2-fluoro-4-nitrophenol (OFPNP) was observed at a chemical shift of 59 to 61 ppm. The chemical shift response is sufficient to observe b-gal activity using chemical shift imaging (CSI).414 The adsorption isotherms of sodium perfluorooctanoate and sodium decyl sulfate and their 1:1 mixture on g-alumina were recorded by depletion-type experiments with 1H and 19F 106 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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NMR spectroscopy as the detection tool. The 19F chemical shift of adsorbed perfluorooctanoate suggests that, for saturated surfaces, the two sorts of adsorbed surfactants form molecularly mixed surface aggregates.415 19F NMR spectra of two neutral, organic-soluble helical peptide octamers, each labeled at its N terminus with either 4-fluorobenzamide or 4-trifluoromethylbenzamide, in solvents with widely varying dielectric constants were observed.416 1H-decoupled 19F NMR was used to monitor the highly regioselective oxidation of a fluorine-tagged thia-fatty acid derivative by castor stearoyl-ACP D9 desaturase. The major enzymic product, after reductive work-up, was identified as 9-fluoro-1-nonanol.417 Human manganese superoxide dismutase (MnSOD) is a homotetramer of 22 kDa subunits, a dimer of dimers containing dimeric and tetrameric interfaces. It was studied that conformational mobility at these interfaces by measuring amide hydrogen/deuterium (H/D) exchange kinetics and 19F NMR spectra, both being excellent methods for analysing local environments.418 19F NMR chemical shifts were calculated to study the F- environment in double-four-ring (D4R)-containing Si/Ge-zeolites.419 A series of 19 p-substituted aromatic trifluorovinyl ether compounds were prepared from versatile intermediate p-Br–C6H4–O–CF:CF2 and underwent thermal radical mediated cyclodimerisation to new difunctional compounds containing the 1, 2disubstituted perfluorocyclobutyl (PFCB) linkage. 19F NMR spectra confirmed that p-substitution affects the trifluorovinyl ether group chemical shifts.420 The model mixed surfactant system of sodium perfluorooctanoate and sodium decyl sulfate was carefully reexamined by a combination of NMR methods. Over a wide range of sample concentration, detailed 19F and 1H chemical shift data in combination with self-diffusion coefficients for the perfluorooctanoate and decyl sulfate ions were collected.421 The performance for nuclear magnetic constant calculations for a selective set of density functional methods (B3LYP, PBE0, BLYP, PBEPBE, OLYP and OPBE) was studied. The testing set includes the 13C, 15N, 17O and 19F magnetic shieldings and chemical shifts of 23 molecules with 64 comparisons altogether.372 The effective 19F NMR chemical shift of 3-fluorobenzoic acid as in situ probe of the acidity of extensively frozen electrolyte solutions was reported.422 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.423 For the 1st 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.424 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) was presented.425 Gene therapy has emerged as a promising strategy for treatment of various diseases, but there is a pressing need for the development of non-invasive reporter techniques based on appropriate molecules and imaging modalities to assay gene expression. The design, synthesis and evaluation of novel enhanced reporter molecules, which reveal lacZ gene expression: trifluoromethylated aryl b-D-galactopyranosides were reported. 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.426 It was previously demonstrated that 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 now it was reported that 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.427 19F 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.428 THF solutions of the cationic chiral 1,3-diphenylallyl bidentate phosphine complexes Nucl. Magn. Reson., 2008, 37, 68–123 | 107 This journal is

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[Pd(Z3-PhCHCHCHPh)(Duphos)](CF3SO3), Duphos = 1,2-Bis-[(2R,5R)-2,5-dimethylphospholanoenzene] and [Pd(Z3-PhCHCHCHPh)(P,S)]BF4, P,S = [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.429 It was shown that using a minicoil is feasible for solid-state 19F and 1H NMR experiments that has short pulse widths, good RF homogeneity and excellent signal-to-noise for small samples while using low power amplifiers typical to liquid-state NMR.430 The orientation dependence of the chemical shift of a single crystal of 5-fluoroindole-3-acetic acid was determined, and the 19F chemical shift based on the orientation of the fluorine in the crystal was predicted. 2.17.2 Chlorine (35,37Cl) (I = 3/2, 3/2). Interaction of dissolved aqueous species with natural organic matter (NOM) is thought to be important in sequestering some species and enhancing the transport of others, but little is known about these interactions on a mol. scale. This paper describes a combined experimental 133Cs and 35 Cl NMR and computational mol. dynamics (MD) modeling study of the interaction of Cs+ and Cl with Suwannee River NOM.431 Addition of sparingly solvent Aliquat-336 (Me tri-n-octylammonium chloride) to cetyltrimethylammonium mesylate (CTAOMs) in two-fold molar excess generates comicelles, as shown by changes in 1H and 35Cl NMR spectra, and conformational changes in Aliquat allow it to enter the comicelles.432 A series of alkaline earth chloride hydrates has been studied by solid-state 35,37Cl NMR spectroscopy in order to characterize the chlorine EFG and chemical shift tensors and to relate these observables to the structure around the chloride ions.433 A thorough review of solid-state 35,37Cl, 79,81Br and 127I NMR data was presented. Isotropic chemical shifts, quadrupolar coupling constants and other available information on the magnitude and orientation of the chemical shift and EFG tensors for chlorine, bromine and iodine in diverse chemical compounds was tabulated from over 200 references.434 The results of a detailed systematic solid-state chlorine NMR study of several hydrochloride salts of amino acids implicated in chloride ion transport channel selectivity were reported. 35Cl and 37Cl NMR spectra were obtained for stationary and/or MAS 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, 435 L-valine HCl, L-phenylalanine HCl and glycine HCl. 2.18 Group 18 (3He,

129,131

Xe)

2.18.1 Helium ( He) (I = 1/2). The density functional calculations of 3He NMR chemical shifts in a series of experimentally known endohedral helium fullerenes, Hen@Cmq (n = 1, 2; m = 60, 70, 76, 78; q = 0, 6-), including for the first time anionic and di-helium species were studied.436 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.437 3

2.18.2 Xenon (129,131Xe) (I = 1/2, 3/2). The coordination compounds [Mg(XeF2)2][AsF6]2, [Mg(XeF2)4][AsF6]2, [Ca(XeF2)2.5][AsF6]2, [Ba(XeF2)3][AsF6]2 and [Ba(XeF2)5][AsF6]2 were characterised by solid-state 19F and 129Xe MAS NMR spectroscopy.175 The combination of 2D 1H–13C and 1H–29Si solid state NMR, hyperpolarised 129Xe NMR, synchrotron X-ray diffraction, together with adsorption measurements of vapors and gases for environmental and energetic relevance, was used to investigate the structure and the properties of periodic mesoporous hybrid p-phenylenesilica endowed with crystalline order in the walls.438 The interaction of xenon with copper/6-hydroxydopa (2,4,5-trihydroxyphenethylamine) 108 | Nucl. Magn. Reson., 2008, 37, 68–123 This journal is

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quinone (TPQ) amine oxidases from the plant pulses lentil (Lens esculenta) and pea (Pisum sativum) (seedlings), the perennial Mediterranean shrub Euphorbia characias (latex), and the mammals cattle (serum) and pigs (kidney), were investigated by NMR and optical spectroscopy of the acquire solutions of the enzymes. 129Xe chemical shift provided evidence of xenon binding to one or more cavities of all these enzymes, and optical spectroscopy showed that under 10 atm of xenon gas, and in the absence of a substrate, the plant enzyme cofactor (TPQ), is converted into its reduced semiquinolamine radical.439 This study revealed a linear correlation between the nanometer-scale oil droplet sizes established using small angle X-ray scatterings (SAXS) and the 129Xe NMR chemical shift in an oil-in-water ternary microemulsion system comprising pentaethylene glycol mono-n-dodecyl ether, n-decane and deuterium oxide.440 Hyperpolarised 129Xe NMR spectroscopy was used to investigate the interaction of xenon with four different zinc metal-organic frameworks, IRMOF-1, -7, -8 and -10. Each of the frameworks has a cubic cage of varying size, depending on the organic linker molecules. The 129Xe NMR chemical shifts are influenced by both the cage dimensions and the distribution of xenon within the framework.441 The inclusion complex formation of 4-sulfothiacalix[4]arene sodium salt (STCAS) and Xe was investigated by using hyperpolarised 129Xe NMR spectroscopy.442 15N NMR relaxation and 129Xe NMR chemical shift measurements offer complementary information to study weak protein-protein interactions. 129Xe NMR chemical shifts become selective reporters of one particular oligomer in the presence of arginine and glutamic acid, indicating that a specific Xe binding site is created in the oligomerisation process. It was suggested that the multiple effects of arginine and glutamic acid are related to their effective excluded volume that favors specific protein association and the destabilisation of partially unfolded forms that preferentially interact with xenon and are responsible for nonspecific protein aggregation.443 Xenon is an inert gas with a very large electron environment that makes it sensitive to any interaction. In the case of 129Xe isotope (spin 1/2), the resulting electronic perturbation is directly transmitted to the nucleus and, therefore, affects the NMR chemical shift. Some applications of this technique in both fundamental and applied research in the field of microporous and mesoporous solids was reported.444 Zinc and cadmium hexacyanocobaltates (III) were prepared, and their porous networks were explored using 129Xe spectroscopy.445 The pore environments of isoreticular metal-organic frameworks (IRMOF) were studied using hyperpolarised 129Xe NMR spectroscopy.446 Results of the 1st solid-state 131Xe NMR study of xenon-containing compounds were presented. The two NMR-active isotopes of xenon, 129Xe (I = 1/2) and 131Xe (I = 3/2), were exploited to characterize the xenon magnetic shielding and quadrupolar interactions for two sodium perxenate salts, Na4XeO6 xH2O (x = 0, 2), at an applied magnetic field strength of 11.75 T.447 A method was presented for detecting multiple xenon atoms in cavities of solid-state inclusion compounds using 129Xe double quantum NMR spectroscopy.448 The longitudinal nuclear relaxation rates of 129Xe in Xe–N2 mixtures at densities o0.5 amagats in a magnetic field of 8.0 T were measured. Intrinsic spin relaxation in this regime is principally due to fluctuations in the intramolecular spin-rotation (SR) and chem.-shift-anisotropy (CSA) interactions, mediated by the formation of 129Xe–Xe persistent dimers.449 The local structure and xenon adsorption behaviour of a metalorganic framework system [M(II)2(bza)4(pyz)]n (bza and pyz = benzoate and pyrazine, M = Rh (1a) and Cu (1b)) were investigated by using single-crystal Xray diffraction, xenon adsorption isotherm and 129Xe NMR measurements.450 Cryptophane cages serve as host molecules to a Xe atom. Functionalisation of cryptophane-A has permitted the development of Xe as a biosensor. Synthetic routes used to prepare cryptophanes result in racemic mixtures of the chiral cages. In the preparation of a tethered cryptophane-A cage for biosensor applications, some achiral and chiral substituents such as left-handed amino acids were used. When the substituent is achiral, the NMR signal of the Xe atom in the functionalised cage in solution is a single isotropic peak, since the Xe shielding tensor components in the R Nucl. Magn. Reson., 2008, 37, 68–123 | 109 This journal is

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and L cages differ by no more than the signs of the off-diagonal elements.451 The behaviour of nematic liquid crystal (LC) Merck Phase 4 confined to controlled pore glass (CPG) materials was studied using 129Xe NMR spectroscopy of xenon gas dissolved in the LC.452 NMR spectroscopy was applied to study the monolayer adsorption of 129Xe on a single crystal substrate. The inherently low sensitivity of NMR was overcome by using highly nuclear spin polarised 129Xe that was produced by optical pumping.453 Xenon-129 biosensors offer an attractive alternative to conventional MRI contrast agents due to the chemical shift sensitivity and large nuclear magnetic signal of hyperpolarised 129Xe. It was reported that the first enzyme-responsive 129Xe NMR biosensor.454 A novel method was presented for determining xenon partitioning between a gas phase and a liquid phase. An experimental setup which permits the simultaneous measurement of the 129Xe chemical shift in both the gas and the liquid phases, i.e., under the same experimental conditions, was designed.455 Pressure (0–10 MPa) and local density dependence of 129 Xe NMR chemical shift of xenon in various microporous materials was investigated using an in situ high-pressure probe.456 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 solvents.457 The 129Xe NMR line shapes of xenon adsorbed in the channels of the ()-[Co(en)3]Cl3 ionic crystal were calculated by grand canonical Monte Carlo (GCMC) simulations. The results of our GCMC simulations illustrate their utility in predicting 129Xe NMR chemical shifts in systems containing a transition metal.458 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.459 For the first time, the intermolecular hyperfine tensor at a 129 Xe nucleus close to an O2 molecule was calculated for various configurations. The quality of this quantum mechanical calculation was tested against the experimental measured density and temperature-dependent chemical shifts of 129Xe in the limit of zero mole fraction of Xe in O2 gas.460 129Xe NMR spectroscopy of xenon gas adsorbed on carbon replicas of Y zeolite was carried out at room temperature.461 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 0.71.1 nm was studied using in situ high-pressure 129Xe NMR.462 129Xe NMR spectroscopywas applied for direct observation of Xe confined in the porous Vycor glass.463

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Theoretical aspects of spin–spin couplings Hiroyuki Fukui DOI: 10.1039/b617061g

1

Introduction

Recently, almost all of theoretical calculations of indirect nuclear spin–spin coupling constants have been carried out using the density functional theory. Ab initio calculations are scarce. Now, one of the largest problems in theoretical calculations of spin–spin coupling constants is the determination of appropriate density functionals and basis sets to be employed. The aim of this review is to provide readers with information about important works made in the field of theoretical aspects of spin–spin couplings which appeared from June 2006 to May 2007.

2 Parity-violating effects on the indirect nuclear spin–spin coupling constants of chiral molecules Energy differences between two enantiomers of chiral molecules caused by the parity-violating (PV) electroweak neutral current have been studied theoretically for 20 years.1–6 Parity-violating effects on nuclear magnetic resonance (NMR) spectral parameters,7 that is, nuclear magnetic shielding and indirect nuclear spin–spin coupling, have also gained interest over the years.8–13 Weijo et al.14 examined the quantum chemical calculation results of the PV contributions to the NMR spectral parameters from a methodological point of view. They investigated relativistic effects, electron correlation effects, basis-set effects, and the effects of nuclear charge distribution on the PV contribution to the nuclear magnetic shielding and indirect nuclear spin–spin coupling constants for three chiral molecules, H2O2, H2S2, and H2Se2. The relativistic calculations are all based on the Dirac equation HDcD = EcD

(4.1)

where HD is the four-component Dirac Hamiltonian. We introduce the electroweak neutral-current interaction between an electron and all nuclei into HD using the parity-violating four-component Hamiltonian ~ c h~pv as a perturbation. Here, ~ a is the well-known 4 4 Dirac matrix vector. Then, the Dirac Hamiltonian HD is written as 2 3 !PV ! ! V cs ðp þ h Þ 5: ð4:2Þ HD ¼ 4 !PV ! ! V 2c2 cs ðp þ h Þ Here, atomic units, i.e., h = 1, e = 1, me (rest mass of electron) = 1, 4pe0 (e0 is the permittivity of vacuum) = 1, and c (speed of light in vacuum) = 137.035 989 5 are used. The parity-violating operator h~pv is given as X! !PV ! GF a0 ! h ðr Þ ¼ pffiffiffi ð1 4 sin2 yw Þ I K rK ðr Þ; ð4:3Þ 2 K where the index K runs over all nuclei. GF = 2.22254 1014 a.u. is the Fermi coupling constant, sin2 yw = 0.2319 is the Weinberg parameter, and a0 = 1/c is the fine structure constant. ~ I k and rK are the nuclear spin operator and normalized nuclear charge density of nucleus K, respectively. In eqn (4.2), V is the nuclear 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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attraction potential and ~ p is the momentum of the electron. ~ s is the 2 2 Pauli’s spin matrix vector. The wave function of the Dirac equation cD has four components and is called the four-component spinor. The upper two components are called the large components and the lower two components are called the small components. We write cD with the large two-component spinor jL and the small two-component spinor jS as follows. jL cD ¼ : ð4:4Þ jS Then, the Dirac equation is separated into two equations consisting of jL and jS. That is, VjL + c~ s (~ p + h~PV) js = EjL, ~PV

c~ s (~ p+h

2

) jL + (V 2c ) jS= EjS,

(4.5) (4.6)

We eliminate jS from eqns (4.5) and (4.6) and obtain the equation including jL only. The equation for jL is given by " # 1 ! ! !PV E V 1 ! ! !PV s ðp þ h Þ jL ¼ EjL : ð4:7Þ V þ s ðp þ h Þ 1 þ 2 2c2 At the nonrelativistic limit, the speed of light is infinite. The eqn (4.7) becomes " # 1 ! ! !PV 2 ð4:8Þ V þ fs ðp þ h Þg jL ¼ EjL : 2 Using the relations of sx2 = sy2 = sz2 = 1, sxsy = sysx = isz, sysz = sz sy = isx, and szsx = sx sz = isy, eqn (4.8) is written as 1 1 ! !PV !PV ! HjL ¼ V þ p2 þ fp h þ h p g 2 2 ð4:9Þ 1 ! ! !PV !PV ! þ is fp h þ h pg jL ¼ EjL : 2 Here, 1/2(h~pv)2 term was omitted. The two-component electronic Hamiltonian H for jL in eqn (4.9) is expanded in terms of the nuclear spin operator component IK,g (g A x,y,z). X X PVð1Þ 1 PVð2Þ ðhK;g þ hK;g ÞIK;g ; H ¼ p2 þ V þ 2 g K

ð4:10Þ

GF a0 ! ¼ pffiffiffi ð1 4 sin2 yw Þ½irg ; dðr K Þþ 2 2

ð4:11Þ

X GF a0 ! ¼ i pffiffiffi ð1 4 sin2 yw Þ eabg sa ½irb ; dðr K Þ : 2 ab

ð4:12Þ

where PVð1Þ

hK;g and PVð2Þ

hK;g

r) was replaced by d(~ rK). In the above expression, [A,B] = AB BA and Here, rK(~ eabg is the Levi-Civita symbol. We used the relation ~ s = 1/2 ~ s. hK,gPV(1) and hK,gPV(2) are used to evaluate the leading-order PV contributions to the isotropic nuclear magnetic shielding constant and the indirect nuclear spin–spin coupling constant at the nonrelativistic scheme. In the four-component relativistic scheme, the perturbation Hamiltonian is expanded as Nucl. Magn. Reson., 2008, 37, 124–144 | 125 This journal is

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!

!PV

ca h

XX XX GF ! ¼ pffiffiffi ð1 4 sin2 yw Þ ag rK ðr ÞIK;g ¼ hPV4 K;g IK;g ; 2 g g K K

ð4:13Þ

where ag (g A x,y,z) are the 4 4 Dirac matrices. The PV contributions to the nuclear magnetic shielding tensor and the indirect nuclear spin–spin coupling tensor were evaluated in the formalism of response theory.15,16 The nonrelativistic leadingorder PV correction to the indirect spin–spin coupling tensor component JKL,gd is obtained from a combination of the paramagnetic spin–orbit (PSO) interaction operator 2 3 hPSO L,d = a0 gL lL,d/rL

(4.14)

hK,gPV(1).

In eqn (4.14), gL is the magnetogyric ratio of nucleus L and lL,d = and i(~ rL r)d. The PV contribution to the JKL,gd due to the PSO and PV(1) interactions is computed using a zero-frequency linear response function as h i PVð1Þ PVð1Þ PSO PV ¼ hhhK;g ; hPSO ð4:15Þ JKL;gd L;d iio¼0 þ hhhL;d ; hK;g iio ¼ 0 =2p: The four-component PV correction to the JKL,gd is given by h ! ! PV4 3 ¼ a0 hhhPV4 JKL;gd K;g ; gL ða r L Þd rL iio¼0 i ! ! 3 =2p: þhhhPV4 ; g ða r Þ r ii K K L;d g K o¼0

ð4:16Þ

The PV contributions to the 1JXH, 2JXH, 3JHH, and 1JXX coupling constants in H2X2 (X = 17O, 33S, and 77Se) molecules were calculated using the Hartree-Fock (HF), coupled-cluster (CC), and density-functional theory (DFT) methods. It was shown that the PV correction to the coupling constants is of the order of n Hz. The cc results for PV contributions differ significantly from the HF and DFT data. The effects of electron correlation were very large. Relativistic effects were not so large. However, it was shown that the nuclear charge distribution model is very important for the study of the PV contribution to spin–spin couplings.

3

Relativistic calculation of spin–spin couplings

129

Xe NMR spectroscopy is being developed intensively nowadays,17–19 and an interest in theoretical calculations of NMR shielding and spin–spin coupling constants of xenon is increasing.20–26 Ab initio calculation of NMR parameters of 129 Xe is an interesting and challenging task, since for this nucleus relativistic effects play an important role. Antusˇ ek et al.27 performed nonrelativistic HF and relativistic Dirac-Hartree-Fock (DHF) calculations of the NMR shielding and spin–spin coupling constants of xenon fluorides XeF2, XeF4, and XeF6. Xenon compounds are an interesting group of chemical compounds, and NMR spectroscopy played an important role in their structural investigation.21,22,28,29 Xenon fluorides were among the first xenon compounds to be discovered but they are still in the center of experimental and theoretical studies of NMR parameters of xenon compounds. However, almost all of theoretical calculations for spin–spin coupling constants of xenon fluorides were performed using the zeroth-order regular approximation (ZORA) density functional theory (DFT).22,23,26 The study of Antusˇ ek et al. was the first four-component calculation of the spin–spin coupling constants of xenon fluorides. They computed the 1J(129Xe, 19F) and 2J(19F, 19F) spin–spin coupling constants and compared the obtained values with the available ZORA-DFT results23 and the experimental data.21 The DHF values of 1J(129Xe, 19F) in XeF2 and XeF4 calculated with their largest basis sets were remarkably close to the experiment. The sign is not determined experimentally but all the theoretical calculation results indicated that the 1J(129Xe, 19F) coupling constants will be negative. In contrast to XeF2 and XeF4, the calculated 1J(129Xe, 19F) coupling 126 | Nucl. Magn. Reson., 2008, 37, 124–144 This journal is

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constant in XeF6 (Oh) was in complete disagreement with experiment. Their theoretical value by DHF was 3691.2 Hz while the experimental value is 325 Hz and 331.7 Hz.28 According to recent sophisticated ab initio studies,30,31 the XeF6 molecule can have either a trigonally distorted (C3v) or a regular octahedral structure (Oh). Theoretical studies are not conclusive, since the structure of XeF6 molecule is controlled by a balance of several competing effects. The experimental evidence, based on electron diffraction and photoelectron studies, points to the C3v structure rather than the Oh one,32–35 but this is likely to change with the molecular environment. Antusˇ ek et al. suggested that the large difference from the experimental value of the computed 1J(129Xe, 19F) constant of XeF6 (Oh) may originate from the following reasons; (1) DHF does not account for electron correlation, and the DHF calculations of the spin–spin coupling constants may be plagued by the socalled triplet instability and (2) the coexistence of Oh and C3v forms of XeF6 affects the coupling constant. They were not able to compute spin–spin coupling constants for the C3v structure of XeF6. It was shown that relativity contributes at least 1000 Hz to the total 1J(129Xe, 19F) coupling constants for all the molecules under study. The relativistic effects on 2J(19F, 19F) were much smaller than on 1J(129Xe, 19F). The 2 19 J( F, 19F) coupling constants are experimentally unobservable, but the theoretical calculations showed that there is a large difference between 2J(19F, 19F)cis and 2 19 J( F, 19F)trans. Almost all of measurements for isotropic indirect nuclear spin–spin coupling constants, Jiso, have been performed for couplings between spin-1/2 nuclei. Measurements for spin-pairs consisting of spin-1/2 and quadrupolar nuclei are rare. This is generally due to the rapid relaxation of quadrupolar nuclei in solution, which results in the collapse of splittings due to Jiso in the NMR spectra of the spin-1/2 nuclei. In the solid state, however, the relaxation times of quadrupolar nuclei are generally several orders of magnitude longer than those in solution and thus the NMR spectrum of solid provides a means to measure Jiso values involving quadrupolar nuclei. Willans et al.36 studied one-bond nuclear spin–spin couplings between spin-1/2 group-14 nuclei and quadrupolar 35/37Cl nuclei in triphenyl group-14 chlorides, Ph3XCl (X = C, Si, Ge, Sn, and Pb). The NMR spectrum of a spin-1/2 nucleus J-coupled to a quadrupolar nucleus in the solid state is complicated by direct-dipolar coupling between the two nuclei.37–40 Quadrupolar nuclei are not exclusively quantized by the applied magnetic field but also by the electric field gradient (EFG) at the quadrupolar nucleus. As a result, magic-angle spinning (MAS) will not completely average the dipolar interaction between the spin-1/2 nuclei and the quadrupolar nuclei and a signal broadening due to the residual direct-dipolar coupling remains. For the system studied, the spin-pair of interest, X–Cl, lies on an approximate C3-axis and it is therefore reasonable to assume that the indirect spin–spin coupling tensor Jˆ is axially symmetric. The isotropic indirect spin–spin coupling constant, Jiso, and the anisotropy of Jˆ, DJ, are defined as Jiso = (JJ + 2J>)/3

(4.17)

DJ = JJ J>,

(4.18)

and

respectively. When we compare Jˆ’s between different spin-pairs, it is more appropriate to use the reduced spin–spin coupling tensor, Kˆ, which is defined by 4p2 ^ ^ JðA; BÞ; KðA; BÞ ¼ hgA gB

ð4:19Þ

where gA and gB are the magnetogyric ratios for the two coupled nuclei A and B. Then, Kˆ is independent of the magnetogyric rations of coupled nuclei and is expressed in units of N A2 m3 or equivalently T2 J1. Nucl. Magn. Reson., 2008, 37, 124–144 | 127 This journal is

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The other parameters than the Jˆ tensor which are required to describe the solidstate NMR spectrum of a spin-1/2 nucleus spin–spin coupled to a quadrupolar nucleus are the direct-dipolar coupling tensor Dˆ and the quadrupolar coupling constant CQ = eQVzz/h, where e is the elementary charge, Q is the nuclear quadrupole moment, and Vzz is the largest component of the EFG tensor at the nucleus. When the principal axes of Jˆ and those of Dˆ are collinear, the anisotropy of Jˆ, DJ, and the direct-dipolar coupling constant, RDD, are inherently linked to the effective direct-dipolar coupling constant, Reff, as Reff = RDD DJ/3

(4.20)

RDD(A,B) = (m0/4p)(h/2p)gA gB/hrAB3i

(4.21)

where RDD is given by

hr3ABi

is the motional average of the cubic Here, m0 is the permeability of vacuum and distance between two coupled nuclei A and B. The anisotropy DJ can be determined from an experimental value of Reff and a calculated value of RDD. Willans et al. determined experimentally 1Jiso and D1J values for X-35/37Cl spinpairs, where X is a spin-1/2 nucleus from group-14 (13C, 29Si, 117/119Sn), in triphenylmethyl, triphenylsilyl, and triphenyltin chlorides. The sign of 1Kiso for all spin-pairs was negative and the magnitude of 1Kiso increased as one moves down group-14. Similar to 1Kiso, all the experimental D1K values for the spin-pairs were of the same sign, positive, and the magnitudes increased down the group. Willans et al. performed the nonrelativistic and relativistic calculations of 1K and D1K values for the X–Cl spin-pairs in Ph3XCl, where X = C, Si, Ge, Sn, and Pb. They used the ZORA-DFT method for the relativistic calculation. The calculation reproduced the negative sign of 1Kiso. It was shown that the Fermi-contact (FC) mechanism dominates the 1Kiso(X, Cl)s. The relativistic effects on 1Kiso were not so large except the Pb–Cl spin-pair. For the Pb–Cl spin-pair, the relativistic effects were considerable. The sign and magnitude of the calculated D1K values were in agreement with available experimental values (D1K(C, Cl), D1K(Si, Cl), D1K(Sn, Cl)). It was shown that the SD(spin–diplor) + (FC SD) term is dominant for the D1K(X, Cl) values. The relativistic effects were not so large except the D1K(Pb, Cl). For Ph3PbCl, relativistic effects were extremely large.

4

Theoretical calculation of spin–spin couplings

4.1 Choice of exchange-correlation functional Helgaker et al.41 computed the NMR shieldings and indirect nuclear spin–spin coupling constants of o-benzyne (Scheme 1), using DFT and coupled-cluster singlesand -doubles (CCSD) theory methods. Because of its special structure and biradical character, the calculation of the NMR parameters for o-benzyne is difficult, the results depending critically on the choice of exchange-correlation functional and on the reference geometry. Since o-benzyne was found as an unstable intermediate in nucleophilic aromatic substitution reactions,42 much effort has been made to characterize this highly reactive and short-lived molecule. Warmuth43 obtained

Scheme 1


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experimentally the NMR parameters for o-benzyne, using a technique of guest incarceration inside a molecular container to stabilize o-benzyne in solution. In general, Helgaker et al. found that the DFT results become significantly more reliable when calculated at the optimized geometry, using the same functional for the geometry optimization and the calculation of NMR parameters. At the optimized geometry, the triplet excitation energy becomes large, indicating that the geometry optimization moves the molecule away from the nearby triplet instability. Comparing the performance of many different exchange-correlation functionals at the optimized geometries, they found that the best results (in comparison with CCSD results) are obtained with the Keal-Tozer’s KT1 and KT2 functionals44 for the shielding constants and by the Perdew-Burke-Ernzerhof (PBE) functional45 for the indirect spin–spin coupling constants. Numbering the carbon atoms clockwise, beginning with the triply bonded carbon atoms, C1RC2, they obtained 3.3, 61, and 51 ppm for the C1, C3, and C4 carbon shieldings, respectively, compared with the experimental values of 3.7, 60, and 48 ppm. For the spin–spin coupling constants, they found the performance of the single-reference PBE method similar to the performance of the single-reference CCSD method for o-benzyne having a weak biradical character. They obtained 209, 49, 75, and 71 Hz for 1J(C1, C2), 1 J(C3, C4), 1J(C2, C3), and 1J(C4, C5), respectively, compared with the experimental values of 178, 51, 76, and 71 Hz. Clearly, the calculated 1J(C1, C2) was too large. They concluded that the large discrepancy of the calculated 1J(C1, C2) value with the experiment arises from the effects of incarceration inside a molecular container used in the experiment. Because incarceration may affect the geometry of o-benzyne, it will also affect the geometry sensitive coupling across the triple bond. A critical decision to be made in DFT calculations of indirect nuclear spin–spin coupling constants (SSCCs) is the choice of exchange-correlation functional. In a recent study, Maximoff et al.46 calculated 96 one-bond 1JCH couplings using 20 exchange-correlation functionals of varying levels of sophistication, from the local density approximation (LDA) to generalized gradient approximations (GGAs), hybrid GGAs, and meta-GGAs. They found that the PBE functional45 performs well, significantly outperforming the popular Becke three-parameter Lee-Yang-Parr (B3LYP) hybrid functional. Keal et al.47 assessed various exchange-correlation functionals using two groups of SSCCs. The first group, denoted A, comprises the 96 one-bond 1JCH SSCCs in the 72 molecules considered by Maximoff et al.,46 involving 22 aromatic, 28 sp3, 34 sp2, and 12 sp C atoms. The second group, denoted B, comprises 1JHF, 1JCO, 1JNN, 1JOH, 1JCN, 2JHH, 3JHH, 4JHH, 5JHH, 1JNH, 2JNH, 1 JCC, 2JCC, 3JCC, 1JCH, 2JCH, 3JCH, and 4JCH SSCCs in the 11 molecules of ref. 48. PBE showed a notable improvement over B3LYP for the group A, which is consistent with the observations of Maximoff et al. However, PBE was considerably less accurate than B3LYP for couplings involving N, O, and F atoms in the simple non-hydrocarbon molecules HF, CO, N2, H2O, HCN, and NH3 in the group B. By contrast, the B97-249 and B97-350 semi-empirical functionals provided good, consistent quality couplings for all atoms in the two groups A and B. 4.2 Basis set dependence of coupling constants Deng et al.51 presented a general and systematic scheme of basis set improvement in NMR SSCC calculation. The basis set used to compute the FC term in the DFT scheme was derived by uncontracting the original basis and then adding tighter s functions. The added tighter s functions had even-tempered exponents starting from the tightest s function exponent in the original basis set. For hydrogen and first row atoms, a ratio of 3 for successive exponents was used while for second row atoms, a ratio of 2 was used. Four tighter s functions were added for hydrogen and two tighter s functions added for first and second row atoms. It was suggested that adding tighter d functions is rather unnecessary because of marginal improvements. Tighter p functions had virtually no effects on the FC term. The three original basis Nucl. Magn. Reson., 2008, 37, 124–144 | 129 This journal is

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sets of aug-cc-pVTZ, aug-cc-pVDZ, and 6-311+G(d,p) were tested. The uTZ-w basis set which was derived from the original aug-cc-pVTZ basis by uncontracting and augmenting by the tighter s functions was close to the basis set limit at moderate cost. Even the uDZ-w basis set, derived from aug-cc-pVDZ, was a much better choice than the unmodified or uncontracted aug-cc-pVTZ basis set. The non-contact terms, i.e., spin–dipolar (SD), paramagnetic spin–orbit (PSO), and diamagnetic spin–orbit (DSO) contributions were calculated using an unmodified original contracted basis set. Jensen52 proposed a sequence of pc J–n basis sets, optimized for DFT calculations of spin–spin coupling constants. Jensen et al. had previously proposed a series of polarization–consistent basis sets, pc–n, optimized specifically for density functional method calculating molecular properties.53–58 The number n in the notation pc–n indicates the level of polarization functions included in the basis set pc–n, beyond the free atomic system; that is, the unpolarized set pc–0 consists of s functions only for hydrogen atom and s and p functions only for first and second row atoms, pc–1 includes p functions as the polarization functions for hydrogen and d polarization functions for first and second row atoms, and so forth. The polarization functions included in pc–4 are p, d, f, and g type functions for hydrogen and d, f, g, and h type functions for first and second row atoms. The pcJ–n basis sets, newly proposed by Jensen, are augmented from pc–n sets by adding tight s, p, d, and f functions for improving the basis set convergence for calculating SSCCs with DFT methods. The analysis showed that tight s functions are required for the FC term, tight p functions are necessary for the PSO contribution, while tight p, d, and f functions are required to converge the SD contribution. Addition of tight functions is necessary for improving the quality of the wave function near the nuclear position. However, good representation of the excited states needed in the response wave function part demands the high quality of basis functions in the region far from the nucleus. Jensen also investigated the effect of diffuse functions using the aug-pc J–n basis sets. The effect of diffuse functions was system-dependent; that is, some molecules were sensitive to augmentation with diffuse functions, while the effect for the other systems was very marginal. The pc J–1 basis set provided results within B5% of the limiting value, and it was suggested that only in special cases it is necessary to go beyond the pcJ–2 basis set in practical calculations. It was concluded that the pcJ1 and pcJ2 basis sets should be efficient basis sets for calculating SSCCs. 4.3

77

Se–13C and

17

O–11B spin–spin coupling constants

Wrackmeyer et al.59 studied 1J(77Se, 13C) experimentally and computationally for various organoselenium compounds. Organoselenium compounds are important reagents in organic synthesis,60–66 and they play an increasingly important role as ligands in organometallic chemistry.67–70 The advent of highly efficient NMR spectrometers enables one to measure 77Se–13C SSCCs nJ(77Se, 13C) at natural avandance of the isotopes from 13C NMR spectra even for fairly dilute solutions within reasonable time. Although a negative sign of nJ(77Se, 13C) is likely for n = 1, independent of the bonding situation in organoselenium compounds,71–73 the signs for n Z 2 are still unknown. The recent improvement in calculating various SSCCs by DFT methods is promising for DFT calculations of nJ(77Se, 13C).74–85 Wrackmeyer et al.59 calculated 1J(77Se, 13C) in numerous selenium carbon compounds with largely different Se–C bonds using DFT methods at the B3LYP/6-311+G(d,p) level of theory. The calculated results revealed a satisfactory agreement with experimental values for 1J(77Se, 13C). Although the FC term was dominant for 1J(77Se, 13C), both the SD and PSO terms contributed significantly to the one-bond 77Se–13C coupling constants. Wrackmeyer and Tok86 calculated 1J(17O, 11B) coupling constants using DFT. Since both 11B and 17O are quadrupole nuclei, it is therefore difficult to measure 1J(17O, 11B) coupling. It proved possible to obtain experimental data of 1 17 J( O, 11B) (22 and 18 Hz) by measurement of 17O NMR spectra at high 130 | Nucl. Magn. Reson., 2008, 37, 124–144 This journal is

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temperature (120 1C and 160 1C). The magnitude of experimental coupling constants was in reasonable agreement with the calculated data. In the case of the diboroxane, it was shown that the B–O–B angle is close to 1801 than to 1401. 4.4 The effects of structural motions For several decades, the phosphorus pentafluoride molecule (PF5) has been the subject of intensive research from an experimental and theoretical point view. This typical fluxional molecule exhibits a rapid internal conversion of axial and equatorial fluorine atoms in the D3h trigonal bipyramid. Despite the fact that the axial P–F bond length is found different from the equatorial one,87–92 19F NMR spectroscopy exhibits the same chemical shift for five fluorine atoms89,93–95 and only one 1J(31P, 19 F) coupling constant (929 Hz),86,93,95 even at low temperature (76 K). The Berry pseudorotation mechanism (Scheme 2)97,98 is commonly invoked to explain the 19F NMR spectrum of PF5. Raynaud et al.99 presented a theoretical investigation of the 19 F NMR spectrum of PF5 in the framework of DFT. They employed a conventional static approach and an ab initio molecular dynamic (MD) approach. The static approach showed a relatively good agreement with previously reported values. In order to explain the experimentally observed NMR equivalence of all fluorine atoms, molecular dynamic simulations of all the five 19F nuclear magnetic shielding constants, sF’s, and the five 1J(31P, 19F) SSCCs in PF5 molecule were performed at 298 K and 1000 K. The NMR parameters of sF and 1J(31P, 19F) were calculated for 2000 molecular structures per one trajectory, i.e., for total 10 000 structures of five trajectories. All trajectories at 298 K were characterized by geometrical fluctuations around the D3h equilibrium geometry and no Berry pseudorotation mechanism was observed. However, the dynamical analysis procedure performed at 1000 K showed that several Berry pseudorotation events D3h - C4v - D3h take place during a simulation time of 10 ps, depending on the initial conditions of each trajectory. The evolution of the shielding and coupling averages as a function of the number of structures was calculated for all fluorine atoms. All the five averaged 1J(P, F) coupling constants almost converged towards the same mean value (1103.73 13.67 Hz) at 1000 K. Woodford and Harbison100 investigated effects of zero-point and thermal vibrational averaging on nuclear magnetic shieldings and spin–spin coupling constants of 1 0 -imidazolyl-2 0 -deoxy-b-ribofuranose (IDR), a model compound for purine nucleosides, at the B3LYP/6-311++G(2d,p) level of theory. The potential energy curve of vibration was fitted to a fourth-order polynomial of the normal coordinate for each normal mode. Next, for each mode, the nuclear magnetic shielding constants and spin–spin coupling constants are calculated at each displaced geometry and fitted to a second-order polynomial of the normal coordinate. The overall thermal average for the magnetic shieldings and coupling constants was taken by summing the electronic contribution, the zero-point vibrational (ZPV) contribution, and the thermal excitation contribution. The calculation showed that 1 J(C, H) and 1J(C, C) tend to increase but 1J(C, N) tends to decrease upon ZPV correction. The thermal excitation correction of SSCCs was negligible. The calculated coupling data were in good agreement with the experimental DNA coupling data.

Scheme 2


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4.5 Nuclear spin–spin coupling via electronic current induced by nuclear magnetic dipole moment A widely accepted rule of thumb for the interpretation of NMR SSCCs dominated by the FC mechanism is provided by the Dirac-van Vleck (DVV) vector model.101 Due to the DVV model, the induced electron spin polarization is mediated along the chemical bonds with alternating signs of spin density. Therefore, if the number of bonds separating the coupled nuclei along a given path is odd (even), a positive (negative) coupling constant will be produced. For example, 1J and 3J will be positive and 2J will be negative if the DVV model is correct. However, no prediction of the coupling magnitude is provided by such a simple rule, although experience shows that the FC contribution decays exponentially with the distance between the coupled nuclei.102 In general, it is known that the DVV vector model accounts correctly for nJ(13C, 13C) constants in saturated hydrocarbons, and the magnitude of 1 J(C, C) is proportional to the percent of s character of the bonding hybrid orbitals.103–106 Accordingly, the magnitude of 1J(C, C) diminishes strongly on increasing of the p character of the hybrids.107 Another issue in the DVV model concerns the role of multipath transmission for spin–spin coupling in saturated carbocycles. An unusual example of negative 1J(C, C) coupling constants between bridgehead carbons of bicyclobutane moiety in polycycloalkanes was suggested to be referred to the multipath coupling mechanism.108 Soncini and Lazzeretti109 investigated the 1J(C, C) couplings in three saturated hydrocarbons: ethane, cyclopropane, and bicyclobutane, using the technique of electronic current density.110–112 The reduced spin–spin coupling tensor component between two nuclei I and J is ~I generated by presented as the interaction energy between the vector potential A the magnetic dipole moment of nucleus I and the electronic current density J~J induced by the magnetic dipole moment of nucleus J. The interaction energy ~I and J~J. The electronic current density is computed from density is the product of A the wave function of the system quantum mechanically. It was shown that the significant variation in magnitude and sign of 1J(C, C) in characteristic these three hydrocarbons can be related to different topological features of the magnetic field due to the electronic current density. 1J(C, C) did not appear to be significantly affected by the multipath coupling processes usually suggested in the literature. 4.6 Effects of aggregation on 1J(Li, C) couplings Alkyl lithium compounds are widely used reagents in organic synthesis.113,114 Their structure in solution exerts a dramatic influence on reactivity and selectivity, especially due to aggregation and solvation processes.115–121 In order to study aggregation and solvation processes, the 1J(Li, C) coupling constant is a useful parameter because it can be directly related to the degree of aggregation of the organolithium compounds. Indeed Bauer, Winchester, and Schleyer have proposed an empirical formula (BWS rule) 1

J(Li, C)/Hz = (17 2)/n,

(4.22) 122

where n is the number of carbon atoms directly linked to the lithium atom. This rule has been used for determining the degree of aggregation from experimental data of the Li–C coupling constants. de la Lande et al.123 performed the application of Car-Parrinello (CP) molecular dynamics (MD) to sample conformations of various models of organolithium aggregates. Taking thermal effects into account is essential when we are dealing with the conformational effects of associative/dissociative reaction processes. The influence of such effects on the 1J(Li, C) coupling constants was investigated at a constant temperature (300 K). In order to observe the effects of aggregation, the 1J(Li, C) coupling constants for the monomer, dimer, and tetramer of MeLi were computed with DFT for each snapshot at a time period smaller than 50 fs, in which the MD trajectory started from the optimized structure. It was shown 132 | Nucl. Magn. Reson., 2008, 37, 124–144 This journal is

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that the averaged (for snapshots) values and the static (at the optimized geometry) values for the computed 1J(Li, C) coupling constants are quite close each other. The agreement with the empirical BWS rule was not good. In order to study the effects of solvation, the impact of thermal fluctuations on the 1J(Li, C) coupling constants was evaluated by means of a CP molecular dynamics simulation on the solvated species CH3Li(OMe2)3. It appeared that decoordination of one of the three solvent Me2O molecules in CH3Li(OMe2)3 occurs within 4 ps. It was shown that the 1J(Li, Cl) value is significantly affected by thermal effects. For the trisolvated case of the simulation (n = 3), 1J(Li, C) was 1 Hz larger (19.8 Hz) than the static value (18.8 Hz). This increase of 1J(Li, C) was due to the partial decoordination of solvating dimethyl ether molecule. 4.7 Coupling constants in water clusters and hydrogen-bonded complexes NMR spectra are a very valuable source of information on the molecular structure due to the sensitivity of measured parameters to the changes in the conformation of a molecule and to the influence of the environment. In particular, NMR spectroscopy plays an important role in detection and characterization of hydrogen bonds in complexes and clusters. Cybulski et al.124 carried out the calculations of the nuclear spin–spin coupling constants in small water clusters (H2O)n, n = 26, 12, and 17, using DFT and second-order polarization propagator approximation (SOPPA) methods. The indirect nuclear spin–spin coupling constants in water are less widely investigated than the shielding constants. The calculations of the nuclear magnetic shielding constants were done for water dimmer125–128 and for small water clusters,129–135 while the spin–spin coupling constants had been calculated only for water dimer.136–138 The calculation by Cybulski et al. was the first computational study of SSCCs for water clusters larger than water dimer. The structures of water monomer and water clusters with n = 2–6 and n = 12 were optimized by means of the frozencore second-order Møller-Plesset (MP2) perturbation theory with the aug-cc-pVDZ basis set.139,140 Only the structure of the largest water cluster with n = 17 was optimized using DFT with the B3LYP functional141,142 and with the 6-31G* basis set. The change in the SSCC caused by complexation DJ was defined as a difference between the value of coupling in cluster and the corresponding value in water monomer, that is, DJ = JclusterJmonomer. The complexation-induced changes of 1 J(O, H) were within a range from 0.3 to 13.1 Hz. The experimently estimated gasto liquid shift of water 1J(O, H) coupling, that is, (JliquidJgas) value of 1J(O, H) coupling was about 10 Hz, which is comparable with the range of the calculated complexation-induced changes in 1J(O,H). The rigid water cluster model seemed to be sufficient to reproduce properly the sign and magnitude of the gas-to-liquid shift of 1J(O, H). It was shown that the average intermolecular 1hJ(O,H) coupling constant decays slowly with the H O distance in the cyclic clusters n = 2–6. The average 2hJ(O, O) coupling decreased exponentially with the O O separation for the cyclic clusters n = 2–6. The sign of D2J(H, H) depended on the types of complexation. In recent years, new NMR spectroscopic parameters, intermolecular indirect nuclear spin–spin coupling constants, have been measured, providing a unique, direct experimental evidence for the existence of hydrogen bonds.143–155 Hydrogen bonds are represented by the notation X–H Y, where X refers to a conventional proton donor atom (such as O, N) and Y a proton acceptor atom (an electronegative atom with a lone pair of electrons). The dihydrogen bond (DHB) complexes, Y–H H–X, consist of two parts in which the Y–H molecule acts as a proton acceptor (Y being less electronegative than H) and the H–X molecule acts as a proton donor (X being more electronegative than H). In DHB interactions, typical proton-acceptor elements that create partially negatively charged hydrogens, are the transition or alkali metals, or boron. Cybulski et al.156 investigated DHB complexes of BeH2 H2, BeH2 C2H2, BeH2 CH4, BeH2 HCN, BeH2 HNC, and Nucl. Magn. Reson., 2008, 37, 124–144 | 133 This journal is

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BeH2 NH4+, all of which have BeH2 as the proton acceptor molecule. They calculated and partitioned the intermolecular interaction energy using the symmetryadapted perturbation theory (SAPT) method.157 The intermolecular interaction energy was represented as the sum of the first- and second-order polarization and exchange contributions. Each term in the total interaction energy was computed as a function of the H H intermolecular distance. The distance dependence varied for different terms. The slowest, linearly decreasing term was the dispersion energy, which became most significant for the weak van der Waals complexes. The electrostatic and exchange energy terms decreased exponentially with the H H distance. The strongest distance dependence appeared for the induction energy term. Thus, for shorter H H distances, the dominance of the induction and exchange interaction terms indicates a partial covalency of the hydrogen bond. It was shown that the values of the intermolecular 2hJ(X, H) and 3hJ(Be, X) coupling constants correlate well with the interaction energy and with the intermolecular distance. Afonin et al.158 previously demonstrated that the one-bond 1J(N, H) coupling constant can serve as a useful probe for understanding the nature of hydrogen bonding in pyrrole derivatives. It was shown that on the one hand, an increase in the one-bond 1J(N, H) coupling constant is observed if the hydrogen bonding is predominantly an electrostatic interaction;158–161 on the other, a decrease of the 1J(N, H) constant takes place when the hydrogen bond is mainly covalent.162–164,148,161 Using these criteria, one can elucidate the mechanism of hydrogen bonding by means of the 1J(N, H) couplings in various molecules. Afonin et al.165 presented a report on 19F–1H, 19F–13C, and 19F–15N coupling constants in the presence of hydrogen bonding in the trifluoroacetyl pyrroles. It was shown that the pyridine ring rotation in 2-trifluoroacetyl-5-(2’-pyridyl)-pyrrole operates as a quantum switch controlling the spin information transfer between the 19F and 15N nuclei. 4.8 Structural studies of alkaloids using spin–spin coupling constants Galasso et al.166 studied quinolizidine alkaloids by measuring and calculating NMR parameters. Quinolizidine alkaloids are polycyclic molecules renowned for their toxicological and pharmaceutical activity.167–169 Galasso et al. calculated a representative set of NMR chemical shifts and nuclear spin–spin coupling constants by means of DFT formalism. The theoretically evaluated values compared favourably with experimental data. The measured chemical shifts and spin–spin coupling constants were correctly accounted for by the DFT results. Galasso et al.170 also investigated the molecular and electronic structure of matrine-type alkaloids using NMR measurements and DFT calculations. Bisquinolizidine alkaloids of matrine type represent an important class of natural products that exhibit a wide range of pharmacological activity.171–176 Theoretically evaluated 2J(1H, 1H), 3J(1H, 1H), and 1J(13C, 1H) coupling constants of bridgehead and lactamic protons well reproduced experimental values. 4.9 Coupling constants of phosphonium cations Jimeno et al.177 previously published a paper about computed and experimental coupling constants in X(CH3)nH(4n) moieties where X = 13C and 15+N, and n = 0– 4. In the paper, some discrepancies between computed and experimental coupling constants were referred to the formation of hydrogen bonds. Jimeno et al.178 extended their research to phosphonium cations [P(CH3)nH(4n)]+ where n = 0–4. They found that the experimental 1J(31P, 1H) values decrease when the number of H atoms surrounding the P+ atom increases. The 1J(P, H) coupling decreases by about 13 Hz per H atom. They suggested that this decrease of 1J(P, H) could be related to hydrogen bonding between the salt and the solvent. Taking hydrogen bonding with the solvent into account improved the agreement between computed and 134 | Nucl. Magn. Reson., 2008, 37, 124–144 This journal is

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experimental coupling constants. However, significant deviation from experimental values was observed for calculated 1J(31P, 13C) coupling constants.

4.10 29

n

J(29Si,

13

C) coupling constants

13

Si– C couplings over two or more bonds, though occasionally exploited for line assignments,179–181 are scarce and scattered throughout the literature.182–189 Sy´kora et al.190 presented the first systematic study of 29Si–13C couplings in silylated phenols, 4-X–C6H4–O–SiR1R2R3, where R1, R2, R3 = H, CH3, C(CH3)3, and C6H5 and X = NO2, CF3, Cl, F, H, CH3, and CH3O. The substituent X is in the para position for –O–SiR1R2R3 on the benzene ring. It was shown that the found low sensitivity of all the nJ(29Si,13C) (n = 2, 3, 4, and 5) couplings to substitution both on the silicon atom and in the para position on the benzene ring, together with the sharp distinction between magnitudes of 2J and 3J on one side (1.4–2.7 Hz) and 4 J and 5J (0.2–0.7 Hz) on the other, makes these coupling constants very suitable for solving line assignment problems in 13C and 29Si NMR spectra of the compounds containing such fragments. The experimental results were in reasonable agreement with theoretical calculations. The two-bond and three-bond couplings, which were of similar magnitudes, were of opposite signs. If the signs of these geminal and vicinal 29Si–13C couplings could be determined experimentally , they would greatly facilitate the line assignment.

4.11

13

C–13C coupling constants

Carbon–carbon spin–spin coupling constants which are closely related to electron distribution in the most important bond in organic chemistry belong to crucial physicochemical data. Recently, they have drawn considerable attention because modern NMR techniques have made it possible to measure nJ(13C, 13C) couplings precisely and within a reasonable period of time for small samples at natural abundance of carbon-13. Biedrzycka et al.191 presented quantum mechanical DFT calculations of aromatic carbon–carbon couplings in benzene, nitrosobenzene, p-substituted nitrosobenzenes, and o-nitrosotoluene. It was found that the simplest relationship possible, J(C, C)exptl = J(C, C)calcd., can be obtained over a broad range of the couplings, starting from 2.5 Hz for 2J(C, C) in benzene, through the range of about +8 to +10 Hz for 3J(C, C)’s in benzene and nitrosobenzene, up to the span of +55 to +70 Hz for 1J(C, C)’s in p-substituted nitrosobenzenes, for a total of 34 couplings. Attractive potential applications of the combination of experiment and theory for aromatic 1J(C, C) couplings were indicated in assessing syn-anti equilibria.

4.12 Coupling constants of five-membered heterocycles There have been numerous 1H and 13C NMR studies of five-membered heterocycles both in general192–195 and specific systems including pyrroles,196–198 furans,199–201 thiophenes,202–204 pyrazoles,205–212 imidazoles,206,213 isoxazoles, and thiazoles.214–216 In spite of these works, NMR data of nitro-substituted five-membered heterocycles are rather limited.217–223 Katritzky et al.224 carried out DFT calculations of proton and carbon chemical shifts and coupling constants for 25 nitro-substituted fivemembered heterocycles. The assigned NMR data (chemical shifts and coupling constants) for all compounds were found to be in good agreement with theoretical calculations. It was shown that the magnitudes of nJ(13C, 1H) coupling constants can be utilized for unambiguous differentiation between regioisomers of nitro-substituted five-membered heterocycles. Nucl. Magn. Reson., 2008, 37, 124–144 | 135 This journal is

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4.13 Coupling constants in biological molecules It is well known that many factors such as ionising radiation, free radicals, oxygen, etc. can induce DNA damage leading to production of a number of oxidized purines. These products are known to cause mutations and cellular damage. On the other hand, these compounds are also produced by catabolism of nucleotides and nucleosides, and occur in urine and other body fluids.225–230 The abnormal levels of the products of purine and pyrimidine metabolism provide the basis for the diagnosis of various inherited metabolic defects. Dybiec and Gryff-Keller231 studied isoguanine (Scheme 3), also called 2-hydroxyadenine, and 8-oxoadenine (Scheme 4) using 1H and 13C NMR techniques and DFT calculations. These compounds are considered to be the candidates for the biomarkers of some metabolic diseases.230 The 1H and 13 C NMR spectra of these investigated compounds in DMSO-d6 solutions provided information on their tautomeric forms and the mobility of their exchangeable protons. The 1J(15N, 1H) coupling constants obtained from the NMR spectra were in good agreement with the values calculated theoretically.

Scheme 3

Scheme 4

5

Spin–spin couplings and conformations

Hu and Snyder232 investigated the conformation of an organocopper compound (Scheme 5). The cyano group can be either cis or trans to the ring methine carbon. Additionally, the Cu–methine carbon bond can rotate to direct the Cu–CN bond syn or anti to the methine hydrogen. The 2J(13C, 13C) coupling constants were calculated for the optimized geometries using the DFT method with the B3LYP density functional. The calculated coupling constants were in good to excellent agreement with experimentally assigned couplings with respect to both absolute and relative magnitudes. Aril- and hetarylazo-pyrrole dyes have been attracting much attention over the past decade owing to their rapidly increasing role in the design of advanced polymer materials and chemical optoelectronic devices possessing conducting and non–linear optical properties.233–240 Rusakov et al.241 performed conformational study of 2-phenylazo-1-vinylpyrrole (in Scheme 6, R1 = R2 = H) and 2-(4-bromophenyl)136 | Nucl. Magn. Reson., 2008, 37, 124–144 This journal is

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Scheme 5

Scheme 6

azo-5-methyl-1-vinylpyrrole (in Scheme 6, R1 = CH3, R2 = Br) on the basis of the experimental measurements and SOPPA level calculations of their 13C–13C and 13 C–1H spin–spin coupling constants. In liquid phase, both compounds were found to adopt predominant s-trans conformation with considerable population (ca 30%) of the second s-cis-trans conformation in 2-(4-bromophenyl)azo-5-methyl-1-vinylpyrrole. Vogt et al.242 carried out a computational and spectroscopic study of 2-hydroxymutilin to obtain assignments for the configuration of the carbon at the 2-position. Gas-phase structural models for (R)- and (S)-2-hydroxymutilin were optimized using DFT calculations. The optimized structural models were subsequently used to predict NMR chemical shifts and coupling constants using the hybrid B3LYP density functional. Calculated 1H–1H and 1H–13C coupling constants were compared to experimental values. The theoretically predicted coupling constants were within 10% of their experimental values of an allowed level for relative stereochemical assignments of the isomers. It was shown that the DFT calculation of coupling constants gives more useful information than empirical parametrizations. The tetracycline class of antibiotics243 has achieved importance beyond their therapeutic use as broad-spectrum antibiotics because many tetracyclines are inducers of the tetracycline repressor protein (TetR), which has been used as an experimental switch to regulate gene expression.244,245 Improving this functionality to be able to switch several genes with different inducers would be experimentally invaluable. In order to achieve this goal, it is necessary to understand the induction process of the TetR protein,246 for which knowledge of the exact structures (conformations and tautomeric forms) of important tetracyclines in solution is essential. Othersen et al.247 calculated NMR parameters of chemical shifts and coupling constants using DFT and compared them with experimental NMR data to assign conformational equilibria for the systems of tetracycline and 5a,6-anhydrotetracycline in water at pH 1.7, and 10 and 5a,6-anyhydrotetracycline in chloroform and tetracycline in methanol. The results suggested that tetracycline always prefers the extended conformation but that 5a,6-anhydrotetracycline exists in water as a mixture of the two conformers and in chloroform exclusively in the Nucl. Magn. Reson., 2008, 37, 124–144 | 137 This journal is

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Scheme 7

twisted conformation. The conformational equilibria were also shown to be pH dependent. Functional diversity of nucleic acids (NAs) makes their structural study crucial for deeper understanding of biological processes. It has become evident that functional variability of NAs is a reflection of their structural diversity.248 A variety of advanced NMR techniques can be used for determination of structures of NAs. Sychrovsky´ et al.249 calculated spin–spin coupling constants between 31P, 13C, and 1 H, and related them to the backbone torsion angles of NAs. It was shown that SSCCs can offer accurate and reliable structural information. Coupling constants were calculated in 16 representative conformations of an NA fragment, two principal double-helical DNAs (A-DNA and B-DNA), A-RNA, and 13 other RNA conformations. The predicted coupling constants correlated reliably with available experimental data from the literature. Burgueno-Tapia et al.250 calculated the minimum energy conformation of five eremophilanolides using DFT at the B3LYP/6-31G* level. Comparison of the experimental 1H–1H coupling constant values of the five eremophilanolides with those generated employing a generalized Karplus-type relationship and dihedral angles which were extracted from the DFT calculation and from their crystal structures showed good agreement. Eremophilanolides are sesquiterpenoids, which exhibit antioxidant251 and antimicrobial252 activities. Hricovı´ ni253 analyzed structures of three most stable conformers of methyl 2-O-sulfo-a-L-iduronate monosodium salt using DFT at the B3LYP/6-311++G** level. Time-averaged DFT calculation of 1H–1H and 1H–13C coupling constants agreed with the experimental data and indicated that only two chair forms contribute to the conformational equilibrium of methyl 2-O-sulfo-a-L-iduronate monosodium salt. The presence of charged groups considerably affected the magnitudes of coupling constants. Reyes-Trejo et al.254 investigated the formation of (—)-[4.3.3] propellane 4 from (—)-14-hydroxymodhephene. The reaction proceeds through a Wagner-Meerwein rearrangement via C3–C4 bond-shift to form a stable intermediate, dimethylcyclohexadienyl cation A, which undergoes deprotonation to give a compound (–)-4 (Scheme 7). Reyes-Trejo et al. carried out the conformational analysis of (–)-4 using DFT energy calculations at the B3LYP/6-31G* level. The weighted time-average vicinal coupling constants were obtained using the equation: 3Jobs = nA 3JA + nB 3 JB, where nA and nB are the mole fractions of the two lowest energy conformers of (4)-4. The vicinal coupling constants 3JA and 3JB for the two lowest energy conformers were evaluated by means of the generalized Karplus-type relationship.255,256 Comparison with experimental data provided a 56:44 ratio for the boat-chair and boat-boat conformers, which was consistent with the theoretical energy calculations.

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Applications of spin–spin coupling Krystyna Kamien´ska-Trela*a and Jacek Wo´jcik*b DOI: 10.1039/b617222a

1. Introduction The material in this chapter covers the period from 1 June 2006 to 31 May 2007. 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 IUPAC,2 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–115In, 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 historical review on the scientific life of Martin Karplus, a man who played the pivotal role in NMR couplings has been given by Karplus himself.3 Recent advances in theoretical calculations of indirect spin–spin couplings have been reviewed by Krivdin and Contreras.4 An application of vicinal–vicinal spin–spin couplings to study the stereochemistry of eight- and nine-membered medium ring cis-cycloalkenes has been discussed by Glaser et al.5 In a short review Fukushi6 has presented several 2D methods to measure 2,3JHC values, which are useful for stereochemical assignment in detailed structure analysis of natural products. The use of NMR spectroscopy to study tautomerism has been reviewed by Claramunt et al.7 A review on applications of chemical shifts d(29Si) and one-, two- and three-bond couplings, JSiX, has been written by Wrackmeyer.8 Also couplings across more than three bonds are briefly discussed. 1 JPCu couplings have been collected by Szyman´ska9 in her review on application of the Cu and P NMR to characterize Cu(I) complexes with P-donor ligands. An application of multinuclear NMR spectroscopy to study the action mechanism of Pt anticancer drugs has been reviewed by Berners-Price et al.,10 and a critical review on the progress in Pt NMR over the last 25 years has been written by Still et al.11 who collected, among others, Pt couplings with various nuclei. The work on computational NMR recently carried out at the University of Padova has been reviewed by Bagno and Saielli.12 It covers the calculations of chemical shifts and spin–spin couplings for a variety of compounds and interactions including hydrogen bonding and van der Waals CH-p forces. Overviews on NMR techniques used for measurement of scalar and dipolar couplings applied in solution structure elucidation of very large proteins and RNAs have been written by Tzakos et al.13 and by Foster and co-workers.14 Al-Hashimi and co-workers15 have reviewed the use of dipolar couplings in characterisation of structural plasticity and dynamics of RNA. a

Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, [01-224], Warszawa, Poland. E-mail: [email protected]; Fax: (48-22) 632-6681; Tel: (48-22) 343 2221 b Institute of Biochemistry and Biophysics, Polish Academy of Sciences, ul. Pawin´skiego 5a, [02-106], Warszawa, Poland. E-mail: [email protected]; Fax: (48-22) 658-4683; Tel: (48-22) 658-4683


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Mittag and Forman-Kay16 have described the use of RDCs among other data in atomic level characterisation of disordered proteins.

2. New methods A satellite-selective 1D-TOCSY experiment that measures the sign and the magnitude of nJHC in small organic molecules in a fast, sensitive and accurate way has been described by Parella and co-workers.17 Modifications of time-shared HSQC-like experiments originally developed by Griesienger and co-workers have been proposed by Nolis et al.18 They have shown that simultaneous acquisition of 1H,13C and 1H,15N HSQC-TOCSY and HSQMBC experiments can afford experimental sensitivity enhancements of 20–40% with respect to the separate acquisition of individual 13C or 15N data. Among others, these modifications allow simultaneous measurements of long-range proton–carbon and proton–nitrogen couplings. The knowledge of the true value of long-range couplings, which are usually rather small, is crucial for elucidation of torsion angle restraints in molecules of biological importance such as proteins and carbohydrates. It has been shown by Clore and coworkers19 that cross-correlated relaxation may alter the apparent J-coupling through interference with passive longitudal relaxation, thereby counteracting the self-decoupling effect and bringing the measured J-coupling closer to its true value. A 13C-detected IPAP-INADEQUATE experiment for simultaneous measurement of one-bond and long-range scalar or residual dipolar couplings has been designed by Jin and Uhrı´ n.20 The method gives accurate values of one-bond and long-range couplings and is illustrated by the measurement of interglycosidic 3JCCOC couplings in a disaccharide molecule providing important information on the conformation of the glycosidic linkage. A 1D pulse sequence which converts double quantum coherence of y phase with optimal efficiency, relying on single transition selection has been designed by Ramesh and Chandrakumar.21 Its application to 1D 13C INADEQAUATE has been demonstrated by the use of a sucrose sample. 13 C direct detected methods that improve detectability of scalar and residual dipolar couplings have been proposed by Bertini and co-workers22 and by Piccoli and co-workers.23 The first group22 has applied protonless ReCACO and ReCON experiments for measurement of RDCs in the case when the proton spectrum of protein contains broad signals. The second group23 has used the COCO-TOCSY experiment to measure 3JC 0 C 0 couplings in proteins that provide the first dihedral angle constraints obtained with protonless approach. A Java applet that can be executed from a web page has been built by Evans et al.24 It allows prediction of NOEs and NMR couplings, as well as easy visualization of three-dimensional molecular structures. Two-dimensional25 and three-dimensional through-bond homonuclear/heteronuclear26 correlation experiments have been designed by Deschamps and co-workers for quadrupolar nuclei in solid-state NMR. The experiments can be realized 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. Both experiments have been tested and demonstrated on AlPO4-14 samples where they allowed a detailed characterization of the Al–O–P–O–Al motives. These experiments open new possibilities for the characterization of complex chemical bond networks in perfectly crystalline, disordered or amorphous solids. It has been shown by Fayon et al.27 that simple pulse sequences based on scalar J-couplings and previously developed for liquid-state NMR, can be applied under MAS condition to obtain homonuclear triple-quantum-single-quantum correlation spectra of crystalline and disordered solids. The feasibility of these experiments in coupled spin-1/2 systems has been demonstrated for fully 13C-labelled L-alanine and 146 | Nucl. Magn. Reson., 2008, 37, 145–179 This journal is

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Pb3PO4O13 crystalline compounds, used as models for three-spin and four-spin systems, respectively. The experiments which select only the magnetization from I nuclei bound to S nuclei have been designed by Iuga et al.28 These methods can be applied for samples where the spin I and the spin S have spectra spread over a large frequency range. In order to show their feasibility the spectra of (XeF+)(AsF6) have been recorded, where the 19F isotropic chemical shift is ca. 278 ppm and 1JFXe is 6900 Hz. A new analytical method based on the 2D HSQC NMR sequence, which can be applied for quantitative structural determination of complicated polymers, has been designed by Zhang and Gellerstedt.29 It takes into account the influence of T1 and T2 relaxations, off-resonance effects, and homo- and heteronuclear couplings. The authors claim that the methodology developed by them can be widely applied in areas where a quantitative analysis of structurally complicated polymers is necessary. The first two-dimensional correlation NMR (COSY) spectra have been obtained by Robinson et al.30 at ultra low frequencies using the Earth’s magnetic field. The spectra were measured for trifluoroethanol and para-difluorobenzene. A method for the automatic multiplet analysis in weakly coupled systems which relies on a multistep procedure forming the automatic J algorithm has been proposed by Prost et al.31 To show its usefulness the spectrum of sucrose and a multiplet of the methine proton of 3-bromo-2-methyl-1-propanol have been simulated. The P.E.HSQC experiment for simultaneous, sign-sensitive measurement of DHH and DHC couplings in small and medium sized molecules has been introduced by Luy and co-workers.32 Kobzar and Luy33 have compared three experimental schemes used for measuring nDHC couplings at natural abundance. The aim of their work was the technical analysis and improvement of those sequences. Several new methods have been introduced for accurate and precise measurement of scalar and dipolar spin–spin couplings in proteins. The 3D BEST-JcompHMQC2 experiment for the measurement of DHH couplings between amide protons has been introduced by Schanda et al.34 A modified version of the HACACO experiment has been presented by Bazzo and co-workers35 as a sensitive and accurate method to measure 1DHaCa dipolar couplings. 1J(15N–HN)-modulated[1H–15N]-HSQC pulse schemes aimed for accurate measurement of 1DHN couplings in deuterated and non-deuterated proteins have been reported by de Alba and Tjandra.36 Luy and co-workers37 have applied the J-evolution spectroscopy with a BIRDd,X element during J-evolution (JE-N-BIRDd,X-HSQC experiment) for accurate measurement of 1DHN couplings in small to medium sized biomolecules. New methods for extracting information concerning multiplicities of different types in a single NMR experiment have been elaborated. Szyperski and co-workers38 have presented G-matrix Fourier transform (GFT) NMR spectroscopy for mutually correlated nuclear couplings and implemented the constant-time J-GFT (6,2)D (HA–CA–CO)–N–HN experiment for simultaneous measurement of 1DHC, 1DHN, 1 DCC and 1DCN couplings in proteins. TS–1H,13C/1H,15N–HSQC–F1(and F2)-IPAP experiments have been developed by Nolis and Parella39 for simultaneous measurement of 1DHC and 1DHN couplings in 13C/15N-labelled proteins. Liu and co-workers40 have reported a new strategy, isotopomer-selective IS-TROESY, for the simultaneous assignment of backbone and side chain amides in large proteins. Ying and Bax41 have described a novel 3D constant-time HMQC-IPAP-NOESY experiment that permits measurement of 3JHOC couplings in helical RNA through the E.COSY principle. A novel S3E-19F-a,b-edited NOESY experiment for quantitation of long-range scalar JHF couplings in 5-fluoropyrimidine-substituted RNA has been developed by Hennig and co-workers.42 A quantitative adiabatic JNN HNN-COSY experiment that provides observations of hydrogen bonding interactions in oligonucleotides where donor and acceptor nitrogens are separated by up to 140 ppm has been reported by Hennig and co-workers.43 Nucl. Magn. Reson., 2008, 37, 145–179 | 147 This journal is

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The new approaches for data collection in NMR experiments are constantly being developed. The 2D HIFI HNCO experiment for measuring small 1DC 0 N couplings in proteins has been proposed by Cornilescu et al.44 In that method the approach called ‘High Resolution Iterative Frequency Identification of couplings’ is applied. Rovnyak and co-workers45 have used maximum entropy reconstruction (MaxEnt) processing for nonuniformly sampled data in 1DC 0 Ca measurements for proteins. Both approaches offer a substantial shortening of the time of NMR experiments, which is important in the case of unstable proteins. An enhanced CPMG-HSQMBC experiment has been presented by Ko¨ver and coworkers.46 The method allows accurate measurement of long-range heteronuclear couplings. Merlet and co-workers47 have demonstrated the 13C-J-resolved-BIRD and J-HSQC-BIRD experiments that make possible the visualization of enantiomers dissolved in chiral ordering solvent on the basis of the 1DHC couplings. A program for simulation of splittings in the one-dimensional 1H NMR spectra has been designed by Constantino et al.48

3. One-bond couplings to hydrogen Perera and Bartlett49 have proposed a bond-parity model that predetermines signs of the Fermi-contact contributions to the NMR couplings and demonstrated its validity by numerical calculations which have been performed for H4 and CO2. Partially deuterated samples of complexes [(C5Me5)Os(H2)H2(L)][BHF4], where L is PPh3, AsPh3 or PCy3, have been prepared by Gross and Girolami50 and H–H distances within the bound H2 ligands have been deduced from the observed 1 JHD(av) couplings. A substantial JHD of 22.0 Hz has been measured by Dutta and Jagirdar51 for the HD isotopomer of the [Ru(Z2-H H)(PP)2]–[OTf]2 complex, PP = [(C6H5CH2)2PCH2CH2P(CH2C6H5)2], which corresponds to the H–H bond distance of 1.05 A˚ and corresponds to an elongated dihydrogen ligand. The complex OsCl(NHQC(Ph)C6H4)(P-i-Pr3)2(H2) has been recently studied by Barea et al.52 who assigned to it an elongated dihydrogen structure on the basis of JHD = 6.3 Hz observed in its d1- isotopomer. However, the new low-temperature NMR results obtained by Schloerer et al.53 provide evidence that rather quantum mechanical exchange takes place in this compound. Mixtures of deuterium labelled complexes (p-XPOCOP)IrH2XDX where POCOP denotes C6H2-1,3-[OP(t-Bu)2]2 and X = MeO, Me, H, F, C6H5, 3,5-(CF3)2–C6H3, have been studied by Go¨ttkerSchnetmann et al.54 JHD of 3.8–9.0 Hz observed in the spectra of these compounds measured in toluene and pentane between 296 and 213 K suggest the presence of an elongated H2 ligand. The detection of one-bond hydrogen–boron coupling, 1JHB = 154 Hz, provided evidence of the existence of a nucleophilic, anionic organoboryl species synthesized recently by Segawa et al.55 The correct choice of exchange-correlation functional for computing NMR indirect spin–spin couplings has been the subject of studies conducted by Keal et al.;56 modifications of standard basis sets for use in spin–spin coupling calculations have been analysed by Deng et al.57 Nuclear magnetic shielding and indirect spin–spin couplings including 1JHC in gaseous and liquid cyclopropane have been measured by Makulski and Wilczek.58 The 1JHC couplings in conformationally constrained sulfoxides, bissulfoxides, sulfoxide-sulfones and sulfilimines derived from 2-benzylidene-1,3-dithiane and 2(2,2-dimethylpropylidene)-1,3-dithiolane have been measured by Wedel et al.;59 the Perlin effects have been also calculated. It has been found that the relative configuration of SQX groups (X = O, Ntos) in these compounds exerts a strong influence on the magnitude of couplings for axial and equatorial C–H bonds. An unprecedented large reverse Perlin effect (1JHaxC 4 1JHeqC) for all three methylene groups has been observed experimentally and calculated theoretically by Shainyan et al.60 in 1-(methylsulfonyl)-3,5-bis(trifluoromethylsulfonyl)-1,3,5148 | Nucl. Magn. Reson., 2008, 37, 145–179 This journal is

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triazinane and interpreted in terms of the presence at the a-position of the nitrogen atom bearing a very strong electron-withdrawing group CF3SO2, which makes it almost positively charged. The magnitudes of one-bond 1JHC and long-range ones (nJHC, n 4 1) have been applied by Katritzky et al.61 for unambiguous differentiation between regioisomers of nitro-substituted five-membered heterocycles. The increase of 1JHC occurring in [Ti(N-t-Bu)(Me3[9]aneN3)Me]+ upon formation from Ti(N-t-Bu)(Me3[9]aneN3)Me2, Me3[9]aneN3 = 1,4,7-trimethyltriazacyclononane, has been interpreted by Bolton et al.62 in terms of intrinsic global changes in carbon 2s orbital contribution to the Ti–C and C–H bonds upon cation formation; 116 Hz has been observed for the cation and 111 Hz for its methyl precursor. Theoretical and experimental studies on the molecular and electronic structures of cytosine and unsaturated keto-sparteines63 as well as matrine-type alkaloids64 have been performed by Galasso and co-workers. It has been found for both groups of compounds that hyperconjugative stereoelectronic effects on Dd(Heq/Hax) and D(1JHCeq/1JHCax) of the 4N–CO– groups are correctly accounted for by the DFT results. The plane wave periodic DFT calculations of models of the Re based olefin metathesis catalyst, [(RSiO)Re(RC-t-Bu)(QCH-t-Bu)(CH2-t-Bu)] have been performed by Solans-Monfort et al.65 The calculated low 1JHC (111 Hz) couplings for the key alkylidene group well reproduce those observed experimentally (109 Hz) for the syn isomers and are in agreement with agostic interactions suggested by other parameters. The 1JHC coupling in the anti isomer, where such interaction does not occur, is much higher (159 Hz). A comparison of the analytical data of (RSiO)Hf(CH2-t-Bu)3-SiO2 and (RSiO)Zr(CH2-t-Bu)3 complexes, which also included 1JHCa couplings, has been made by Tosin et al.66 during their studies on reactivity of tetraneopentylhafnium, Hf(CH2-t-Bu)4 with silica surfaces. A lower value of 1JHCa coupling observed for the hafnium complex has been interpreted in terms of a larger steric hindrance in the coordination sphere of the Hf metal. Disappearance of the 1JHC coupling has been used by Tanaka et al.67 as evidence that a metal-free acetylide anion is formed during the deprotonation of phenylacetylene when treated by the strong non-metallic base t-Bu-P4. Proton–carbon and proton–nitrogen couplings across one and more bonds have been computed by Jimeno et al.68 by the use of DFT with the B3LYP functional and ab initio EOM-CCSD method for the ten species in the two series of X(CH3)nH4n, where the central atom X is 13C or 15N. Overall, good agreement between the computed couplings obtained from both methods and the experimental data has been found as well as between the total EOM-CCDD couplings and the FC terms. Proton–carbon and proton–nitrogen couplings across one and more bonds have been used by Pazderski et al.69 to investigate tautomerism and protonation patterns in bis(6-purinyl) disulfide and ionic forms of 6-mercaptopurine. Effects of methyl substitution in 4-silathiane S-oxides on the stereochemistry and 1 JHC couplings have been studied by Shainyan et al.70 Almost all compounds have shown the normal Perlin effect except for 2,4,4-trimethyl-4-silathiane-S-oxide and S,S-dioxide possessing the axial SQO group and showing the reverse Perlin effect for the 3- and 5-CH2 groups. The scalar 1JHC and restored dipolar H–C dipolar couplings have been applied by Chaffee et al.71 to study chloroform@cryptophane-A and chloroform@bis-cryptophane inclusion complexes oriented in thermotropic liquid crystals. Indirect spin–spin couplings including those across one C–H bonds, experimental dipolar couplings and chemical shifts have been reported for 1,3-butadiene by Celebre et al.72 who analysed its conformation in a nematic phase. The authors confirmed the presence of a small but significant percentage of the s-cis or s-gauche conformer (ca. 1–2%) as was previously found both experimentally and theoretically for an isolated molecule. Nucl. Magn. Reson., 2008, 37, 145–179 | 149 This journal is

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The one-bond 1H–14N coupling of 54 Hz has been observed by Helm et al.73 in the spectrum of the [Cd([18]aneS4N2)](PF6)2 complex ([Cd([18]aneS4N2)] = 1,4,10,13tetrathia-7,16-diazacyclooctadecane). The coupling is absent in dry samples and is temperature dependent. This is the first example of 1H–14N coupling observed in a coordinated [18]aneS4N2 ligand. It has been demonstrated by Afonin et al.74 that the bifurcated NH N and N–H O intramolecular hydrogen bond is present in 2-trifluoroacetyl-5-(2 0 pirydyl)-pyrrole causing an increase in the absolute size of the 1JHN coupling by about 6 Hz. 1 JHN couplings have been applied by Przybylski et al.75 to study some gossypol derivatives, and by Lycˇka et al.76 to establish the structure of 1-(indazol-3-yl)-1,2dihydro-benzimidazol-2-one, the product of the reduction of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene. 1 JHN coupling has been calculated by Yan et al.77 for the prototypical model system [imidazole–(H2O)n–imidazole]+, n = 1–9, in order to gain insight into the factors regulating the proton transfer along hydrogen-bonded water chains. Effects of the relativistic treatment of parity violation contributions to the spin–spin couplings of H2O2 (1JHO, 1JOO, 2JHO, 3JHH), H2S2 (1JHS, 1JSS, 2 JHS, 3JHH) and H2Se2 (1JHSe, 1JSeSe, 2JHSe, 3JHH) have been studied by Weijo et al.78 1 JHSi couplings in SiHnCl4n (n = 0–4) dissolved in THF-d8 have been recorded by Thorshaug et al.79 as a function of temperature and the experimental data has been compared with the DFT calculated J values. It has been observed by Vyboishchikov and Nikonov80 that the magnitude of JHSi couplings in the family of the [Fe(Cp)(L)(SiMenCl3n)2H] (L = CO, PMe3; n = 0–3) complexes primarily depends on the orientation of the silyl group rather than on the number of electron-withdrawing groups at a silicon atom. Proton–phosphorous spin–spin couplings of hypophosphorous acid complexes with proton acceptors such as nitromethane, acetonitrile, acetone or pyridine have been measured by Golubev et al.81 under slow exchange conditions. The formation and strengthening of the hydrogen bond by the OH bond results in a strong shielding of the phosphorous nucleus and decrease of 1JHP coupling. The Z2-coordination of the Si-H bond to the tungsten atom takes place upon irradiation of W(CO)6 and HSiEt3 in cyclohexane-d12 solution as has been reported by G˛adek and Szyman´ska-Buzar82 who found 1JHSi of 89 Hz and 1 JHW of 35 Hz for this complex. For comparison, 1JHSi coupling in Et3SiH is of 179 Hz. Spectroscopic data including 1JHSi couplings and crystal structure has been reported by the same group of authors83 for the bis{(m-Z2-hydridodiethylsilyl)tetracarbonylmolybdenum(I)} complex, [{Mo(m-Z2-H-SiEt2)(CO)4}2]. 1 JHP couplings have been measured by Paris et al.84 for a series of Ru(II) complexes, [(p-cymene)RuCl(L)2](PF6) where L = PH2CH2Fc and PH(CH2Fc)2 (p-cymene = p-i-PrC6H4Me, Fc (ferrocenyl) = C5H5FeC5H5) and trans-[RuCl2(L4)] where L = PH2Fc, PH2CH2Fc and PH(CH2Fc)2. A significant increase of the 1 JHP value has been observed for ruthenium(II)-bound phosphine complexes compared with the free phosphines. The data obtained seem to be generally consistent with a suggestion that the increase in 1JHP approximately correlates with the Lewis acidity of the complexed metal ion and hence with the s-donor strength of the phosphine. The presence of two diastereisomeric forms has been proved by the use of the NOE effect and 1JHSn couplings in (R,S)(S,R)-[2-(4-(R)-isopropyl-2-oxazoline)-5phenyl]t-butylphenyltin and (R,S)(S,R)-[2-(4-(R)-isopropyl-2-oxazoline)-5-phenyl]tbutylmetyltin hydrides studied by Stalin´ski and co-workers.85 The 1JH119Sn couplings of 1549/1908 and 1444/1770 Hz, respectively have been observed for these two compounds. The 1JH117Sn couplings are correspondingly smaller: 1480/1823 and 1380/1692 Hz.


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4. One-bond couplings not involving hydrogen NMR spectral data including LiB coupling has been computed by Del Bene et al.86 for Li-diazaborole, (C2H4B1N2)Li, and its complexes with one H2O or LiF molecule. Additionally, solvent effects on this coupling have been analysed.87 One-bond Li–C couplings, 1JLiC of ca. 4 Hz, have been measured by Fraenkel et al.88 for three internally solvated allylic lithium compounds with different potential ligands tethered at C2: CH3OCH2CH2NCH3CH2-; 1-TMS, (CH3)2NCH2CH2NCH3CH2-; 1-TMS and ((CH3)2NCH2CH2)2NCH2-; 1-TMS. The coupling pattern observed (triplet) provided evidence that all three compounds are monomers. The 1JLiN couplings of 20 different tetra- (3.7 to 4.6 Hz), 25 tri- (4.5 to 5.7 Hz) and 4 dicoordinated lithium atoms (6.5 Hz) in chiral lithium amides and their mixed complexes have been measured by Granander et al.89 The results clearly show that the coordination number for a given lithium nucleus in a lithium amide or its mixed complex can be obtained directly from the magnitude of the 1JLiN coupling. Ab initio EOM-CCSD calculations have been carried out by Del Bene et al.90 on iminoboranes RBNH, HBNR, and RBNR, for R = H, CH3, NH2, OH, and F, to evaluate substituent effects on one- and two-bond 11B–15N, 1H–11B, and 1H–15N couplings. For comparison purposes, they have also performed calculations on corresponding isoelectronic acetylene derivatives RCRCH and RCRCR. Both 11B and 17O are quadrupole nuclei which makes the measurements of the corresponding spin–spin coupling a difficult task. Experimental 1JBO coupling values have been determined for the first time by Wrackmeyer and Tok91 for trimethoxyborane (22 Hz) and tetraethyldiboroxane (18 Hz) by the measurement of 17O NMR spectra at high temperature (1201 and 1601 C, respectively); the magnitudes of these couplings have been found to be in reasonable agreement with the DFT calculated data. The 1JBP couplings have been measured by Dornhaus et al.92 for BH3(H)PPh2, BH3(CH3)PPh2 and [(BH3)PPh2], 42, 55 and 64 Hz, respectively. Basing on these results, the authors came to the conclusion that the phosphanylborohydride ligand [BH3PPh2] possesses a higher Lewis basicity towards [BH3] than its neutral isoelectronic and isostructural congener P(CH3)Ph2. Excellent linear correlation between experimental and DFT calculated nJCC values (n = 1, 2, 3), has been found by Witanowski et al.93 in a series of disubstituted benzenes; the range of the couplings studied was from about 3 to +83 Hz. DFT and CCSD calculations of the nuclear shielding and J(CC) spin–spin couplings in o-benzyne have been performed by Helgaker et al.94 Several papers on application of carbon–carbon spin–spin couplings in structural studies have been written by Krivdin and co-workers. This included elucidation of the structure of 2,3,4,6-tetra(O-vinyl)methyl-a-D-glucopyranoside,95 conformational study of 2-arylazo-1-vinylpyrroles96 and pyrrolylpyridines,97 and configurational assignment of carbon, silicon and germanium containing propynal oximes.98 Lonepair orientation effect of an a-oxygen atom on 1JCC couplings in o-substituted phenols has been studied by Taurian et al.99 The full 1H and 13C NMR spectral characterization of a- and g-1,2,5,6,9,10hexabromocyclodecane has been reported by Arsenault et al.100 Among others, oneand two-bond carbon–carbon couplings have been measured for a-diastereoisomer. One-, two- and three-bond carbon–carbon couplings have been measured for [18,19,21,22-13C4]—labelled tautomycin, the compound synthesized by Isobe et al.101 and used as an NMR probe of protein phosphatase inhibitor. A method based on ab initio calculations and first-order perturbation theory has been developed by Woodford and Harbison102 to include thermal averaging in calculated magnetic properties, such as chemical shielding and J couplings. Using this approach chemical shielding values and J couplings including those across one C–C and H–C bonds have been calculated for 1 0 -imidazolyl-2 0 -deoxy-ribofuranose, a model compound for purine nucleosides in DNA. Nucl. Magn. Reson., 2008, 37, 145–179 | 151 This journal is

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Experimental and DFT studies on the transmission mechanisms of nJHC and nJCC, n = 1, 3, 4, have been performed by Contreras et al.103 for 1-X- and 1-X-3methylbicyclo[1.1.1]-pentanes. The existence of inverse relationship between 1JCC and carbon–carbon bond length was suggested by Unkefer et al.104 some time ago on the basis of the data obtained for derivatives of naphthalene. It has been invoked recently by White and co-workers105 to interpret the mechanism of the Alder-Rickert ethylene extrusion reaction in the structures of bicyclo[2.2.2]octadiene and bicyclo[2.2.2]octane derivatives. However, the authors have not noticed the recent works106,107 in light of which Unkefer’s suggestions that 1JCC is directly related to the CC bond length can be questioned. The 13C CPMAS spectra of oxybuprocaine hydrochloride, modification II1 measured by Harris et al.108 revealed crystallographic splittings arising from the fact that there are two molecules, with substantially different conformations, in the asymmetric unit. A 2D INADEQUATE spectrum has been used to link signals for the same independent molecule. The one-bond 1JCN couplings have been reported by Schraml and co-workers109 for the parent benzonitrile (X = H, J = 17.59 Hz) and two para derivatives (X = 4-F, J = 17.63 Hz and X = OCH3, J = 17.69 Hz). 1 JCN, 2JCN, 1JHN and JHH couplings measured by Sega et al.110 for acetylcholine in a variety of solvents remain practically constant, which indicates that there are no solvent effects on the conformational equilibrium of this compound. The C–N couplings across one, two and three bonds have been reported by Langer et al.111 for the Ni(II) complex of the Schiff base of (S)-N-(2-benzoyl-4-chlorophenyl)-1-benzylpyrrolidyne-2-carboxamide and glycine. 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. 112 to yield the magnitudes and signs of the scalar couplings, J, and total anisotropic couplings, T, between all the 1H, 19F and 13C nuclei, except for those between 13C nuclei. This also included one- and two-bond carbon–fluorine couplings, 1,2JCF. nJCF couplings (n = 1–4) have been measured by Laihia et al.113 in order to characterize ten variously substituted 1,2-diaryl-(4E)-arylidene-2-imidazolin-5-ones. 1JCF and 2JCF couplings have been reported by Iriarte et al.114 for 2-chloro-2,2-difluoroacetamide, ClF2CC(O)NH2. Good agreement has been observed between experimental and DFT calculated 1 JCSi coupling values in two exceptionally stable pentaorganosilicates studied by Couzijn et al.115 (Fig. 1); the data obtained provided useful information on the electronic structure of these compounds.

Fig. 1


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The 13C and 31P DE (direct excitation) MAS spectra of the Pd/PDMP catalyst (PDMP = polydimethylphosphazene) have been measured by Panziera et al.116 providing an interesting piece of information on the structural features of this compound. This included information on the conformation and mobility of the methyl side groups for which 1JCP coupling of 90 Hz has been determined. Experimental NMR parameters, which included 1JCFe and 1JNFe couplings, have been reported by Wrackmeyer and Herberhold117 for the tetrahedrane [Fe2(CO)6(m-SNH)] and compared with the DFT calculated data. 1 JCSe couplings have been measured and calculated by the DFT method at the B3LYP/6-311+G(d,p) level of theory by Wrackmeyer et al.118 for variously substituted 1-cyclohepta-2,4,6-trienyl-selanes, Se(C7H7)2, R–Se–C7H7 with R = Bu, t-Bu, Ph and 4-F–C6H4, and relatively good agreement has been found between the experimental and computed data. 1 JCPt, 2JCPt and 1JPPt couplings have been measured by Lind et al.119 in order to characterize two Pt(II) complexes with thiophenyl and phenyl groups in the ligands, trans-Pt(P(n-Bu)3)2(CRC–Ar)2, where Ar = –C4H2S-CRC-p-C6H4-n-C5H11 and –p-C6H4–CRC–C4H3S, and to obtain information about the electronic coupling between Pt and the alkyne ligand. The presence of the one-bond 15N–117/119Sn couplings of 112.6 and 116.3 Hz in major diastereoisomers of (R)-2-[(R,S)(S,R)-(2-iodo-t-butyl-phenylstannyl)-phenyl]4-iso-propyl-4,5-dihydro-oxazole and (R)-2-[(R,S)(S,R)-(2-bromo-t-butyl-methylstannyl)-phenyl]-4-iso-propyl-4,5-dihydro-oxazole provided evidence that the Sn–N interaction takes place in these compounds.85 Two papers on computations of one-bond spin–spin couplings in HmX-YHn molecules, where X = N, O, P, S, have been published by Del Bene and Elguero.120,121 1 JOTc coupling of 80 5 Hz has been measured by Grundler et al.122 for the fac-[(CO)3Tc(H2O)3]+ complex. 1 JFP coupling of 1045 20 Hz has been determined by Weil et al.123 for disilver(I) monofluorophosphate, Ag2PO3F, from the solid-state MAS NMR spectra, which is on the same order of magnitude as the 1JFP couplings reported earlier in the literature for other monofluorophosphates.124 1 JFS coupling of 242 Hz has been measured by Tervonen et al.125 for gaseous SF6 at 223 K and 3 atm; 1JFS about 254 Hz has been found in TLC (thermotropic liquid crystals) solution. The non-relativistic Hartree-Fock and relativistic Dirac-Hartree-Fock calculations of 1JFXe couplings have been performed by Antusˇ ek et al.126 for XeFn, n = 2, 4, 6. The calculations relatively well reproduced the experimental J values reported for the first two compounds, whereas a dramatic discrepancy between the experiment and theory has been found for XeF6; its possible causes are discussed by the authors. The first example of quadrupolar effects from 127I has been reported by Gerken et al.127 who recorded the solid-state 19F NMR spectrum of powdered, microcrystalline [N(CH3)4][IO2F2]. It showed broad lines that arise from residual dipolar coupling and result from the large quadrupole moment of the 127I nucleus. The 19 F lineshape was simulated using 1JFI = 1000 Hz and a 127I quadrupolar coupling of 5000 Hz as preliminary values. A variety of 9-phospha-10-silatryptycenes and some derivatives, such as the phosphine selenides and cis-platinum complexes, has been synthesized by Tsuji et al.128 The 1JPSe couplings have been measured for the phosphine selenides and 1JCPt couplings for the Pt complexes. The 1JPSe coupling values have been interpreted in terms of the large s-character of the lone pair orbital on the phosphorus atom. Two new phospholanes, (3aR,4aR,7aR,7bR)-4-phenylperhydrofuro-[2 0 ,3 0 :4,5]phospholo[3,2-b]furan-2,6-dione and (3aS,4aS,7aS,7bS)-4-cyclohexylperhydrofuro[2 0 ,3 0 :4,5]phospholo[3,2-b]furan-2,6-dione have been synthesized by Bilenko et al.129 and their s-donor properties have been estimated by the use of 1JPSe in the corresponding phosphine selenides. 1JPSe couplings of ca. 850 Hz have been Nucl. Magn. Reson., 2008, 37, 145–179 | 153 This journal is

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measured by Anderson et al.130 for (1-diphenylphosphanylselenido-1H-pyrrol-2ylmethylene)phenylamine, (bis-(di-iso-propyloamino)phosphanylselenido-1H-pyrrol-2-ylmethylene)phenylamine and their derivatives and used to estimate the donor characteristics/basicity of the corresponding P–N chelating N-pyrrolylphosphino-Narylaldimine ligands. The 1JPSe couplings of a series of trisarylphosphine selenides derivatised with a variety of different perfluoroalkyl groups have been measured by Adams et al.,131 which allowed the authors the direct comparison between phosphine ligands that is not possible via other spectroscopic methods. A linear correlation has been observed between 1JPSe and 1JPPt for both the cis and trans-[PtCl2L2] complexes. The 1JPSe couplings have been used by Hrib et al.132 to characterize two complexes of bidendate phosphane selenide ligands with mesitylenetellurenyl iodide, dppmSe2[Te(I)Mes]2 and dppeSe2[Te(I)Mes]2; 1JPSe of 717.7 and 711.6 Hz have been found, respectively. A reaction of RuCl2(PPh3)3 with LiNN 0 , where NN 0 = 2-[(2,6-diisopropylphenyl)imino]pyrrolide, yielded an a-pyrrolato complex, [RuCl(k2-N,N 0 133 ArNQCHC4H3N)(PPh3)2]2. Its structure shown in Fig. 2 has been established by Foucault et al.133 by the use of extensive NMR studies. 31P CP MAS NMR experiments yielded the largest 1JPRu coupling = 244 20 Hz measured so far. An inverse relationship between the 1JPRh coupling and the electronic parameter (w) of the phosphine has been observed by Tiburcio et al.134 in the mononuclear complexes with the isosteric phosphines, [RhCl(Z4-COD)(PR3)], where COD = 1,5cyclooctadiene, R = 4-(OCH3)C6H4, 4-(CH3)C6H4, C6H5, 4-FC6H4, 4-(CF3)C6H4 and 4-ClC6H4. 1 JPPt couplings have been used by Gallego et al.135 to characterize the triphenylphosphine derivatives of the [Pt(II)Br(CC5H4C6H4CHNBzI)(SMe2)] complex which contains a seven-membered cyclometalated ring. An experimental and relativistic DFT investigation of one-bond spin–spin coupling, 1JClX, where X = C, Si, Sn and Pb, has been performed by Willans et al.;136 it represents the first of this type study of spin–spin coupling involving spin-pairs containing quadrupolar nuclei. A spin–spin coupling between chlorine and selenium, 1JClSe = 110 Hz, has been measured by Demko et al.137 for Ph2SeCl2 by the use of CP MAS spectra. This seems to be the first reported coupling between these nuclei. The hexacoordinated organotin(IV) complexes [RSnCl3(cis-Ph2PCHQCHPPh2)] (R = Me, n-Bu, Ph) synthesized by Ebrahim et al.138 can adopt two configurations (I or II, see Fig. 3) but only in configuration I do the Sn and two P atoms represent an ABX type spectrum. An analysis of the low-temperature 31P NMR spectra of these compounds yielded two different 1JPSn couplings (for example 2419 and 1283 Hz for R = Me), which is consistent with structure I. Very large 1JPPt couplings between 4689 and 5233 Hz have been found by Keglevich et al.139 for a series of novel bis(dibenzo[c.e][1,2]oxaphosphorino)dichloroplatinum complexes, which confirmed the cis arrangement of the P-ligands

Fig. 2


c


Fig. 3

(or that of the chloro atoms). For the trans isomers 1JPPt couplings of ca. 3000 Hz are expected. 1 JPPt couplings, which have been determined by Bortoluzzi et al.140 for a series of square-planar bis(diphenylphosphinoethyl)phenylphosphine complexes of Pt(II) with pyridines and anilines, [Pt(L)(triphos)](ClO4), revealed dependence upon the pKa of L (L are 4-substituted pyridines or anilines). 1 JSePt and 1JTePt couplings have been determined by Risto et al.141 for a series of mononuclear arylchalcogenaloto-platinum(II) complexes: [Pt(MAr)2(dppe)] where M = Se, Te; Ar = phenyl, 2-thienyl; dppe = 1,2-bis(diphenylphosphino)ethane. The couplings helped the authors to establish the structures of the studied compounds, in particular the information that the 1JSePt couplings of the cis isomers are larger than those of the trans isomers was important.

5. Two-bond couplings to hydrogen An extensive study of the conformational/structural dependencies of the geminal proton–proton coupling, 2JHH 0 , in substituted methanes has been presented by Barfield.142 The temperature dependence of two-bond couplings between protons of the methyl group has been observed by Czerski and Szyman´ski143 in 1,4-dibromo-9methyltryptycene and invoked as a new argument that the DQR effect occurs in substituted 9-methyltryptycenes (DQR = damped quantum rotation; for the theory of this phenomenon see refs. 144–146). A 2JHH coupling of 13.8 Hz, typical of geminal coupling of diastereotopic protons, has been observed by Hahn et al.147 in the room-temperature spectra of three pincertype complexes: [2,6-bis(N-alkyl-methylenebenzimidazolin-2-ylidene)phenylene]bromopalladium (alkyl = Et, n-Pr, n-Bu). The diastereotopic behaviour of the benzylic protons in these compounds differs significantly from the behaviour of the protons for the methylene bridges in the analogous complexes with lutidine-bridged bis(benzimidazolin-2-ylidene) ligands studied earlier by the same group of authors148 where the resonances for the methylene protons appear as broad singlets at room temperature. Liu and co-workers40 have measured 2JHC 0 couplings for trans and cis protons in amide groups of the side chains in proteins. The values found range from +2.5 to +5.0 Hz and 5.0 to 2.5 Hz; respectively. The presence of all four optically isomeric conformers in hexamethylene triperoxide diamine has been detected by Harbison and co-workers.149 The isomers, which coexist at slow equilibrium on the NMR timescale at room temperature, have been characterized by the use of 1H NMR including geminal proton–proton couplings. Complete NMR analyses with full assignments of 1H and 13NMR data have been performed by Dillner and Traficante150 for both epimers of menthane-1-carboxylic acid. This also included two- and three-bond proton–proton couplings. Nucl. Magn. Reson., 2008, 37, 145–179 | 155 This journal is

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An analysis of 2,3JHH couplings has been carried out by Krawczyk et al.151 for five derivatives of creatinine yielding information on the conformation of these compounds in solution, by Krivoshey et al.152 who studied the structure of (Z)-(5R)methyl-2-(4-phenylbenzylidene)cyclohexanone as chiral component of liquid-crystalline systems and by Goodall et al.153,154 who investigated a variety of derivatives of 3-azabicyclo[3.3.1]nonane including eight new 3-azabicyclo[3.3.1]nonanes with N-(3-phenylpropyl) substitution. Tormena et al.155 who studied the stereoelectronic behaviour of 2JHH in heterocyclohexanes containing either oxygen or sulfur came to the conclusion that these couplings can be applied instead of 2JHC’s for structure elucidation of these compounds. 2JHH’s have been found to be sensitive to the occupancy of the sCH* antibonding orbital and, as the authors indicate, are much easier to measure at low temperatures than the corresponding 2JHC couplings. The method for assigning the configuration in natural products based on 2,3JHC and 3JHH couplings was proposed by Murata and co-workers156 several years ago. It has been recently applied by Hassfeld et al.157 for determination of the stereostructure of the structurally unique 24-membered myxobacterial macrolides, archazolid A and B, highly potent vacuolar-type ATPase inhibitors, by Oh et al.158 in their studies on the new cyclic depsipetides emericellamides A and B from the marine-derived fungus Emericella sp., by Iranshahi et al.159 to establish the configuration of stereocentres in a phenylpropanoid derivative, 2-epihelmanticine isolated from Ferula szowitsiana, and by Park et al.160 who analysed the relative and absolute structure of versipelostatin, a down-regulator of molecular chaperone GRP78 expression. The same approach has been applied by Matveeva et al.161 to establish the structures of the benzylidene dichlorides and a-chlorocinnamic derivatives, the products of the reaction of aromatic aldehydes with triphenylphospine and ethyl trichloroacetate or trichloroacetonitrile, correspondingly. Although J-based configuration analysis has been shown to be a powerful tool in solving stereochemical problems in acyclic structures, there are some cases when it does not give a clear solution. Such an example has been presented by Sharman162 who studied a small molecule related to reboxetine by the use of this approach. However, the study was complicated by the fact that the molecule exists in the form of several conformers and only a quantitative fitting procedure in which the couplings and NOEs from all possible conformers were used allowed a clear indication of the stereochemistry of the compound studied. 2 JHP and 2JPP couplings have been applied by Kuznetsov et al.163 to establish the structures of four isomers of RuHCl[2,6-(CH2P-(t-Bu)2)2C6H8] obtained upon heating of the starting RuH2Cl[2,6-(CH2P-(t-Bu)2)2C6H9] complex. 2 JHSn coupling of 87 3 Hz has been measured by Bagno et al.164 for the D-ribonic acid-dimethyltin(IV) complex and used in the Lockhart-Manders equation165 to obtain the value of ca. 1411 for the C–Sn–C angle, which suggests a skewed octahedral geometry around tin. 2 JHSn of 83 Hz and 1JCSn of 675 Hz observed by Bertazzi et al.166 in the Me2Sn(IV)NANA complex correspond to a C–Sn–C angle of ca. 1351 (NANA = b-N-acetyl-neuraminic acid = 5-amino-3,5-dideoxy-D-glycero-b-D-galactononulosic acid). Two-bond H–119Sn and H–117Sn couplings of ca. 110 and 40 Hz, respectively have been measured by Gholivand et al.167 for four novel organotin(IV) complexes of the formula SnCl2(CH3)2(X)2 where X = C6H5C(O)NHP(O)(NC4H8)2, C6H5C(O)NHP(O)(NC5H10)2, C6H5C(O)NHP(O)[N(CH3)(C6H11)]2 and C6H5C(O)NHP(O)[NH– C(CH3)3]2. However, the 2JHSn and 1JCSn coupling values reported in this paper are obviously erroneous; the ratio JH119Sn/JH117Sn is far from 0.9558, which corresponds to the ratio of the gyromagnetic coefficients of 119Sn and 117Sn isotopes. The same applies to JCSn couplings.


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6. Two-bond couplings not involving hydrogen Values of the 2JCN and 1JCN couplings have been used by Schwalbe and coworkers168 as the criteria for the identification of a protein in the random coil state. 2 JCN couplings have been applied by Sˇimu˚nek et al.169 to establish the regiochemistry of some azo coupled cyclic b-enaminones formed by the reaction of 3phenylamino-1H-inden-1-one with 4-methylbenzene- or benzenediazonium tetrafluoroborates. The compounds studied exist in solution as a mixture of three forms. Two- and three-bond carbon-phosphorus couplings have been measured by Stockland et al.170 for a large series of gold complexes of ethynyl-17b-hydroxyandros-4-en-3-one and related ethynyl steroids, R3P–Au–steroid; correlations between common measures of phosphine donor ability and these couplings have been made. Two- and three-bond proton–phosphorus and carbon–phosphorus couplings have been extensively applied by Gholivand and co-workers to establish the structures of some new phosporamidates,171,172 several new phosphoramidates and the corresponding cyclophosphazanes,173 novel carbacylamidophosphate derivatives,174 novel phosphorictriamide derivatives with morpholine,175 and several new 1,3,2diazaphosphorinanes.176 A dependency of these couplings on the ring size, hybridisation and substituents in new diazaphospholes and diazaphosphorinanes has also been studied by this group of authors.177 For the first time the 2JNN coupling of 2.4 Hz across HgII has been reported by Ono and co-workers,178 confirming the chemical structure of T–HgII–T pairs in a DNA duplex. Two-bond Si–Si couplings have been determined for a large series of oligosiloxanes by Kurfu¨rst and Schraml.179 The couplings are small (0–5 Hz) and their values depend on the branching or on the number of electronegative substituents on the Si–O–Si moiety. It has been shown by Emsley and co-workers180 that incorporating a z-filter results in an efficient method for measuring pure J-coupling modulations between selected pairs of nuclei in an isotopically enriched spin system. In a combination with a selective double-quantum (DQ) filter it allows the measurement of 2JSiOSi couplings in isotopically enriched solids as has been demonstrated by the use of a 50% 29Si enriched sample of surfactant-templated layered silicate lacking long-range 3D crystallinity. J coupling values of ca. 15 Hz have been obtained and their accuracy was sufficient enough to distinguish between different 29Si–O–29Si pairs, shedding insight on the local structure of the silicate framework. It has been shown by Coelho et al.181 that the Si–P MAS-J-INEPT experiment can be a useful tool in investigation of silicophosphate compounds. An analysis of the 1D Si–P MAS-J-INEPT build-up curves allowed the determination of the 2JSiNP couplings in the crystalline Si5O(PO4)6; the couplings have been found to be strongly dependent on the crystallographic path. 2 JSiNP coupling across the N - Si dative bond of the range 5.1 through 14.0 Hz has been measured by Sivaramakrishna et al.182 for a series of novel hypercoordinate silicon bis-chelate complexes with the phosphinimino-N ligand group. Their magnitudes increase with the increasing electron withdrawal by the monodendate ligands reflecting the increase in the strength of coordination. The existence of J coupling distributions and their effects on the measurement of average J coupling values have been analysed and discussed by Emsley and coworkers.183 Using a z-filtered spin-echo experiment they have demonstrated the existence of a pair-specific distribution of 2JPNP couplings in a slightly disordered bis-phosphino amine sample. Two-bond phosporus–phosphorus couplings have been measured by Bilge et al.184 for a large series of novel spiro–ansa–spiro–, spiro–bino–spiro–, spiro-phosphazene derivatives, obtained via the condensation reaction of N2Ox (x = 2, 3) donor-type aminopodand and dibenzo–diaza–crown ethers with hexachlorocyclotriphosphazatriene, N3P3Cl6. Nucl. Magn. Reson., 2008, 37, 145–179 | 157 This journal is

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The first example of a two-bond P–Tl coupling and the first example of a P–Tl coupling in the solid state has been reported by Gave et al.185 who observed them in the CP MAS spectra of TlBiP2S7 and Tl4Bi2(PS4)2(P2S6); the coupling values varied from 481 to 1390 Hz. Rarely observed two-bond Se–Se couplings through a transition atom metal have been measured by Hayes and co-workers186 in the clusters [Re5OsSe8(CN)6]3– and [Re4Os2Se8(CN)6]2– at natural abundance of 77Se isotope.

7. Three-bond hydrogen–hydrogen couplings Van Gunsteren and co-workers187 have used 3JHH couplings as time-dependent restraints in molecular simulations in order to generate a conformational ensemble of molecules. Weinstock et al.188 have applied 3JHH scalar couplings together with other NMR parameters to identify simulated ensembles of the GB1 peptide that best match the experimental data. Examples of peptides and proteins for which couplings have been used as structural parameters are given in Table 1. The presence of the b-structures has been shown in urea-denaturated ubiquitin with the aid of 3JHH couplings: Avbelj and Grdadolnik209 have proven the presence of the fluctuating b-strands and Grzesiek and co-workers210 have observed b-hairpin. In the latter case the analysis of DHH couplings was also of importance. An analysis of 3JHH couplings allowed Forman-Kay and co-workers211 to suggest that the drkN SH3 domain exists in the unfolded state as a compact ensemble with native-like and non-native structures. Table 1 Peptides and proteins for which the solution structure has been calculated with 3JHH Name

a

b

Ref.

Proline zwitterion H–(AAKA)–OH Uperolein, amphibian tachykinin A peptide from a respiratory syncitial vitrus fusion protein GB1 peptide [N] NWr6, NOWA cysteine-rich domain (647–671) [N] Nwr1, NOWA cysteine rich domain repeat 1 (466–492) [N] NWr8, NOWA cysteine-rich domain (720–747) Magi 5, a spider Macrothele gigas toxin [N] phospho-T30-ItchWW3 [N]ItchWW3 (399–432) complexed with PY peptide (54–62) [C/N] C-terminal SH3 domain of c-Crk-II [C/N] PF1455 from Pyrococcus furiosus [C/N]Parkin IBR (307–384) zinc loaded [C/N] FecA TonB [C/N] PupA TonB [C/N] KIV8 module of apolipoprotein(a) [C/N] Nrho, N-terminal domain of P. aeruginosa rhomboid [C/N] pMSP, b-microseminoprotein [C/N] domain III of Langat flavivirus E protein [C/N] KSRP KH3 domain (317–418) [C/N] KSRP KH4 domain (423–525) [N] N-DCX (45–150) (refinement) [D/N] [C/N] talin F3 domain (305–405) complexed with a chimeric b3 integrin-PIP kinase peptide (717–749) [C/N] Mlc1p N-lobe (2–79) [N] FADD (1–191)

1 4 11 13 16 25 27 28 29 34 34 + 9 58 75 78 80 82 85 87 91 96 102 103 106 101 + 33

10 3 8 9 14 14 15 19 26 —c —c 49 47 26 37 43 43 48 59 67 27 47 93 11

189 190 191 192 188 193 193 193 194 195 195 196 197 198 199 199 200 201 202 203 204 204 205 206

149 191

63 120

207 208

a

The number of amino acid residues. b The total number of vicinal backbone and side chain proton–proton couplings measured. c Number not specified.


c


3

JHH couplings have been extensively used by Corzana et al.212 to study the effect of b-D-O-glucosylation on L-serine and L-threonine diamides and by Gudasheva et al.213 to perform a conformational analysis of retropeptide analogues of 4cholecystokinin. Relationship between structure and 3JHH couplings in glycosoaminoglycans has been studied by Hricovı´ ni and Bizik,214 and a conformational analysis of 5-thiopyranose monosaccharides by the use of computed NMR chemical shifts and 3JHH couplings has been performed by Aguirre-Valderrama and Dobado.215 Further examples include conformational analyses of galactose-derived bicyclic scaffolds,216 methyl 5-O-methyl septanosides,217 and aldonamides derived from D-glycero218 D-gulo-heptono-1,4-lactone. The stereochemistry of guaiacylglycerol-8-O-4 0 -(sinapyl alcohol) ether, an 8-O-4 0 neolignan which consists of coniferyl and sinapyl alcohol moieties in Eucommia ulmoides, as well as four synthetic 8-O-4 0 neolignans, guaiacylglycerol-8-O-4 0 (sinapyl alcohol) ether, syringylglycerol-8-O-4 0 (coniferyl alcohol) ether, guaiacylglycerol-8-O-4 0 (coniferyl alcohol) ether and syringylglycerol-8-O-4 0 -(sinapyl alcohol) ether have been investigated by Lourith et al.219 by the use of 1H NMR spectroscopy. All of the erythro-acetonide derivatives of these compounds have larger couplings (ca. 9 Hz) for the C7–H bonds than those of the threo ones (1.5–2.0 Hz). Table 2 lists the examples of carbohydrates and nucleic acids whose structures have been found with the aid of 3JHH couplings. It has been shown by Seike et al.226 that it is possible to assemble 3JHH profiles from NMR data collected on relevant, but not necessarily specific, NMR database compounds representing a given stereocluster. They have created the 3JHH profile for the contiguous tetraol peracetate cluster and showed the reliability and applicability for the peracetates derived from two heptoses. Vicinal H–H couplings have been also extensively applied to establish the structures of a variety of natural terpenoids such as: a new 2(3 - 20)abeotaxane227 with an unusual 13b-substitution pattern and a new 6/8/-ring taxane isolated from the needles of Taxus cuspidata, three cucurbitane triterpenoids from Momordica charantia,228 five eremophilanolides from Psacalium paucicapitatum,229 a new eremophilanolide from Senecio sinuatus Gilib,230 two new cucurbitane-type triterpenoids isolated from the fruits of Cayaponia racemosa,231 and several clerodane diterpenoids of Salvia splendens.232 Another example includes four briarane diterpenoids isolated from the gorgonian coral Pachyclavularia violacea whose structures have been determined by Uchio et al.233 by the use of the experimental vicinal proton–proton couplings and the molecular mechanics calculations. It is worth noting that the authors did not resort to the aid of X-ray crystallographic studies and emphasised that the molecular mechanics calculation is a method of choice for the elucidation of the structure of highly flexible medium ring compounds. Proton– Table 2 Nucleosides, nucleotides, oligonucleotides and carbohydrates for which 3JHH has been used as a structural parameter Name

Ref.

A glyconucleoside with S-glycosidic linkage The RNA hairpin with GCUA tetraloop

220 221

Carbohydrates b-D-furanurono-6,3-lactones A series of 5-thio-pyranose monosaccharides A series of glycosaminoglycans C-glycosyl analogue of sulfatide A series of hyaluronan oligosaccharides [N] hyaluronan, HA4 and HA6

222 215 214 223 224 225


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proton couplings have been measured by Kazmi et al.234 for sorbinols A and B, new terpenes from Sorbus cashmariana, and by Zhou et al.235 for two new triterpenoid saponins from Ilex hainanensis in order to assign their spectra and elucidate structures, by Macı´ as et al.236 for four saponins isolated from the Agave brittoniana Trel.spp. Brachypus leaves and by Santos et al.237 for two new bidesmoside triterpenoid saponins isolated from Cordia piauhiensis. 3JHH couplings have been applied as crucial parameters in structure analysis of four new acyclic diterpene glycosides obtained from the fresh sweet pepper fruits of Capsicum annuum L. by Iorizzi and co-workers.238 Another group of natural products studied by the use of 3JHH couplings were alkaloids: a new chlorotryptamine alkaloid and its already known hallucinogenic analogues isolated from the Chinese shrub Acacia confusa239 and four unusual alkaloids isolated from Pseudoxandra cuspidata by Roumy et al.240 The 3JHH couplings have been used to establish the structure of four dehydrotriand dehydrotetraferulic acids isolated from insoluble maize bran fiber by Bunzel and co-workers241 and the structure of new destruxins from the marine-derived fungus Beauveria felina by Berlinck and co-workers.242 Sasaki and co-workers have used 3 JHH couplings to confirm the stereochemistry of brevenal243 which they soon revised.244 Collison and co-workers245 have traced with these couplings the first total synthesis of montiporyne E. The axial or equatorial positions of the cyclohexanic protons in kallisteine A and B, two new coumarins from the roots of Peucedanum paniculatum L, have been assigned by Vellutini et al.246 by taking into account the 3JHH coupling values and the NOESY correlations. It is worth noting that kallisteine B represents the first example of a furanocoumarin bearing a spiro substituent. Two novel angular-type furanocoumarin glycosides, peucedanoside A and peucedanoside B, along with a known compound apterin have been isolated from the roots of Peucedanum praeruptorum Dunn by Chang et al.247 and their structures established by the use of vicinal proton–proton couplings. A furanocoumarin glycoside named turbinatocoumarin has been isolated by Ngameni et al.248 from the twigs of Dorstenia turbinata and its structure established as 5-methoxy-3-[3-(b-glucopyranosyloxy)-2hydroxy-3-methylbuthyl]psoralen by the use of an NMR method including proton– proton couplings. Vicinal proton–proton couplings have been applied to perform a structural analysis of complex saponins from the mesocarp of Balanites aegyptiaca fruit,249 to identify a new biophenolic secoiridoids with antioxidant activity from Australian olive mill waste250 and to determine the structure and conformation of two native procyanidin trimers.251 3 JHH couplings have been measured by Bertazzi et al.166 for two R2Sn(IV)-b-Nacetyl-neuraminate (R = Me, Bu) complexes in D2O and DMSO-d6, and their values compared with the corresponding dihedral angles for the pyranosidic ring. Vicinal couplings 3JHH helped to assign the conformational arrangement of the cyclohexane ring of hexahydro-furo[3,2-c]benzofuran-2-one studied by Xie et al.252 A rapid method based on simple indirect determination of values and numbers of the 3JHH couplings involved in the pattern of the most deshielded proton signal which allows to identify and assign the diastereoisomers of 1-decalols and 2-decalols has been described by Solladie´-Cavallo et al.253 The compounds have been obtained by heterogeneous hydrogenation of 1-naphtol and 2-naphtol. A conformational analysis by the use of 3JHH couplings has been performed by Reyes-Trejo et al.254 for (-)[4.3.3]propellane obtained via the Wagner-Meerwein rearrangement of a [3.3.3]propellane. 3 JHH couplings have been reported for three monocyclic benzoannelated dilactam polyethers by Smith et al.255 and for di-pentacyclo-undecane cyclic ether by Kruger et al.256 Vicinal proton–proton couplings and deuterium isotope effects on 13C chemical shifts have been applied by Rozwadowski257 to estimate the position of the 160 | Nucl. Magn. Reson., 2008, 37, 145–179 This journal is

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tautomeric equilibrium in a series of the optically active Schiff bases, derivatives of ortho-hydroxyaldehydes and their dirhodium adducts. Large 3JNHH coupling values of the range 11–14 Hz found for the most compounds studied indicate that they exist in the NH form. Another paper published by this author concerned an application of the 3JHH couplings to estimate the position of the proton transfer equilibrium in the tetrabutylammonium salts of Schiff bases amino acids.258 Structure elucidation of two novel spiro[2H-indol]-3(1H)-ones by the use of NMR including proton–proton spin–spin couplings has been performed by Kosˇ mrlj et al.259 and by Matijevic´-Sosa260 for 2-hydroxy-1-naphtylidene Schiff bases with chloro and hydroxyl substituted aniline moiety. A complete 1H and 13C NMR assignment of trans,trans-2,3-divinylfuran derivatives has been performed by Sˇkoric´ et al.;261 the 3JHH coupling values across double bonds confirmed their trans,trans configuration. 3 JHH couplings can be also helpful in structure elucidation when NMR spectroscopy is coupled with high-performance liquid chromatography. Schefer and coworkers262 have applied the HPLC-NMR method for separation and characterization of eight limonoids from Switenia macrophylla.

8. Three-bond couplings to hydrogen Saielli and co-workers263 have applied the 3JH10B and 3JH11B couplings to confirm the structure of the product in their mechanistic studies of Fries rearrangement of aryl formates. Recently, Schmidt has published two papers264,265 devoted to 3J couplings that correspond to dihedral angles in peptides in proteins. In the first paper264 incremental component couplings are proposed to account for substituent effect on each type of 3J (j and w1 related) arising from the peptide sequence. In the second paper265 asymmetric Karplus curves have been proposed for the protein side-chain 3 J couplings. The asymmetry arises from two effects: the type of a particular substituent and its positioning, and the coupling path. Time-average three-bond proton–carbon and proton–proton couplings DFTcalculated by Hricovı´ ni266 have agreed with the experimental data which led the author to the conclusion that only two chair forms contribute to the conformational equilibrium of methyl 2-O-sulfo-a-L-iduronate monosodium salt. The influence of the charged groups upon the magnitudes of spin–spin couplings has been also observed. The conformational behaviour of 2-O- and 4-O-sulfated derivatives of linear (1 3)-linked di-, tri-, and tetrafucosides and 2,3-branched tetrafucosides has been studied by Grachev et al.267 by the use of molecular modelling and trans glycosidic vicinal couplings 3JHC. The 3JHC couplings have been applied by Borba´s and coworkers268 for determination of the anomeric configuration of a series of ketopyranosyl glycosides. The angular dependence of 3JOH,C, 2JOH,C and 2JOH,H couplings have been calculated by Carlomagno and co-workers269 using DFT to derive the Karplus-like relations essential for the accurate determination of the 2 0 -hydroxy group conformation in RNAs. An analysis of the experimental and hybrid B3LYP DFT calculated 3JHC and 3 JHH couplings of two epimers of antibiotic 2-hydroxymutilin has been performed by Vogt et al.270 in order to obtain relative stereochemical assignments of the isomers. A large set of three-bond proton–carbon couplings supplemented by numerous two-bond couplings has been obtained by Lacerda et al.271 for eight different derivatives of cyclopentane. These 2,3JHC couplings have been shown to be useful in the determination of the relative stereochemistry of these compounds. It has been emphasized by DiMichele et al.272 that the measurements of the proton–carbon three-bond couplings have been necessary to establish the regiochemistry of the products of regioselective halogen/metal exchange reactions carried out on a series of 3-substituted-1,2-dibromoarenes. Nucl. Magn. Reson., 2008, 37, 145–179 | 161 This journal is

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3

JHC couplings have been applied by Grosˇ elj et al.273 to establish the configuration around double bonds in some N-substituted(1R,4S)-3-aminomethylidene-1,7,7-trimethylbicyclo[2.2.1]-heptan-2-ones, by Senior et al.274 to obtain unambiguous structural characterization of hydantoin reaction products and by Sanz et al.275 to prove the structure of 3-phenyl-5-(R)-7-trifluoromethylpyrazolo[1,5-a]pyrimidines. Proton–carbon couplings across one, two and three bonds have been measured by Larina et al.276 for a large series of acetylation products of heterocyclic thiosemicarbazones in order to confirm their structures. The effect of substituents on the acid assisted proton transfer in 4-[(4-R-phenylimino)methyl]pyridin-3-ols (R = H, CH3, OCH3, Br, Cl, NO2) has been studied by Perona et al.277 by the use of NMR and UV spectroscopies as well as by DFT calculations. Proton–carbon couplings across one and three bonds and proton– proton couplings have been reported for the compounds studied and their salts. Three- and two-bond proton–carbon and proton–nitrogen couplings have been measured for a series of 7-substituted pyrazolo[3,4-c]pyridines by Kourafalos et al.278 who studied the tautomerism of these compounds; for some compounds also low-temperature spectra have been recorded. 3 JHN couplings have been applied by Damberg and co-workers279 to determine distribution of conformations of motilin in aqueous solution. Coxon280 has proposed a Karplus-like equation for 3JHN couplings in amino sugar derivatives: 3JHCCN = 3.1cos2 j 0.6 cos j + 0.4. For other examples of carbohydrates and nucleic acids whose structure has been solved with heteronuclear couplings see Table 3. 3 JHN couplings have been measured by De Benassuti et al.287 for a series of 1-(4-substituted)phenyl-3-methoxycarbonyl-5-ethoxycarbonyl-4,5-dihydropyrazoles at natural abundance of the 15N isotope. The couplings encompass the range 5.7–6.4 Hz and are scarcely dependent on the nature of R (R = H, Me, OMe, Cl, NO2). Spectral assignments for 1H, 13C and 15N solution NMR spectra of s-tetrazine and dihydro-s-tetrazine derivatives which included proton–carbon and proton–nitrogen couplings have been reported by Palmas et al.288 The configuration of heptaene moiety has been determined by Oishi and coworkers289 based on 3JHF and 3JHH values in the synthesis of 28-19F-amphotericin B methyl ester.

Table 3 Nucleosides, nucleotides, oligonucleotides and carbohydrates for which heteronuclear vicinal couplings have been used as a structural parameter Name d(TL4T) and d(TGLGLT) quadruplexes [C/N] from helix-35 of E.coli 23S ribosomal RNA d(CGCGAATTCGCG)2 Tel26 G-quadruplex, K+ The JunFos oligomer 5-Fluoropyrimidine-substituted TAR RNA [C/N] HJ1 RNA and HJ3 RNA

a

b

Ref.

12 24 24 26 28 30 35

3

JHP JHOC 3 JHP 3 JHP 3 JHP 5 JHF 3 JHP

281 41 282 283 284 42 285

3

286 280 266 267

Carbohydrates a -L-Rhap-(1-2)-a-L-Rhap-OMe [N] a series of amino sugar derivatives Methyl 2-O-sulfo-a-L-iduronate monosodium salt A series of tetrafucosides

3

JHC JHN 3 JHC 3 JHC 3

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


c


Conformational studies for a series of 2-fluoro-substituted 19b,28-epoxy-18aoleanane triterpenoids have been performed by Tislerova et al.290 by the use of vicinal proton–proton, proton–fluorine and carbon–fluorine couplings. Vicinal H–Pt couplings have been helpful in differentiating species and assigning the metal oxidation states of a series of 2,2 0 -bipyridine complexes of Pt(II) and Pt(IV) studied by Nakabayashi et al.291 3JCH3N,Pt of 29.8, 31.6 and 31.6 Hz have been observed for mer-[PtCl3(2,2 0 -bpy)-(MeNH2)]Cl–H2O, trans-[PtCl2(2,2 0 -bpy)(MeNH2)2]Cl2 and trans-[Pt(2,2 0 -bpy)(MeNH2)2(OH)2]Cl2, respectively. Analogous vicinal couplings between methyl resonances of the MeNH2 ligand and Pt atom in [PtCl(2,2 0 -bpy)(MeNH2)]Cl and [PtCl(2,2 0 -bpy)(MeNH2)2]Cl2 were approximately 40 and 43 Hz, respectively.

9. Three-bond couplings not involving hydrogen 3

JCC and 3JCN scalar couplings together with RDCs have been used by Lee and coworkers to study side-chain rotamers of valines and threonines (and transmissions of structural changes) in multiple V to A mutations in protein eglin c292 and for evaluation of energetic and dynamic coupling networks in a PDZ domain protein.293 For more examples of peptides and proteins for which heteronuclear couplings have been applied as structural restraints see Table 4. The benzyl-substituted triazacycloheksane complexes of Ni(II) studied by Ko¨hn et al.298 revealed unusually broad ortho-C signals with apparently small vicinal C–F or H–C couplings. This phenomenon has been interpreted in terms of T1 spin decoupling from much faster relaxing 1H or 19F nuclei in close proximity to the paramagnetic nickel centre. The authors suggest that quantitative treatment of this effect can provide improved relaxation data for the 13C nucleus and attached to it 1H and 19F nuclei. It is noteworthy that this effect was already described over 30 years ago by Navon and Polak.299 It has been shown by Khudina et al.300 that fluoroalkyl-containing 1,2,3-trione 2-arylhydrazones exist in CDCl3 exclusively and in (CD3)2CO preferentially as isomers in which the acyl or aryl group is involved in the intramolecular hydrogen bond. The structures of these compounds have been assigned, among others, on the basis of carbon–fluorine couplings across one, two, three and more bonds. Theoretical studies on relationship between 2,3JHC, 2,3JHP, 2,3JCP and the backbone torsion angles of nucleic acids have been performed by Sychrovsky´ et al.301 3 JCP and 3JHP couplings have been determined by Maghsoodlou et al.302 for several phosphonato esters obtained by the reaction between triphenylphosphite and acetylenic esters in order to establish their configuration. The relative configuration of diastereomers in electrophilic substitution of rigid 2-lithio-N-methylpyrrolidines has been established by Gawley and co-workes303 with the help of 3JCSn and 3JHH couplings. Table 4 Peptides and proteins for which heteronuclear couplings have been used as a structural parameter in 3D structure calculations Name

a

b

c

A series of alanine peptides, selectively labelled [C/N] Brk BDB-omb12T5 complex [D/N] zzTM dimer [C/N] calbindin D9K, Ca2Cb [C/N] EmLEM (1–47) complexed with [C/N] BAF2 selectively deuterated

3 to 7 59+ 33 2 75 47 + 89 2

Up to 40 30 21 49 46

3

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

Ref. 1,2

JCN

294 295 296 23 297

Number of residues. b Total number of vicinal couplings measured (homonuclear 3JHH couplings are also included if measured). c Types of heteronuclear couplings measured. a


c


2

JCSn and 3JCSn couplings have been observed by Bordinhao et al.304 for the olefinic carbons of 4,5-bis[(triphenyltin)thiolato]-1,3-dithiole-2-one and 4,5-bis[(triphenyltin)thiolato]-1,3-dithiole-2-thione compounds, but the authors have not been able to distinguish between these two types of couplings. Several new papers devoted to investigation of a variety of Pt–amine complexes by the use of 2,3JHPt and 2,3JCPt couplings have been published by Rochon et al. This included characterization of [Pt(amine)4]I2 and trans-[Pt(CH3NH2)2(H3C– NQC(CH3)2)2]I2,305 Pt(II) complexes containing amines and bidendate carboxylate ligands,306 as well as Pt(II)–aromatic amines complexes of the types cis- and transPt(amine)2I2 and I(amine)Pt(m-I)2Pt(amine)I.307 An analysis of 3JNF and 4JNF couplings has allowed Kline and Cheatham unambiguous assignment of trifluoromethylpyrazole regioisomers.308 Vicinal couplings between ring attached fluorine atoms have been determined and analysed by Brey et al.309 for a large series of variously substituted cyclopropanes. It has been found that the couplings display unusual behaviour and are not helpful in assigning the fluorine resonances. The Si–P couplings across three and two bonds of 2.6, 4.5 and 15.0 Hz have been observed by Nakata et al.310 for the hafnium-silylene phosphine complex, (Z-C5H4– Et)2(PMe3)HfQSi(SiMe-t-Bu2)2 and have been assigned by the authors to two tBu2MeSi groups and the silylene signal.

10. Couplings over more than three bonds and through space It has been shown by Katrizky et al.311 that the values of nJHH (n = 3, 4, 5) and nJHC (n = 1, 2, 3, 4) couplings can be correctly predicted using the larger 6-31+G(d,p) and 6-311++G(d,p) basis sets at the B3LYP/6-31+G(d,p) and B3LYP/6311++G(d,p) levels of theory. The calculations have been performed for a large number of derivatives of five-membered aromatic heterocycles and the theoretical results have been compared with the experimental data. Proton–proton couplings across three- and four bonds have been measured by Barros and Silva for 26 new aminoflavones.312 A paper devoted to the orientation of molecules by magnetic field as a new source of information on their structures has been published by Chertkov and co-workers 313 who measured and analysed a series of high resolution 1H NMR spectra of 1,2,3trichloronaphtalene on spectrometers operating at frequencies 200, 400, 500 and 600 MHz. This allowed them to determine with a high accuracy all possible proton– proton couplings in this molecule including that across six bonds. The long-range couplings, 5,6JHF and the chemical shifts of trifluoromethyl groups in the 19F NMR spectra have been used by Khudina et al.314 for the determination of regio-isomeric structures of mono(trifluoromethyl)-substituted pyrazoles. Long-range H–F couplings across two, four and seven bonds have been used by Prekupec et al.315 to confirm the chemical structure of a series of novel C-6 fluorinated acyclic side chain pyrimidine derivatives. It has been demonstrated by Chan et al.316 that the proton–fluorine and carbon– fluorine couplings, 1hJHF of ca. 3 Hz and 2hJCF of ca. 6, observed in a series of group 4 postmetallocene catalysts, supported by fluorine-functionalized tridendate ligands with the fluorine substituent close to the metal centre (Fig. 4), occur through space rather than through bond or by M–F coordination. Through-space JHTl and JTlTl couplings in the model Tl2(C6H6)2+ system have been calculated by Bagno and Saielli.12 The computed data reasonably well reproduced the experimental data reported by Howarth et al.317 for the dithallium(I) cryptate. A series of substituted 3-phenoxy-3-perfluoroalkylprop-2-enals has been synthesized by El Kharrat et al.318 and 4JCF coupling has been found to be a crucial parameter in determination of their configuration and conformation in solution. 164 | Nucl. Magn. Reson., 2008, 37, 145–179 This journal is

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Fig. 4

A large set of nJCSi couplings (n = 2, 3, 4, 5) over Si–O–Carom link has been measured and calculated by Schraml and co-workers319 in para substituted silylated phenols, XC6H4–O–SiR1R2R3 where X = NO2, CF3, Cl, F, H, CH3, CH3O. The low sensitivity of these couplings to substitution both on the silicon atom and the benzene ring has been observed. A through-space P–P coupling, JPP = 8 Hz has been observed by Kuhn et al.320 in the large, unsymmetrical diphosphine 5,11,17,23-tetra-t-butyl-25,26-bis(diphenylphosphinomethoxy)-27(or 28)-benzyloxy-28(or 27)-hydroxycalix[4]arene in which the phosphorus atoms are separated by ten bonds. Another example of a phosphorus–phosphorus coupling which at least in part occurs across through space has been reported by Hatnean et al.321 who observed JPP of ca. 15 Hz across formally six bonds in three complexes: [P(CH2NPh)3]2Mg3(THF)3 1.5THF, [P(CH2N-3,5-(CF3)2C6H3)3]2Mg3(THF)3 and [P(CH2N-3,5-Me2C6H3)3]2Mg3(THF)3.

11. Couplings through hydrogen bonds The 4hJHH couplings through C–H O hydrogen bonds in the C–H O–C–H moieties have been investigated in three lariat ethers and their alkali-metal ionic complexes by Ding et al.322 OH OH hydrogen mediated scalar couplings in syn- and anti-1,3-diols are usually too small to be observed directly as splittings in 1D NMR spectra. However, it has been recently shown by Loening et al.323 that the cross-peaks due to these couplings can be readily observed in a 2D COSY experiment modified with a refocusing delay (COSYLR). Using this method the authors have measured JOH OH couplings for a series of anti and syn-polyacetate and polypropionate derivatives which covered a range of 0.16 through 0.42 Hz with the accuracy 0.02 Hz. The first example of a O–H N hydrogen bond, 1hJNOH = 1.8 Hz, in a relatively small biologically active natural product, nocathiacin I, has been reported by Huang et al.324 This observation afforded a restraint to further refine the 3D solution structure of this compound. The intramolecular C–H N hydrogen bond has been identified in (E)-9-benzyl-6-[isobenzofuran-1(3H)-ylidene-methyl]-9H-purine by Gundersen and co-workers.325 The differences in hydrogen bond lengths between RNA and DNA found earlier with the help of 1hJHN and 2hJNN couplings have been confirmed now with the help of trans-hydrogen bond deuterium isotope shifts by Li Wang and co-workers.326 Several examples of proteins and nucleic acids for which couplings through hydrogen bonds have been used in structural analysis are given in Table 5. Nucl. Magn. Reson., 2008, 37, 145–179 | 165 This journal is

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Table 5 Compounds for which scalar couplings have been measured through the hydrogen bond Name cyclo-(-D-Pro-Ala4-) [C/N] ScYLV RNA pseudoknot [C/N] the P4 element of RNase P

a

b

N–H OQC N–H N N–H N

3h

JCN JNH, 2h JNN 1h

2h

a

JNN

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

b

c

Ref.

2 18 10

327 43 328

Type of couplings

Sychrovsky´ and co-workers329 have used the DFT method to calculate 2hJHP and JCP couplings across the C–H OQP hydrogen bond between the nucleic acid backbone phosphate and the C–H group of a nucleic base and proposed application of these couplings for structure determination of nucleic acids. The coupling between hydrogen and selenium nuclei in selones, JHSe = ca. 12–13 Hz which occurred through the N–H SeQC hydrogen bond in these compounds was already observed some time ago by Wu et al.330 A similar type of coupling, JHSe = 5.4 Hz, has been found recently by Okamura et al.331 in the (NEt4)2[Mo(IV)O(Se-2-t-BuCONHC6H4)4] complex. The coupling of similar value, JHSe = 6 Hz occurring in the fragment NH SeQP, has been observed by Mansfield et al.332 in phospha(V)guanidine, Ph2P(Se)C{NCy}{NHCy}. This interaction, although rather weak, is strong enough to slow rotation about the P–Camidine bond on the NMR time scale and to generate the conformation with intramolecular hydrogen bond. A relatively large JHCd coupling of ca. 9.0 Hz has been observed by Chmielewski et al.333 in S-confused thiaporphyrin 5,10,15,20-tetraphenyl-2-thia-21-carbaporphyrin providing evidence that the interaction takes place between the spin-active nucleus (111Cd, 113Cd) and the proximate 1H nucleus despite the absence of a direct Cd–thiophene bond. Formally, these two nuclei are six bonds apart and the geometry of the coupling path is unfavourable. Systematic ab initio studies of N–N and H–N spin–spin couplings across N–H+– N hydrogen bonds have been performed by Del Bene and Elguero.334 A CLOPPA analysis of the distance dependence of 2hJFF and 1hJHF in FH FH has been performed by Giribet and de Azua.335 Ab initio calculations have been performed by Del Bene et al.336 in order to obtain structures, energies, P–P and H–P couplings of 22 open and 3 cyclic complexes formed from the sp2 [H2CQPH and HPQPH (cis and trans)] and sp3 [PH2(CH3) and PH3] hybridised phosphorus bases and their corresponding protonated ions. 3h JC 0 N couplings have been helpful in studying residual structures of ureadenaturated ubiquitin by Grzesiek and co-workers.210 Vendruscolo and co-workers337 have described a method of using this type of couplings as ensemble-averaged restraints in molecular dynamics simulations. 3h

12. Residual dipolar couplings An easy to use toolkit for RDC analysis, iDC has been created by Wei and Werner.338 The program can perform most experimental RDC analyses including simultaneous estimation of tensor alignment of an entire structure family. De Alba and Tjandra339 have shown that the effect of cross-correlation is a source of error in quantitative J experiments. The authors found that in the case of methylene moieties the error of measured RDC values can amount to several Hz. Systematic studies on solvent effects exerted on RD and 1JHC couplings in acetonitrile have been performed by Gronenborn and co-workers.340 No significant influence of alignment media on these parameters has been observed. The authors conclude that the structural features of small rigid molecules determined using 166 | Nucl. Magn. Reson., 2008, 37, 145–179 This journal is

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RDCs are in good agreement with the geometric parameters derived from other structural methods. A new system for partial alignment of polar organic molecules to measure residual dipolar couplings has been proposed by Klochkov et al.341 and as examples the H, C residual dipolar couplings for the amino acid methionine and for an a-methylene-gbutyrolactone have been obtained. Ramamoorthy and co-workers342 have demonstrated the usefulness of a solidstate NMR approach that can be used to measure dipolar couplings between 1H, 13C and 31P nuclei in the structural studies of membrane-associated molecules without the need for isotopic enrichment. 1DHN couplings have been applied by Zweckstetter and co-workers343 for characterisation of interaction of protein Tau with microtubules. 1 DHN residual dipolar couplings have been used by Shortle and co-workers344 in their efforts to describe the residual structure in denaturated staphylococcal nuclease; by Ho and co-workers345 for demonstration of spontaneous preferential orientation of deoxyhemoglobin in solution at high magnetic fields; by Gehring and co-workers346 to compare the structure of BCL-xL dimer with the crystal structure of this protein; by McIntosh and co-workers347 for direct demonstration of the flexibility of the glycosylated proline–threonine linker in the modular xylanase Cex; by Iwahara et al.348 for structural and kinetic characterization of the HoxD9 homeodomain diffusing on non-specific DNA; by Wand and co-workers349 to study the structure of several proteins in reverse micelles; by Zweckstetter and co-workers350 to demonstrate that molecular alignment in unstructured proteins in charged nematic media strongly depends on electrostatic interactions between the protein and the alignment medium, and by Avbelj and Grdadolnik209 to prove the presence of the fluctuating b-strands in denaturated proteins. The theoretical framework for residual dipolar couplings in unfolded proteins has been given by Obolensky and co-workers.351 1 DHN residual dipolar couplings induced by a rigid lanthanide-binding tag used for site-specific labelling of proteins have been applied for structural studies of Nterminal domain of E.coli arginine repressor by Otting and co-workers,352 and for investigating global fold of the TM domain of outer membrane protein A by Johansson et al.353 1 DHC and 1DHN residual dipolar couplings have been used by Grzesiek and coworkers354 to show that in short peptides individual amino acids reveal systematic conformational preferences, and by Ohnishi and co-workers355 to prove that polyglycine in solution exhibits conformational preference to an elongate structure. Best et al.356 have shown that experimentally measured residual dipolar couplings are well reproduced by their respective ‘high-sequence similarity PDB ensembles’. A polynomial-time algorithm for de novo protein backbone structure determination that utilizes residual dipole couplings as restraints has been formulated by Donald and co-workers.357 The list of proteins whose structures have been elucidated with the use of residual dipolar couplings is given in Table 6. It has been shown by Lukavsky and co-workers381 that complementary segmental labelling of large RNAs simplifies NMR spectra and doubles the number of measurable residual dipole couplings. Iverson and co-workers382 have applied 1 DHC, 1DHN, 1DCN and 3DHH couplings in their studies on the structure of the d(CGGTACCG)2 complex with a new threading bisintercalator. Several examples of nucleic acids and carbohydrates for which resiudal couplings have been measured and applied in structural analysis are listed in Table 7. The 1DCC dipolar couplings between the labelled methyl and carbonyl carbons of the acetyl groups have been used for structural monitoring of oligosaccharides by Yu and Prestegard.393


c


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

Name

b

c

Ref.

[C/N] TM domain (7–39) of the z chain of the T cell receptor complex [D/N] zzTM dimer [N] hTpoR (479–519) [C/N] EmLEM (1–47) GB3, immunoglobulin G-binding protein G precursor (298–352) [D/C/N] GB1

33

46

1

33 2 41 47 55

35 27 110 750

1

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

296 359 297 360

56

352

361

[C/N] Brk BDB (43–101) -omb12T5 complex Conk-S1 and S2, conkunitzin-S1 and S2

59+ 60/65

92 190/138

[C/N] calbindin D9K, CaTmCb [C/N] PF1455 from Pyrococcus furiosus [C/N] Aa(406–483) aC-domain fragment of bovine fibrinogen [C/N] FecA TonB [C/N] PupA TonB [C/N] HPV16 E2C (283–363) bound to DNA [C/N] the 2F13F1 module pair of the N-terminal of human fibronectin [C/N] pMSP, b-microseminoproteins [C/N] hMSP, b-microseminoprotein [C/N] domain III of Langat flavivirus E protein [N] N-DCX (45–150) (refinement) [C/N] the CH domain of human MICAL-1 (506–614) [C/N] GatB (IIBgat), PTS system, galactitol-specific IIB component [C/N] HsSen15 (36–157), a subunit of human tRNA splising endonuclease [C/N] PACAP(6 0 -38 0 ) complexed with [N] hPAC1-RS (21–122) [D/C/N] Ly49A NKD (127–262) [D/C/N] the L11 protein from Thermotoga maritima complexed with 60 nt RNA and thiostrepton [C/N] C26S SAP18 (6–149) [C/N] Wzb of E.coli [C/N] Mlc1p N-lobe (2–79) + C-lobe (80–149) [C/N] Spc24p/Spc25p globular domain of the yeast kinetochore [C/N] CaM/RYR1, calmodulin complexed with a ryanodine receptor target [D/C/N] OmpA, the membrane protein [N] FADD (1–191) [N] the Ig doublet Z1Z2, N-terminus of titin [C/N] Rv1980c, an antigen MPT64 from Mycobacterium tuberculosis [C/N] EmLEM (1–47) complexed with [C/N] BAF2 selectively deuterated [D/C/N] calbindin-D28K, Ca2+ loaded [D/N] ClC-0, a Cl channel,d

75 75 78

136 178 71

DHH, 1DHN, 2,3DHC, 1 DCC, 1DCN 1 DHC, 1DHN 1 DHC, 1DHN, 1 DCC, 1DCN 1 DHC, 1DHN, 1DCC 1 DHN, 1DHC, 2DHH 1 DHN

80 82 81+ 90

42 54 102 59

1

DHN DHN 1 DHN 1 DHN

199 199 364 365

91 94 96 106 109

157 140 80 74 74

1

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

202 202 203 205 366

113

82

1

367

122

94

1

368

33 + 102

23

1

369

136 141+

104 120

1

370 371

144 147 78 + 70 89 + 76

62 97 254 + 232 173

1

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

372 373 207 374

143 + 27

90

1

375

177 191 194 205

434 137 53 253

1

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

376 208 377 378

47 + 89 2 140

1

297

261 302

1

379 380

304 140

DHC, DHN

1

1

1

DHN DHN DHC, 1DHN DHN DHN

1

1

DHN

1

DHN DHN, 1DCN DHN

1

a Number of residues. b The total number of residual dipolar couplings measured. dipolar couplings measured. d Global fold only.


c


1

c

358

295 362 22 197 363

Types of residual

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

Name

b

c

Ref.

1

DHC DHC, 1DCC 1 DHC, 1DCC 1 DHC 1 DHC, 1DHN, 1 DHP, DHH 1 DHC 1 DHC 1 DHC 1 DHC 1 DHC 1 DHC, 1DHN 1 DHC, 1DHN 1 DHN

221 383 383 384 282

The RNA hairpin with GCUA tetraloop Human U2 stem I RNA [C/N] yeast U2 stem I RNA [C/N] TER RNA SLIV d(CGCGAATTCGCG)2

14 20 20 21 24

17 42 71 17 964

[C/N] RNA hairpins Ycu and Yuu [selective-uridine lab.] the pgRNA of HVB [C/N] HRV-14 SLD TAR RNA [C/N] RNase P P4 [C/N] the bulge-containing HIV-1 TAR RNA [C/N] SL1m HIV-1 RNA, free and Mg2+ loaded The GAAA tetraloop-receptor RNA Mn2+ and Co(NH3)63+ loaded [C/N] SL1 RNA HIV-1 dimer initiation site

22/22 27 27 29 29 29 36 43

39/39 28 66 29 43 62 52/52 24/24

35 2

65 2

1

392

2 2 2

10 2 11

1

286 393 394

Carbohydrates a -L-Rhap-(1 - 2)-a-L-Rhap-OMe Doubly 13C-labeled N-acetyl O-butyl-chitobiose Lactose bound to galectin-3 C251-CRD and S-propyl-C252-CRD

1

DHC

DHC DCC 1 DHC, 2DHH 1

385 386 387 388 328 389 390 391

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

Fig. 5

Relative configuration of the stereogenic centres in a five-membered flexible lactone, a-methylene-g-butyrolactone (Fig. 5) has been determined by Thiele and co-workers395 with the aid of nDHC, 1DCC and 3DHH residual dipolar couplings. Residual dipolar couplings have been applied by Voda et al.396 to analyse the morphology of thermoplastic polyurethanes, and homo- and heteronuclear residual dipolar couplings have been used by Bertmer et al.397 to study segmental mobility in a series of short poly(dimethylsiloxane) chains grafted onto hydrophilic silica. Orientational ordering of short and intermediate n-alkanes confined to silicon nanotubes has been studied by Valiulin and Khokhlov398 by the use of 1H NMR. They established that the residual nuclear dipolar couplings characterizing the degree of molecular ordering depend on the pore size and the molecular length in a complex way.

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367 L. Volpon, C. R. Young, A. Matte and K. Gehring, Protein Sci., 2006, 15, 2435. 368 J. Song and J. L. Markley, J. Mol. Biol., 2007, 366, 155. 369 C. Sun, D. Song, R. A. Davis-Taber, L. W. Barrett, V. E. Scott, P. L. Richardson, A. Pereda-Lopez, M. E. Uchic, L. R. Solomon, M. R. Lake, K. A. Walter, P. J. Hajduk and E. T. Olejniczak, Proc. Nat. Acad. Sci. USA, 2007, 104, 7875. 370 J. Dam, J. Baber, A. Grishaev, E. L. Malchiodi, P. Schuck, A. Bax and R. A. Mariuzza, J. Mol. Biol., 2006, 362, 102. 371 H. R. A. Jonker, S. Ilin, S. K. Grimm, J. Wo¨hnert and H. Schwalbe, Nucleic Acids Res., 2007, 35, 441. 372 S. A. McCallum, J. F. Bazan, M. Merchant, J. P. Yin, B. Pan, F. J. de Sauvage and W. J. Fairbrother, Biochemistry, 2006, 45, 11974. 373 E. Lescop, Y. F. Hu, H. M. Xu, W. Hu, J. Chen, B. Xia and C. W. Jin, J. Biol. Chem., 2006, 281, 19570. 374 R. R. Wei, J. R. Schnell, N. A. Larsen, P. K. Sorger, J. J. Chou and S. C. Harrison, Structure, 2006, 14, 1003. 375 A. A. Maximciuc, J. A. Putkey, Y. Shamoo and K. R. MacKenzie, Structure, 2006, 14, 1547. 376 T. Cierpicki, B. Y. Liang, L. K. Tamm and J. H. Bushweller, J. Am. Chem. Soc., 2006, 128, 6947. 377 M. Marino, P. J. Zou, D. Svergun, P. Garcia, C. Edlich, B. Simon, M. Wilmanns, C. Muhle-Goll and O. Mayans, Structure, 2006, 14, 1437. 378 Z. Wang, B. M. Potter, A. M. Gray, K. A. Sacksteder, B. V. Geisbrecht and J. H. Laity, J. Mol. Biol., 2007, 366, 375. 379 D. J. Kojetin, R. A. Venters, D. R. Kordys, R. J. Thompson, R. Kumar and J. Cavanagh, Nature Struct. Mol. Biol., 2006, 13, 641. 380 S. Alioth, S. Meyer, R. Dutzler and K. Pervushin, J. Mol. Biol., 2007, 369, 1163. 381 A. G. Tzakos, L. E. Easton and P. J. Lukavsky, J. Am. Chem. Soc., 2006, 128, 13344. 382 Y. J. Chu, S. Sorey, D. W. Hoffman and B. L. Iverson, J. Am. Chem. Soc., 2007, 129, 1304. 383 D. G. Sashital, V. Venditti, C. G. Angers, G. Cornilescu and S. E. Butcher, RNA, 2007, 13, 328. 384 R. J. Richards, H. Wu, L. Trantirek, C. M. O’Connor, K. Collins and J. Feigon, RNA, 2006, 12, 1475. 385 J. Zoll, M. Tessari, F. J. M. Van Kuppeveld, W. J. G. Melchers and H. A. Heus, RNA, 2007, 13, 781. 386 S. Flodell, M. Petersen, F. Girard, J. Zdunek, K. Kidd-Ljunggren, J. Schleucher and S. Wijmenga, Nucleic Acids Res., 2006, 34, 4449. 387 S. J. Headey, H. Huang, J. K. Claridge, G. A. Soares, K. Dutta, M. Schwalbe, D. Yang and S. M. Pascal, RNA, 2007, 13, 351. 388 C. Musselman, S. W. Pitt, K. Gulati, L. L. Foster, I. Andricioaei and H. M. Al-Hashimi, J. Biomol. NMR, 2006, 36, 235. 389 A. Casiano-Negroni, X. Sun and H. M. Al-Hashimi, Biochemistry, 2007, 46, 6525. 390 X. Sun, Q. Zhang and H. M. Al-Hashimi, Nucleic Acids Res., 2007, 35, 1698. 391 J. H. Davis, T. R. Foster, M. Tonelli and S. E. Butcher, RNA, 2007, 13, 76. 392 N. B. Ulyanov, A. Mujeeb, Z. H. Du, M. Tonelli, T. G. Parslow and T. L. James, J. Biol. Chem., 2006, 281, 16168. 393 F. Yu and J. H. Prestegard, Biophys. J., 2006, 91, 1952. 394 T. Zhuang, H. Leffler and J. H. Prestegard, Protein Sci., 2006, 15, 1780. 395 C. M. Thiele, A. Marx, R. Berger, J. Fischer, M. Biel and A. Giannis, Angew. Chem. Int. Ed., 2006, 45, 4455. 396 M. A. Voda, D. E. Demco, A. Voda, T. Schauber, M. Adler, T. Dabisch, A. Adams, M. Baias and B. Blu¨mich, Macromolecules, 2006, 39, 4802. 397 M. Bertmer, M. Wang, D. E. Demco and B. Blu¨mich, Solid State NMR, 2006, 30, 45. 398 R. Valiullin and A. Khokhlov, Phys. Rev. E, 2006, 73, 051605.


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Nuclear spin relaxation in liquids and gases R. Ludwig DOI: 10.1039/b617228h

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 2006 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. As last year the subsection ‘‘Molten Salts’’ is replaced by the 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 represented 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. 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.3 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. Solution NMR spectroscopy represents a powerful tool for examining the structure and function of biological macromolecules. The advent of multidimensional (2D–4D) NMR, together with the widespread use of uniform isotopic labeling of proteins and RNA with the NMR-active isotopes, 15N and 13C, opened the door to detailed analyses of macromolecular structure, dynamics, and interactions of smaller macromolecules. Over the past 10 years, advances in NMR and isotope labeling methods have expanded the range of NMR-tractable targets by at least an order of magnitude. Foster et al.4 briefly described the methodological advances that allow NMR spectroscopy of large macromolecules and their complexes and provide a perspective on the wide range of applications of NMR to biochemical problems. Department of Physical Chemistry, University of Rostock, Dr-Lorenz-Weg 1, Rostock, 18051, Mecklenburg-Vorpommern, Germany


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The paramagnetism of lanthanide ions offers outstanding opportunities for fast determinations of the three-dimensional (3D) structures of protein–ligand complexes by NMR spectroscopy. It is shown how the combination of pseudocontact shifts induced by a site-specifically bound lanthanide ion and prior knowledge of the 3D structure of the lanthanide-labeled protein can be used to achieve (i) rapid assignments of NMR spectra, (ii) structure determinations of protein–protein complexes, and (iii) identification of the binding mode of low-molecular weight compounds in complexes with proteins. Pintacuda et al.5 summerized strategies for site-specific incorporation of lanthanide ions into proteins. Greaves and Sen6 reviewed the current understanding of relaxation in glasses, liquids and polyamorphic states. This included phenomenological models and theories of relaxation in different dynamical regimes, spectroscopic studies of atomic–scale mechanisms of viscous flow in inorganic glass-formers and the signatures of relaxational behaviour embedded in the low-frequency vibrational dynamics of glasses including the Boson peak and the Two-Level Systems (TLS) that control conformational transformation. The authors concluded their review by extending concepts of the dynamics of the glass transition from the supercooled liquid in order to understand the solid-state amorphization of crystals under temperature and pressure and to determine the thermodynamic limits of the crystalline and glassy state. The time-dependence of relaxation during the radiofrequency pulse becomes important for the successful analysis of NMR data. Sorce et al.7 reviewed the general problem of relaxation during adiabatic radiofrequency. McInnes8 reviewed spectroscopic studies of single-molecule magnets, covering electron paramagnetic resonance, nuclear magnetic resonance, inelastic neutron scattering, and magnetic circular dichroism spectroscopies. The range of important information available from each technique on this class of compounds is highlighted, including, for example, cluster spin states, zero-field splitting parameters, exchange coupling constants, and nuclear spin dynamics.

2. General, physical and experimental aspects of nuclear spin relaxation 2.1 General aspects Cross-correlated relaxation rates have proven to be useful to obtain detailed information on molecular structure9,10 internal dynamics,11–15 and chemical shift anisotropy (CSA) tensors.16–18 Usually, only transverse cross-correlation rates are measured, but measurements of longitudinal crosscorrelation rates can enhance the accuracy of the determination of anisotropic rotational diffusion tensors of proteins and of chemical exchange rates.19 Correlated fluctuations of the CSA of a spin S (e.g., 15N) and the dipole–dipole (DD) interaction between two spins S and I (e.g., 1 N H ) lead to an interconversion of the operators Sz and 2IzSz. This is known as ‘‘cross-correlated cross relaxation.’’ The rate of their interconversion, which will henceforth simply be referred to as ‘‘cross-relaxation rate,’’ can be evaluated by detecting the decay of the operator P and by monitoring the buildup of the other term Q in two separate experiments.11 However, since the two operators P and Q usually have different autocorrelated relaxation rates rP and rQ, the crossrelaxation rate d is difficult to quantify.20,21 Kroenke et al.19 developed a method to overcome this problem. This method greatly enhances the accuracy of the measurement of longitudinal cross-correlation rates but also introduces new systematic errors. Moreover, errors may arise due to differences in the detection efficiencies of the relevant operators P and Q.22,23 To overcome these problems, Pelupessy et al.22 have recently introduced a scheme called ‘‘symmetrical reconversion,’’ which was originally designed for the measurement of transverse cross-relaxation rates. Instead of merely measuring the decay of the operator Q = 2SxIz and its conversion into P = Nucl. Magn. Reson., 2008, 37, 180–207 | 181 This journal is

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Sx, they suggested to detect the rates of the decay of both operators P and Q and the two interconversion rates P - Q and Q - P. Pelupessy et al.23 demonstrated that this method was accurate, despite differences in detection efficiencies, and that errors arising from violations of the secular approximation remained tolerable even when the scalar couplings are small compared to the line widths. The authors showed that the application of symmetrical reconversion can also increase the accuracy of the measurement of longitudinal crossrelaxation rates. Nuclear magnetic resonance (NMR) in liquids and solids is primarily detected by recording the net dipolar magnetic field outside the spin-polarized sample. But the recorded bulk magnetic field itself provides only limited spatial or structural information about the sample. Most NMR applications rely therefore on more elaborate techniques such as magnetic field gradient encoding24 or spin correlation spectroscopy,25 which enable spatially resolved imaging and molecular structure analysis, respectively. Savukov et al.26 demonstrated a fundamentally different and intrinsically information-richer modality of detecting NMR, based on the rotation of the polarization of a laser beam by the nuclear spins in a liquid sample. Optical NMR detection has in fact a long history in atomic vapours with narrow resonance lines,27,28 but has so far only been applied to highly specialized condensed matter systems such as quantum dots.29 It has been predicted30 that laser illumination can shift NMR frequencies and thus aid detection, but the effect is very smhall and has never been observed. In contrast, the measurements on water and liquid 129Xe by Savukov et al.26 showed that the complementary effect the rotation of light polarization by nuclear spins—is readily measurable, and that it is enhanced dramatically in samples containing heavy nuclei. This approach to optical NMR detection should allow correlated optical and NMR spectroscopy on complex molecules, and continuous two-dimensional imaging of nuclear magnetization with spatial resolution limited only by light diffraction. So far high-resolution structure determination by NMR spectroscopy has been limited to proteins o30 kDa, although global fold determination is possible for substantially larger proteins. Xu et al.31 presented a strategy for assigning backbone and side-chain resonances of large proteins without deuteration, with which one can obtain high-resolution structures from 1H–1H distance restraints. The strategy uses information from through-bond correlation experiments to filter intraresidue and sequential correlations from through-space correlation experiments, and then matches the filtered correlations to obtain sequential assignment. The authors demonstrated this strategy on three proteins ranging from 24 to 65 kDa for resonance assignment and on maltose binding protein (42 kDa) and hemoglobin (65 kDa) for high-resolution structure determination. The strategy extends the size limit for structure determination by NMR spectroscopy to 42 kDa for monomeric proteins and to 65 kDa for differentially labeled multimeric proteins without the need for deuteration or selective labeling. An accurate description of hydrogen bonds is essential to identify the determinants of protein stability and function as well as folding and misfolding behavior. Gsponer et al.32 described a method of using J couplings through hydrogen bonds as ensemble-averaged restraints in molecular dynamics simulations. Applications to the cases of ubiquitin and protein G showed that these scalar couplings provide powerful structural information that enables the description of the geometry and energetics of hydrogen bonds with an accuracy approaching that of high-resolution X-ray structures. 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 182 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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was found to be essential to the interpretation of the dispersion profile. Perlo and Anoardo33 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. Steinmetz and Maher34 converted a conventional fourier-transform NMR spectrometer into an MRI imager by installing a triple-axis gradient probe and medical imaging software. This arrangement permits imaging of materials that fit into a 5-mm NMR tube to a resolution of 0.05 mm or better. The experiment introduced the student to the physical principles underlying MRI such as gradients, spin echoes, multidimensional spectroscopy, and relaxation. Manz et al.35 characterized a new portable NMR sensor with a novel one-sided access magnet design, termed NMRMOLE (mobile lateral explorer), in terms of sensitivity and depth penetration. The magnet has been designed to be portable and create a volume with a relatively homogeneous magnetic field, 15 000 ppm over a region from 4 to 16 turn away from the probe, with maximum sensitivity at a depth of 10 mm. The proton NMR frequency is 3.3 MHz. The authors have demonstrated that with this approach a highly sensitive, portable, unilateral NMR sensor can be built. Such a design is especially suited for the characterisation of liquids in situations where unilateral or portable access is required. Biological function of biomolecules is accompanied by a wide range of motional behavior. Accurate modeling of dynamics by molecular dynamics (MD) computer simulations is therefore a useful approach toward the understanding of biomolecular function. NMR spin relaxation measurements provide rigorous benchmarks for assessing important aspects of MD simulations, such as the amount and time scales of conformational space sampling, which are intimately related to the underlying molecular mechanics force field. Until recently, most simulations produced trajectories that exhibited too much dynamics particularly in flexible loop regions. Showalter and Bru¨schweiler36 performed a series of 5–20 ns molecular dynamics trajectories of human ubiquitin using the AMBER99 and AMBER99SB force fields for different conditions and water models and compare the results with NMR experimental backbone N–H S (2) order parameters. A quantitative analysis of the trajectories shows significantly improved agreement with experimental NMR data for the AMBER99SB force field as compared to AMBER99. Because NMR spin relaxation data (T1, T2, NOE) reflect the combined effects of spatial and temporal fluctuations of bond vectors, it is found that comparison of experimental and backcalculated NMR spin-relaxation data provides a more objective way of assessing the quality of the trajectory than order parameters alone. In order to detect small variations in 13C isotopomers concentrations, high sensitivity, accuracy and precision have to be achieved. To assess such criteria, when using 13C NMR, Caytan et al.37 proposed 13C bi-labelled ethanol as a molecular probe. Advantage has been taken of the pre-established structural relationship between the peak areas of the 13C NMR spectrum of this molecule, i.e. the ratio of signal areas is set to a fixed value. It was shown that the quality performance, required by quantitative 13C NMR spectroscopy, is not affected by a large reduction of the repetition delay using relaxation reagents. 2.3 Relaxation in coupled spin systems Longitudinal NMR relaxation is the return of perturbed nuclear spin level populations in a magnetic field to their thermal equilibrium value.38,39 Microscopically, it is the interactions of the involved nuclear spins, rendered fluctuating by molecular Nucl. Magn. Reson., 2008, 37, 180–207 | 183 This journal is

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motions, that provide the mechanism. Depending on the fluctuation regime and the involved interactions, there is a rich variety of spin relaxation phenomena, often with significant applications. For spin I = 1/2 nuclei, it is arguably the pairwise dipole– dipole interaction that is the most important one in this context. Biomolecular structure determination,40 today one of the most important applications of NMR spectroscopy, relies on the strong distance dependence of dipole–dipole interaction and therefore that of dipolar relaxation. Nordstierna et al.41 measured intermolecular cross-relaxation rates between solute and solvent by 1H–19F nuclear magnetic resonance experiments in aqueous molecular solutions of ammonium perfluoro-octanoate and sodium trifluoroacetate. The experiments performed at three different magnetic fields provide frequency-dependent cross-relaxation rates which demonstrate clearly the lack of extreme narrowing for nuclear spin relaxation by diffusionally modulated intermolecular interactions. Supplemented by suitable intramolecular cross-relaxation, longitudinal relaxation, and self-diffusion data, the obtained cross-relaxation rates are evaluated within the framework of recent relaxation models and provide information about the hydrophobic hydration. Kehr et al.42 presented a formalism permitting the evaluation of the relative meansquared displacement of molecules from the intermolecular contribution to spinlattice relaxation dispersion of dipolar coupled spins. The only condition for the applicability is the subdiffusive power law character of the time dependence of the mean-squared displacement as it is typical for the chain mode regime in polymer liquids. Using field-cycling NMR relaxometry, an effective diffusion time range from nano- to almost milliseconds can be probed. The intermolecular spin-lattice relaxation contribution can be determined with the aid of isotopic dilution, that is, mixtures of undeuterated and deuterated molecules. Experiments have been performed with melts of polyethyleneoxide and polybutadiene. The mean-squared segment displacements have been evaluated as a function of time over five decades. The data can be described by a power law. 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,43,44 provides key data for de novo structure determination,44 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.45–53 Since most of the ‘classic’ treatments of relaxation theory were written before the advent of high polarizing magnetic fields and the availability of 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,45,54,55 the introduction of TROSY (transverse relaxation-optimised spectroscopy) and CRINEPT (cross-correlated relaxation-enhanced polarization transfer) for studies of large molecular and supramolecular structures,48,56–59 and the observation of residual dipole–dipole couplings at high polarizing magnetic fields.60–62 Luginbu¨hl and Wu¨thrich63 discussed selected aspects of semi-classical relaxation theory that are considered to be of central interest for practical applications in macromolecular solution NMR. Eliseo et al.64 showed that simple modifications of the gradient enhanced version of the TROSY experiment allow obtaining four different spectra containing each one of the components of the H–N doublet in 15N labelled proteins. By measuring the difference in peak position among these four spectra, residual dipolar coupling values could be obtained for medium sized proteins. This experiment, which exploits the use of pulse field gradients to select the 15N coherence pathway, produced excellent results in terms of water suppression. Moreover, tuning of a single delay in the sequence reduces 184 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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notably the presence of artifacts. The performance of this suite of experiments, that the authors called TEC (Trosy-E. Cosy) experiment, is tested against a J-modulation method, inherently more accurate but more time consuming, for the accuracy in the observed values of residual dipolar couplings. The nuclear Overhauser effect (NOE) is undoubtedly one of the most important discoveries in NMR spectroscopy.65 Today it is widely used in solving structural and conformational problems of small organic molecules to macromolecular systems alike.66 In particular, the kinetics of the NOE provides quantitative measurements of the internuclear distances involved, which are extremely valuable in the configurational and conformational analysis of small-to-medium sized organic molecules in solution.66 Such measurements are often conducted with selective 1D kinetic NOE experiments,67–70 in which the cross-relaxation rates are extracted from the slopes of the respective NOE buildup curves, assuming a linear dependence of the NOE growth rate on sm, or the initial rate approximation. The corresponding internuclear distances are subsequently calculated from the cross-relaxation rates using some well-defined distances, such as that between the geminal protons of a methylene group. However, the initial rate approximation can cause large errors as the NOE grows, limiting the utility of the NOE buildup method to only the shortest mixing times. Macura and others71–74 have shown that, in the analysis of 2D NOESY and exchange experiments, the linearity of the initial buildup rate can be substantially extended by taking the ratio of the cross-peak to the diagonal peak, a technique we will refer to as peak amplitude normalization for improved cross-relaxation (PANIC) hereinafter for the sake of simplicity. Other benefits of the PANIC approach have also been discussed in the original work. However, their approach does not seem to have been widely adopted today for the analysis of 1D NOE data. Hu and Krishnamurthy75 demonstrated through a detailed analysis that the same approach can be applied to the analysis of 1D NOE data obtained with the DPFGSE NOE pulse sequence, one of the most widely used selective 1D NOE experiments today. They show that this approach allows the inclusion of data points acquired with much longer mixing times in the analysis and thus considerably improves the accuracy of the measured cross-relaxation rates and internuclear distances, while considerably simplifying the data analysis. Solution NMR spectroscopy76 represents a powerful tool for examining the structure and function of biological macromolecules. The advent of multidimensional (2D–4D) NMR, together with the widespread use of uniform isotopic labeling of proteins and RNA with the NMR-active isotopes, 15N and 13C, opened the door to detailed analyses of macromolecular structure, dynamics and interactions of smaller macromolecules (o25 kDa). Work on these proteins and nucleic acids has been very fruitful and has allowed us to learn much about structure-function relationships, but is inherently limited, as the majority of macromolecular complexes of biochemical interest are significantly larger than 25 kDa. Indeed, although much can be learned by examining macromolecules in isolation, mechanistic insights are often only gained upon studying functional higher-order assemblies with partner molecules. NMR studies of large molecules and complexes are complicated by the increased linewidths associated with slower tumbling and the spectral overlap from the large number of unique signals. Over the past 10 years, advances in NMR and isotope labeling methods have expanded the range of NMR-tractable targets by at least an order of magnitude (for recent reviews76,77) Foster et al.4 briefly described the methodological advances that allow NMR spectroscopy of large macromolecules and their complexes and provide a perspective on the wide range of applications of NMR to biochemical problems. Dong et al.78 explored the dipolar interactions between two separate nuclear spin ensembles in a mixture containing oil and water. They expanded initial results79 to the case in which both systems have the shape of flat, stacked disks. They find that-in spite of the strong inhomogeneity of the coupling dipolar field-the signal encoded in one of the components can be made approximately proportional to the Nucl. Magn. Reson., 2008, 37, 180–207 | 185 This journal is

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magnetization in the other. This allows them to use one of these systems as a ‘sensor’ to indirectly reconstruct the resonance spectrum or to determine the relaxation time of the ‘sample’ system. In the regime in which dipolar interactions are sufficiently strong, their method can be set to scale-up weaker signals in a non-linear fashion, which, potentially, could allow one to introduce contrast or to improve detection sensitivity of less magnetized samples. The access to weak alignment media has fuelled the development of methods for efficiently and accurately measuring residual dipolar couplings (RDCs) in NMRspectroscopy. Among the wealth of approaches for determining one-bond scalar and RDC constants only J-modulated and J-evolved techniques retain maximum resolution in the presence of differential relaxation. Furrer et al.80 examined a number of J-evolved experiments are examined with respect to the achievable minimum linewidth in the J-dimension. 2.5 Exchange spectroscopy The fast two dimensional inverse Laplace transform81 has led to the development of many new experiments82–86 to better characterise materials, and especially molecular dynamics in porous media. In previous work, Washburn and Callaghan87 demonstrated a new two-dimensional transverse relaxation exchange experiment88,89 to track the movement of spin bearing water molecules in a Castlegate sandstone. This was accomplished by performing a T2 encode followed by a magnetisation storage interval to allow the molecules to diffuse, and finally a second T2 encode. By correlating the T2 values of the molecules at two different points in time, the authors could see how fluid movement occurs between subpopulations in a sample. As for a Fourier exchange experiment, spins remaining in their original environment lie along the diagonal of an inverse Laplace exchange spectrum. Wahburn and Callaghan90 expanded the previous two-dimensional transverse relaxation exchange technique by the addition of a propagator dimension,91 combining the two inverse Laplace dimensions with a third fourier dimension. This is the first experiment with such a combination of dimensions, though prior work92,93 has paired a single inverse Laplace dimension with a fourier dimension. Kateb et al.94 introduced a method to measure hydrogen exchange rates based on the observation of the coherence of a neighboring spin S such as 15N that has a scalar coupling JIS to the exchanging proton I. The decay of S-x coherence under a CarrPurcell-Meiboom-Gill (CPMG) multiple echo train is recorded in the presence and absence of proton decoupling. This method allows one to extract proton exchange rates up to 105 s1. We could extend the pH range for the study of the indole proton in tryptophan, allowing the determination of the exchange constants of the cationic, zwitterionic, and anionic forms of tryptophan. Chavez et al.95 reported the water 2H and 17O magnetic relaxation dispersion (MRD) profiles from gelatin gels over wide ranges of resonance frequency and pH. For the global analysis of this extensive data set, they used a generalized relaxation theory that remains valid for arbitrarily slow molecular dynamics. The strong pH dependence in the 2H profiles can be rationalized quantitatively as the result of exchange with bulk water of labile hydrogens in gelatin side chains. The global analysis of the MRD data yields hydrogen-exchange rate constants, acid dissociation constants, and orientational order parameters in agreement with independent structural, thermodynamic, and kinetic data. This study takes a significant step toward a quantitative understanding of water relaxation in aqueous gels and biological tissue. Nikolaev and Pervushin96 presented the resonance assignment, secondary structure, and dynamic properties of a stable noncoiled coil conformation of the dimerization domain from a yeast transcription activation factor. The authors showed that a new line of fully optimized spin state exchange experiments, XYEX-TROSY, applied to 1H–(N), 15N and 1H(a), 13C(a) moieties, established that in broad range of pH and buffer conditions the classical LZ(GCN4) coiled coil 186 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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dimer is in a dynamic equilibrium with another distinct conformation (denoted here as x-form) and enabled complete assignment of the resonances stemming from the x-form. Garcia et al.97 developed hyperpolarized xenon associated with ligand derivatized cryptophane-A cages as a NMR based biosensor. To optimize the detection sensitivity they described use of xenon exchange between the caged and bulk dissolved xenon as an effective signal amplifier. This approach, somewhat analogous to ‘remote detection’ described recently, uses the chemical exchange to repeatedly transfer spectroscopic information from caged to bulk xenon, effectively integrating the caged signal. After an optimized integration period, the signal is read out by observation of the bulk magnetization. The spectrum of the caged xenon is reconstructed through use of a variable evolution period before transfer and Fourier analysis of the bulk signal as a function of the evolution time. LeMaster et al.98 measured the exchange kinetics for amide hydrogens along the protein backbone which continues to offer valuable insights into structural stability and conformational dynamics. Since such studies routinely compare samples that differ in solution conditions or mechanical handling, normalization of the relative exchange rates can present a potentially significant source of experimental uncertainty. The carbon acids 1,3-dimethylimidazolium cation and thiomethylacetonitrile exhibit base catalyzed exchange rates similar to those of the slowly exchanging amides, under conditions typical for protein studies. 2.6 Radiation damping The phenomenon of radiation damping has been known for almost as long as nuclear magnetic resonance has been studied. As far back as 1949, Suryan99 first proposed the interaction of an r.f. coil with the bulk magnetization of a sample as an explanation for the discrepancy between theoretical predictions of relaxation times and experimental observation. Bloembergen and Pound100 formulated Suryan’s hypothesis mathematically by combining the Bloch and Maxwell equations, coining the phrase ‘‘radiation damping’’. Bruce et al.101 highlighted an erroneous assumption in the original Bloembergen paper, but the steady-state limit is the same in both descriptions. Building on the previous work, Bloom102 published modified Bloch equations in which the effects of RD are included directly in a set of non-linear differential equations describing the motion of bulk magnetization. Bloom successfully described the effects of RD on the lineshapes of continuous wave (CW) experiments with and without relaxation, and highlighted the effects on adiabatic rapid passage. Szo¨ke and Meiboom103 showed that for flip angles between 901 and 2701 the free induction decay following a single pulse passes through a maximum before decaying, drawing attention to the fact that the term ‘‘radiation damping’’ is something of a misnomer. Williamson et al.104 examined the effects of RD and probe tuning on the shape and asymmetry of Z-spectra both theoretically and experimentally, in a one-pool system and in an exchanging two-pool model. It is shown that under commonly encountered conditions, the combination of RD and inexact tuning can lead to a relatively large asymmetry in the steady-state Z-spectrum, potentially complicating the interpretation of (pH-dependent) exchange-induced asymmetry. It is also demonstrated that in experiments using short irradiation times, comparable to the T2 of the water pool, RD can change the shape of the Z-spectrum very significantly. The joint action of two feedback fields in solution magnetic resonance (MR), radiation damping and the distant dipolar field, are known to give rise to nonlinear evolution of the magnetization at high fields. Datta et al.105 explored the different stages of the resulting complex dynamics. Standard tools and terminology adopted from the theory of nonlinear dynamics were introduced to analyze the underlying dynamics. The nonlinear spin dynamics were shown to generate unexpected artifacts in routine MR experiments involving bulk solvents. Data et al.106 proposed a conceptually new approach giving rise to contrast enhancement by feedback fields Nucl. Magn. Reson., 2008, 37, 180–207 | 187 This journal is

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in magnetic resonance imaging, and described the detailed mechanism. Nonlinear spin dynamics under the feedback fields of the distant dipolar field and/or radiation damping were examined and shown to amplify contrast due to small variations in spin density and precession frequency. On the basis of a theoretical understanding of contrast enhancement, insight into pulse sequence design and optimal contrast attainable under the individual and joint feedback fields was provided. Walls et al.107 used pulsed-field gradients to modulate the radiation damping field generated by the detection coil in an NMR experiment in order that spins with significantly different chemical shifts can affect one another via the radiation damping field. Experiments performed on solutions of acetone/water and acetone/ DMSO/water demonstrate that spins with chemical shift differences much greater than the effective radiation damping field strength can still be coupled by modulating the radiation damping field. Implications for applications in high-field NMR and for developing sensitive magnetization detectors were discussed. Krishnan108 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. In solution MR, manipulating the spin system in real time is difficult to implement in part due to the challenge of measuring the longitudinal magnetization within the constraints of MR detection hardware. Scarnmann et al.109 exploited the dynamical frequency shift induced by the radiation damping feedback field to estimate the longitudinal magnetization of individual spin species in one-, two-, and threecomponent spin systems. The calculated longitudinal magnetization is found to be in excellent agreement with that measured through independent experiments. Targeting the goal of differential spin control, extensions of this approach to realtime tracking of magnetization trajectories are discussed. The presence and diagnosis of radiation damping could also have major implications in NMR experiments with hyperpolarised gases, where accurate knowledge of the flip angle is imperative. Teh et al.110 observed radiation damping and investigated in a low-pass birdcage resonator with samples of hyperpolarised 3He at 1.5 T. A linear relation between the sample’s magnetisation and the line width of the spectrum was observed which is indicative of radiation damping. Experimental observation of radiation damping could be used as means of measuring coil efficiency as an alternative to the geometrical filling factor the definition of which is open to question for a birdcage resonator. Most established NMR thermometers rely on temperature-dependent chemical shift differences measured from samples that are either neat or concentrated solutions (e.g. ethylene glycol, methanol). These are unsuitable for modern cryoprobes on account of strong radiation damping resulting from the high Q of the probe. Using perdeuterated methanol, Findeisen et al.111 established a relationship between the chemical shift difference and temperature, and could show that this relationship is well fitted by a quadratic equation. The actual temperature within a sample tube in the probe was verified using a Pt-100 resistor. 2.7 Quadrupolar interactions Kantola et al.112 determined deuterium quadrupole coupling constants (DQCC) in benzene both experimentally by NMR spectroscopy in liquid crystalline solutions and theoretically by ab initio electronic structure calculations. DQCCs were measured for benzene-d(1) and 1,3,5-benzene-d(3) using several different liquid crystalline solvents and taking vibrational and deformational corrections into account in the analysis of experimental dipolar couplings, used to determine the orientational order parameter of the dissolved benzene. The experimental DQCC results for the isotopomers benzene-d(1) and 1,3,5-benzene-d(3) are found to be 187.7 kHz and 187.3 kHz, respectively. Kotsyubynskyy et al.113 investigated reorientation of 9188 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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(trideuteromethyl)purine and 7-(trideuteromethyl)purine molecules in methanold(4) solutions on the basis of the interpretation of the nuclear spin relaxation rates of their 14N (or 1H) and 13C nuclei. The transverse quadrupole relaxation rates of 14 N nuclei have been obtained from the line shape analysis of their 14N NMR spectra. Alternatively, the information on the longitudinal 14N relaxation rates has been obtained via the scalar relaxation of the second kind of protons coupled to 14N. Pennanen et al.114 determined NMR parameters are theoretically for the oxygen and hydrogen/deuterium nuclei of differently hydrogen-bonded water molecules in liquid water at 300 K. The parameters were the chemical shift, the shielding anisotropy, the asymmetry parameter of shielding, the nuclear quadrupole coupling constant, and the asymmetry parameter of the nuclear quadrupole coupling. The analysis revealed in detail how the NMR tensors evolve as the environment changes gradually from gas to liquid upon increasing the number of hydrogen bonds to the molecule of interest. Liquid-state distributions of the instantaneous values of the NMR properties showed a wide range of values for each hydrogen-bonding species with significant overlap between the different cases. The authors showed how local changes in the environment affect the NMR parameters in liquid water. For example, a broken or alternatively extra hydrogen bond induced major changes in the NMR tensors, and the effect was more pronounced for hydrogen or deuterium than for oxygen. The data shed new light on the usefulness of NMR experiments in investigating the local coordination of liquid water. The NMR spectra for the I = 3/2 23Na cation dissolved into filamentous bacteriophage Pf1 solutions display line splittings and relaxation times consistent with an interaction between the 23Na nuclear quadrupole moment and the electric field gradient produced by the negatively charged Pf1 particles. Sobieski et al.115 measured the 23Na NMR line splittings and relaxation rates corresponding to magnetization recovery and single, double, and triple quantum coherence decays in Pf1 solutions and compared them to theoretical values. Correlation functions and thus spectral densities for this process were calculated from solutions to the FokkerPlanck equation for radial motion in an electric potential and used to estimate measured relaxation rates. Birczynski et al.116 studied deuteron spin-lattice relaxation both theoretically and experimentally in polycrystalline samples of ammonium hexachlorotellurate with deuteron concentrations ranging from 5% to 100%. A model is derived for the initial deuteron relaxation rate, via the electric quadrupole interaction, under the assumption that the static part of the rotational Hamiltonian and ammonium rotation obeys the same symmetry. The relaxation rates via the deuteron–proton magnetic dipolar interaction were considered. Experimental results were explained by the above model based on the quadrupole interaction at higher deuterations and by so-called limited jumps at lower deuterations. Birczynski et al.117 studied deuteron spin-lattice relaxation in ammonium hexachlorostannate and perchlorate. Of the various ways in which nuclear spin systems can relax to their ground states, the processes involving an interference between different relaxation mechanisms, such as dipole–dipole coupling and chemical shift anisotropy, have become of great interest lately. Ling and Jerschow118 showed that the interference between the quadrupolar coupling and the paramagnetic interaction (cross-correlated relaxation) gives rise to nuclear spin transitions that would remain forbidden otherwise. 2.8 Intermolecular dipolar interaction in diamagnetic and paramagnetic solution Paramagnetic systems contain one or more unpaired electrons and have therefore a positive magnetic susceptibility. The paramagnetic systems of main interest to chemists usually contain either free radicals or transition metal complexes in solution. The unpaired electron spins strongly interact with nuclear spins and influence NMR spectra of liquids mainly in two ways. First, the chemical shift scale can be largely expanded and 1H shifts of more than 100 ppm can be observed due Nucl. Magn. Reson., 2008, 37, 180–207 | 189 This journal is

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to the large magnetic moment of unpaired electrons. Second, the longitudinal, 1/T1, and transverse, 1/T2, nuclear spin relaxation rates are enhanced. This effect is commonly called paramagnetic relaxation enhancement (PRE) and its most palpable effect is a more or less marked broadening of the NMR resonance lines. Although used in chemistry since the 1960s, the number of nuclear magnetic resonance studies of solutions with paramagnetic species started to increase strongly in the 1990s mainly because of its use in biochemistry and in research on contrast agents (CA) for medical magnetic resonance imaging (MRI). Applications of NMR in paramagnetic systems in biochemistry have been the subject of several reviews.119–124 Recent developments in the field have been summarized by several authors.125–132 Helm133 reviewed paramagnetic relaxation enhancement due to transition metal ions in solution. The use of 1H transverse paramagnetic relaxation enhancement (PRE) has seen a resurgence in recent years as method for providing long-range distance information for structural studies and as a probe of large amplitude motions and lowly populated transient intermediates in macromolecular association. Iwahara et al.134 discussed various practical aspects pertaining to accurate measurement of PRE 1H transverse relaxation rates. They first showed that accurate rates can be obtained from a two time-point measurement without requiring any fitting procedures or complicated error estimations, and no additional accuracy is achieved from multiple time-point measurements recorded in the same experiment time. Optimal setting of the two time-points that minimize experimental errors is also discussed. Next they showed that the simplistic single time-point measurement that has been commonly used in the literature, can substantially underestimate the true value of the transverse relaxation rate, unless a relatively long repetition delay is employed. Pronounced paramagnetic relaxation enhancement (PRE) due to paramagnetic metal ions prevents the observation of NMR signals from 1H spins near the metal. While 15 N spins are less prone to PRE, the intrinsic sensitivity of 15N NMR spectroscopy is low. John et al.135 presented a 1H detected out-and-back N-z-exchange experiment which allows the measurement of pseudocontact shifts of 15N spins located as close as 6 angstrom from a Dy3+ ion in a 30 kDa protein complex. The experiment relies on the chemical exchange between paramagnetic and diamagnetic metal ions during two mixing times during which the 15N magnetization is stored as PRE-insensitive longitudinal magnetization. Off-resonance rotating frame technique offers a novel tool to explore the dynamics of paramagnetic agents at high magnetic fields (B0 4 3 T). Based on the effect of paramagnetic relaxation enhancement in the off-resonance rotating frame, Zhang et al.136 described a new method for determining the dynamics of paramagnetic ion chelates from the residual z-magnetizations of water protons. In this method, the dynamics of the chelates are identified by the difference magnetization profiles, which are the subtraction of the residual z-magnetization as a function of frequency offset obtained at two sets of r.f. amplitude o1 and pulse duration t. Effects of hydration water number q, diffusion coefficient D, magnetic field strength B0 and multiple rotational correlation times were explored with the simulations of the magnetization map. This method not only provides a simple and reliable approach to determine the dynamics of paramagnetic labeling of molecular/cellular events at high magnetic fields, but also a new strategy for spectral editing in NMR/ MRI based on the dynamics of paramagnetic labeling in vivo. Rational drug design depends on the knowledge of the three-dimensional (3D) structure of complexes between proteins and lead compounds of low molecular weight. John et al.137 proposed a novel NMR spectroscopy strategy based on the paramagnetic effects from lanthanide ions which allows the rapid determination of the 3D structure of a small ligand molecule bound to its protein target in solution and, simultaneously, its location and orientation with respect to the protein. The method relies on the presence of a lanthanide ion in the protein target and on fast exchange between bound and free ligand. The binding affinity of the ligand and the paramagnetic effects experienced in the bound state are derived from concentration190 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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dependent 1H and 13C spectra of the ligand at natural isotopic abundance. Metal ions play a key role for the function of many proteins. The interaction of the metal ion with the protein and its involvement in the function of the protein vary widely. In some proteins, the metal ion is bound tightly to the ligand residues and may be the key player in the function of the protein, as in the case of blue copper proteins. In other proteins, the metal ion is bound only temporarily and loosely to the protein, as in the case of some metalloenzymes and other proteins where the metal ion acts as a cofactor necessary for the function of the protein. Such proteins are often known as metal ion-activated proteins. Jensen et al.138 reviewed recent NMR studies of a series of metal-dependent proteins and the characterization of the metal-binding sites. In particular, they focus on NMR techniques for studying metal binding to proteins such as chemical shift mapping, paramagnetic NMR and changes in backbone dynamics upon metal binding. Understanding the mechanism of protein–DNA interactions at the molecular level is one of the main focuses in structural and molecular biological investigations. At present, NMR spectroscopy is the only approach that can provide atomic details of protein–DNA recognition in solution. However, determining the structures of protein–DNA complexes using NMR spectroscopy has been dependent on the observation of intermolecular nuclear overhauser effects (NOE) and their assignments, which are difficult to obtain in many cases. Cai et al.139 have shown that intermolecular distance constraints derived from a single spin-label in combination with docking calculations have defined many specific contacts of complexes. One of the main goals of NMR method development is to increase the sensitivity of multidimensional NMR experiments or reduce the required acquisition time. In these experiments, more than 80% of the NMR instrument time is spent on the recycle delay, where the instrument idles to wait for the recovery of proton magnetization. Cai et al.140 reported a method of using paramagnetic relaxation effects to shorten the recycle delays required in multidimensional NMR experiments of biological macromolecules. Fumino et al.141 reported the paramagnetic contributions from dioxygen to solute proton spin-lattice relaxation rate constants for a series of aromatic hydrocarbons and drug molecule fragments, in order to examine the energetic factors for intermolecular exploration in solution. The measurements provide differences in local oxygen concentration at different sites on the solute molecule. The relaxation rate differences caused by steric factors are taken into account using a lattice model calculation to normalize the relaxation rates for intermolecular contact. The lability and structural dynamics of [Fe-II(edta)(H2O)]2 (edta = ethylenediaminetetraacetate) in aqueous solution strongly depend on solvent interactions. Maigut et al.142 applied, 1H, 13C, and 17O NMR techniques to study the solution structure and water-exchange mechanism. The water-exchange reaction was studied through the paramagnetic effect of the complex on the relaxation rate of the 17O nucleus of the bulk water. In addition to variabletemperature experiments, high-pressure NMR techniques were applied to elucidate the intimate nature of the water-exchange mechanism. Lanthanide(III) complexes of polyaminocarboxylates are widely used in MRI as contrast agents. The paramagnetic properties of the metal ion contribute to the increase of 1H relaxation rates, while the chelate offers a stable binding with the metal. The number of water molecules, coordinated directly to the Ln(III) ion, is very important for the relaxivity and, thus, the efficacy of these contrast agents. Djanashvili and Peters143 described convenient methods to determine this parameter by measurement of Ln(III)-induced shifts of the water 17O NMR resonance. Fast T1 mapping techniques are a valuable means of quantitatively assessing the distribution and dynamics of intravenously or orally applied paramagnetic contrast agents (CAs) by noninvasive imaging. Treier et al.144 optimized a fast T1 mapping technique based on the variable flip angle (VFA) approach for accurate T1 quantification in abdominal contrast-enhanced (CE) MRI. Optimization methods were developed to maximize the signal-to-noise ratio (SNR) and ensure effective r.f. Nucl. Magn. Reson., 2008, 37, 180–207 | 191 This journal is

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and gradient spoiling, as well as a steady state, for a defined T1 range of 100–800 ms and a limited acquisition time. 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. Sen et al.145 studied the temporal evolution of the coordination environments of B atoms in simple and complex borosilicate glasses following temperature jumps near the glass-transition temperature using 11B magic-angle-spinning NMR spectroscopy. The relaxation kinetics for boron speciation was found to be in excellent agreement with those for density and shear relaxation at the same temperature, irrespective of the compositional makeup of the glass. Moreover, the temperature dependence of boron speciation was found to be the most important source for the production of configurational entropy in these glasses near the glass-transition range, signifying a direct link between structure, configurational entropy, and viscous flow. Graeves and Sen6 investigated familiar inorganic oxide glasses, non-oxide glasses and liquids for understanding their atomic structure, ranging from the local environments of individual atoms to the long range order which can cover many interatomic distances. The structural characteristics of important glasses and melts, like silicates, borates, alumino-silicates, halides and chalcogenides, were drawn from the results of recent spectroscopy and scattering experiments. The techniques include NMR and X-ray absorption fine structure, neutron scattering and Small- and Wideangle X-ray scattering measurements, and were often combined with computer simulation experiments in order to obtain detailed images of structure and diffusion in the glassy as well as in the molten state. Steuber et al.146 characterized nearest-neighbor chain packing in a homogeneous blend of carbonate 13C-labeled bisphenol A polycarbonate and CF3-labeled bisphenol A polycarbonate using a shifted-pulse version of magic-angle spinning 13C {19F} rotational-echo double-resonance (REDOR) NMR. Complementary NMR experiments have also been performed on a polycarbonate homopolymer containing the same 13C and 19F labels. In the blend, the 13C observed spin was at high concentration, and the 19F dephasing or probe spin was at low concentration. Ramanuja et al.147 reported the results of our 1H-NMR spin-lattice relaxation time (T1) studies in betaine phosphate which is ferroelectric below 86 K and antiferroelectric below 81 K. 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. The low temperature (T o 100 K) T1 data has been analysed following Lourens model which considers the gradual transition from classical motions to quantum regime. At low temperatures, when classical processes tend to freeze, reorienting groups apparently have minute differences and hence create a distribution in the energy values and preexponential factors. Geil et al.148 formulated quantitatively the question regarding a possible correlation of the time scales of primary and secondary relaxations in supercooled liquids. It was shown how this question can be answered using spinlattice relaxation weighted stimulated-echo experiments, which were presented in an accompanying paper by Nowaczyk et al.149 General theoretical expressions relevant for the description of such experiments in the presence of correlation effects were derived. Stretched exponentials are often used to describe quasi-elastic neutron 192 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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scattering (QENS) and nuclear magnetic resonance (NMR) relaxation data from polymer melts. Zanotty et al.150 attempt to derive a more physically meaningful model of the local, short-time dynamics of linear polymers that takes into account (i) orientational diffusion along the polymer chain, (ii) local conformational transitions, and (iii) long-time, large-scale motions. Somma et al.151 investigated orientation molecular dynamics in a series of ‘‘defect-free’’ 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. This is well accounted for by the Landau-de Gennes theory, however, with a strong temperature dependence of the viscosity coefficient, reflecting the proximity of the glass transition. For the trimer the two transitions almost overlap and the molecular orientation coincide with the alpha-relaxation associated with the glass transition. The NMR measurements confirm that the time scale of the dynamics is completely governed by the glass process. 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. Halle152 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). Model-free analysis of NMR relaxation data, which describes the motion of individual atoms, is a problem intricately linked to the Brownian rotational diffusion of the macromolecule. The diffusion tensor parameters strongly influence the optimisation of the various model-free models and the subsequent model selection between them. Finding the optimal model of the dynamics of the system among the numerous diffusion and model- free models is hence quite complex. D’Auvergne and Gooley153 used set theory to encapsulate the entirety of this global problem by the universal set. Ever since the original Lipari and Szabo papers the model-free dynamics of a molecule has most often been solved by initially estimating the diffusion tensor. The model- free models which depend on the diffusion parameter values were then optimised and the best model was chosen to represent the dynamics of the residue. Finally, the global model of all diffusion and model-free parameters is optimised. These steps are repeated until convergence. NMR spin relaxation of 2H nuclei in (CH2D)–13C groups is a powerful method for studying side-chain motion in proteins. The analysis is typically carried out with the original model-free (MF) approach adapted to methyl dynamics. The latter is described in terms of axial local motions around, and of, the methyl averaging axis, mutually decoupled and independent of the global motion of the protein. Methyl Nucl. Magn. Reson., 2008, 37, 180–207 | 193 This journal is

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motion is characterized primarily by the axial squared order parameter, S-axis(2), associated with fluctuations of the methyl averaging axis. This view is shown to be oversimplified by applying to typical experimental data the slowly relaxing local structure (SRLS) approach of Polimeno and Freed154 which can be considered the generalization of the MF approach. Neglecting mode coupling and the asymmetry of the local ordering and treating approximately features of local geometry imply inaccurate values of S-axis(2), hence of the residual configurational entropy derived from it. S-axis(2), interpreted as amplitude of motion, was found to range from near disorder to almost complete order. Contrary to this picture, Meirovitch et al.155 found with the SRLS approach a moderate distribution in the magnitude of asymmetric local ordering and significant variation in its symmetry. The latter important property can be associated implicitly with the contribution of side-chain rotamer jumps. This is consistent with experimental residual dipolar coupling studies and theoretical work based on molecular dynamics simulations and molecular mechanics considerations. Domain mobility plays an essential role in the biological function of multidomain systems. The characteristic times of domain motions fall into the interval from nano- to milliseconds, amenable to NMR studies. Proper analysis of NMR relaxation data for these systems in solution has to account for interdomain motions, in addition to the overall tumbling and local intradomain dynamics. Ryabov and Fushmann156 proposed a model of interdomain mobility in a multidomain protein, which considers domain reorientations as exchange/interconversion between two distinct conformational states of the molecule, combined with fully anisotropic overall tumbling. The authors also compare their model with the ‘‘extended model-free’’ approach and discuss possible future developments of the model. Recording four-time correlation functions in experiments and computer simulations, Vogel et al.157 measured the lifetime of dynamical heterogeneities associated with the ionic jump motion in phosphate glasses. 109Ag NMR four-time correlation functions for a silver iodide doped silver phosphate glass indicatedthat the silver ions exhibit a random new rate from a broad distribution after very few jumps, implying that silver sites featuring fast and slow ionic jumps were intimately mixed rather than grouped into extended domains. Likewise, four-time correlation functions from molecular dynamics simulations of LiPO3 glass showed that the dynamical heterogeneities observed for the lithium ionic jumps are short lived. Hence, rapid rate exchange is an important feature of the ion dynamics in an experimental and a model phosphate glass, i.e., the ionic diffusion is comprised of a random series of fast and slow jumps.

3. Selected applications of nuclear spin relaxation 3.1 Pure liquids Dynamics of simple monomeric liquids at temperatures about and below the melting point are determined by the glass transition phenomenon. Connecting monomers into linear polymer chains leads to further relaxation processes158 that are slow with respect to the glass transition time scale determined by the local segmental dynamics. Depending on the molecular weight relative to the entanglement weight, the dynamics are described either by the Rouse or reptation model. Many studies cover the crossover from Rouse to reptation dynamics, while the transition from a simple liquid to polymer melt received less attention.159–163 In particular, the nature of Tg(M) dependence is still debated. It was, e.g., argued that Me and the Rouse unit size MR are not relevant for Tg(M),164 or that Tg is governed by the concentration of polymer ends.164 Nuclear magnetic resonance (NMR) field cycling (FC) relaxometry is well suited to study slow polymer dynamics by detecting the dispersion of the related spin-lattice relaxation time T1(o). Compared to other methods, it is unique in that it predominantly detects segmental reorientation dynamics (incoherent, local 194 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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response) in a wide range up to 103–108 Hz. Routine FC studies became recently possible with the availability of a commercial spectrometer, which allowed Kimmich and co-workers to thoroughly investigate Rouse and reptation dynamics.165 However, a relaxometric study down to the limit of simple liquid is still missing. Kariyo et al.166 presented such 1H NMR study of simple liquids to a polymer melt. Szymczak et al.167 investigated the effect of hydrogen bonding on the rotational correlation time of an H-bond acceptor, pyridine N-oxide-d(5), in various solvents using the 2H spin-lattice relaxation time T1. The results demonstrated a linear relationship between viscosity and measured rotational correlation times, an example of Stokes-Einstein-Debye behavior. The results also clearly demonstrate reduced rotational rates for the probe in hydrogen bonding solvents in comparison to solvents incapable of forming hydrogen bonds with the probe. The study of water in confined geometries has been receiving much attention in chemistry, biology, and geology.168 A variety of spectroscopic and theoretical investigations have demonstrated that water molecules confined in 1-nm-scale materials such as porous silica show unique properties not seen on the bulk scale.169–174 A 1-nm-scale space is available as an experimental space for characterizing the behavior of an individual single molecule, while this scale is too small to illuminate the collective behaviors of liquid-phase molecules as condensed-phase matter. To elucidate the complicated properties of liquid-phase water molecules, a 10–100-nm-scale space is appropriate but has been almost unavailable. The technologies involved in micro- and nanochemistry on a chip are expected to allow the production of a physicochemically well-defined 10–10-nm-scale space on glass substrates (called an extended nanospace). Tsukahara et al.175 have employed NMR spectroscopy results to characterize the molecular structure and dynamics of water confined in extended nanospaces. Their NMR results will have important implications for both understanding the behavior of nanofluidics and the molecular physical chemistry of liquid-phase molecules and implementing micro- to nanofluidic devices. Hwang et al.176 employed double-quantum-filtered NMR and T1 inversionrecovery spectroscopy to study the temperature-dependent dynamics of D2O confined in MCM-41. Samples with three pore sizes of 1.58, 2.03, and 2.34 nm and two D2O contents were investigated. The reorientation correlation times of confined D2O in variously sized pores exhibit different temperature dependencies. The results reveal that the D2O molecules at fast motion site remain mobile below similar to 225 K and a liquid–liquid phase transition occurs around this temperature for all samples studied. 3.2 Non-electrolyte solutions Birczynski et al.117 studied deuteron spin-lattice relaxation in 5% and 100% deuterated ammonium hexachlorostannate and perchlorate. The relaxation rate was observed to be independent of deuteration down to temperatures slightly lower than that of the maximum. At lower temperatures the rate of the 5% deuterated sample exceeds that of the 100% deuterated sample by four and two orders of magnitude in ammonium hexachlorostannate and perchlorate, respectively. The angular dependence of the deuteron relaxation rate in 5% deuterated ammonium hexachlorostannate at 6 K is explained in terms of existing models on quadrupolar relaxation. Merzliak et al.177 employed a previously derived model to describe intradiffusion coefficients in liquid mixtures based on molecular simulations of spherical Lennard-Jones particles178 an improved set of coefficients was obtained from optimized molecular dynamics simulations. In these simulations, the thermodynamic states were planned with the help of optimal experimental design, which allows reducing 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, 1,4dioxane + cyclohexane and cyclohexane + n-hexane, which have molecular Nucl. Magn. Reson., 2008, 37, 180–207 | 195 This journal is

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properties that correspond to the model assumptions, Experimental intra-diffusion coefficients for the mixtures toluene + cyclohexane, toluene + 1,4-dioxane, n-hexane + toluene and 1,4-dioxane + cyclohexane were determined with NMR techniques in this work.

3.3 Electrolyte solutions Hayamizu et al.179 measured individual ion diffusion (as a weighted average of charged and neutral ions) using pulsed-gradient spin-echo (PGSE) NMR. They studied the lithium transport in an electrolyte including a lithium salt using electrophoretic NMR (ENMR) with non-blocking electrodes. A propylene carbonate (PC) solution doped with LiN(SO2CF3)2(LiTFSI) was inserted in a homemade NMR cell equipped with Li/Li electrodes. The drift migrations of lithium cation (7Li), anion (19F), and solvent (1H) were measured independently under potentials of up to 3.0 V. Greatly enhanced dynamic lithium transport was observed for the first time in the bulk electrolyte under an electric field closely related to real conditions in a rechargeable lithium battery. 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. Using a combination of density functional theory with classical and Car-Parrinello molecular dynamics simulations, Yazyev and Helm180 performed a computational study of the 17O quadrupole coupling constants in model aqua ions and the [Gd(DOTA)(H2O)] complex used in clinical diagnostics. They concluded that the 17O quadrupole coupling parameters of water molecules coordinated to closed shell and lanthanide metal ions are similar to water molecules in the liquid state. Jayakody et al.181 described mass-transport studies of phosphoric acid (PA)doped meta-polybenzimidazole (PBI) fuel cell membranes. They explored the fundamental differences in transport properties between m-PBI/ PA membranes prepared by conventional imbibing procedures and the polyphosphoric acid (PPA) process. The membranes were characterized by proton conductivity and multinuclear (1H and 31P) magnetic resonance measurements. Both short-range and longrange dynamical processes were investigated by spin-lattice and spin–spin relaxation time measurements and by pulsed field gradient diffusion, respectively. The molecular self-association of hydrophobic substances is an important process for many biological systems. Jeufack and Suter182 studied the effect of salt on the molecular self-association of t-butanol in water solution, using NMR techniques. The authors compared the effects of different sodium halides (NaCl, NaBr, and NaI) as a function of their concentration.

3.4 Ionic liquids and molten salts Ionic Liquids (ILs) present a new class of interesting materials which gained tremendous attention in the last 15 years.183–198 Many chemical reactions have been attempted and successfully performed in ionic liquid media and oftentimes these systems show interesting and peculiar features. Most of the work in IL chemistry is still based on trial-and-error rather than fundamental understanding and rational design. Not enough is known to date about properties and structure of these new materials in the liquid phase. To that end, suitable in situ methods that allow for thorough investigations are paramount. NMR spectroscopy is one obvious choice in this respect. In cases where radicals are involved, even more obviously, EPR spectroscopy is the method of choice. Bankmann and Giernoth199 reviewed the chemical literature on NMR and EPR spectroscopy in the context of ionic liquids from the early eighties up to September 2006. The intent is to give the reader a 196 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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comprehensive overview on magnetic resonance spectroscopy on and especially in these media. Trimethylsilylmethyl (TMSiM)-substituted imidazolium bis(trifluoromethylsulfonyl)imide (NTf2-), and tetrafluoroborate (BF4-) ionic liquids (ILs) have lower roomtemperature viscosities by factors of 1.6 and 7.4, respectively, than isostructural neopentylimidazolium ILs. In an attempt to account for the effects of silicon substitution in imidazolium RTILs and to investigate the ion dynamics, Chang et al.200 reported nuclear magnetic resonance (NMR) measurements of 1H and F-19 spin-lattice relaxation times (T1) and self-diffusion coefficients (D) as a function of temperature for ILs containing the TMSiM group and, for comparison, the analogous neopentyl group. Room-temperature ionic liquids (RTILs) are liquids consisting entirely of ions, and their important properties, e.g., negligible vapor pressure, are considered to result from the ionic nature. However, we do not know how ionic the RTILs are. Tokuda et al.201 defined the ionic nature of the RTILs as the molar conductivity ratio, calculated from the molar conductivity measured by the electrochemical impedance method and that estimated by use of pulse-fieldgradient spin-echo NMR ionic self-diffusion coefficients and the Nernst-Einstein relation. Bessda et al.202 used developments of NMR spectroscopy at high temperature to study in situ a great number of molten materials. This technique is sensitive to local environment around the nucleus, and gives selective and quantitative information not limited by the disorder existing in liquids. NMR can thus provide a microscopic approach of the structure and dynamics of molten compounds by means of knowledge of different species existing in the melt, the average coordination, or nature of the first neighbors. The authors presented high temperature NMR approach of molten fluoride systems of nuclear interest and description of the local structure around each nucleus, and its evolution with the composition. Wahlbeck and Carper203 showed the 13C NMR analysis of relaxation data from viscous solutions requires the application of complex mathematical functions. These equations can be combined and solved exactly using a series of iterative algorithms. Correct analysis of typical relaxation data obtained for several viscous ionic liquids provides rotational correlation times that describe the molecular dynamics of these and other viscous solutions. Zhao and Song204 examined the nuclear magnetic relaxations of water in ionic-liquid (IL) solutions at various IL concentrations in order to better understand their hydration behaviors (in terms of nuclear magnetic resonance (NMR) B 0 -coefficients). From these B 0 -values of ILs, the individual ion’s B 0 coefficients were further calculated based on the additivity. These coefficients represent the hydration behavior (‘kosmotropicity’) of ILs in aqueous solutions. Using these data, a linear correlation was found between enzyme enantioselectivity in aqueous solution and the delta’ parameter (difference in NMR B 0 -coefficients of anion and cation). In general, high enzyme enantiomeric ratios (E) could be achieved in solutions of ILs with high delta’ values.

4. Nuclear spin relaxation in gases The NMR 19F spin-lattice relaxation time constant T1 for CF4 gas is dominated by spin–rotation interaction, which is mediated by the molecular collision frequency. When confined to pores of approximately the same size or smaller than the bulk gas mean free path, additional collisions of molecules with the pore walls should substantially change T1. To develop a method for measuring the surface/volume ratio S/V by measuring how T1 changes with confinement, Kuethe et al.205 prepared samples of known S/V from fumed silica of known mass-specific surface area and compressed to varying degrees into cylinders of known volume. They then measured T1 for CF4 in these samples at varying pressures, and developed mathematical models for the change in T1 to fit the data. Ter Horst et al.206 measured spin-lattice relaxation times for the deuterons in CD4 in pure gas and in mixtures with the Nucl. Magn. Reson., 2008, 37, 180–207 | 197 This journal is

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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. These cross sections were compared 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. Acosta et al.207 studied the dependence of the individual mean square displacement of rare gases in binary mixtures by a combined experimental and theoretical approach. They showed that the diffusion constant can be varied in a considerable range by changing the molar fractions of the mixtures. On the experimental side, NMR diffusion measurements are done on hyperpolarized 3He and 129Xe, mixed with several inert buffer gases, in the presence of a magnetic field gradient. The results were compared to diffusion coefficients obtained from atomistic molecular dynamics simulations based on Lennard-Jones type potentials of the corresponding gas mixtures. Chang and Conradi208 reported 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 was 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 D is then known. Segebarth et al.209 presented a novel method for determining xenon partitioning between a gas phase and a liquid phase. An experimental setup which permits the simultaneous measurement of the 129Xe chemical shift in both the gas and the liquid phases, that is, under the same experimental conditions, had been designed. Xenon solubility was obtained via 129Xe chemical shift measurements in the gas phase. The method was validated against xenon solubility data from the literature; in general, the agreement was found to be within 3%. Although laser-polarization increases the NMR signal sufficiently to study small concentrations of adsorbed xenon in biomolecules or host structures, applications remain rare with the dissolution process being the main obstacle. Baumert et al.210 presented a method which simplifies the application of LP 129 Xe (or other gases with short lifetimes) in spectroscopic methods by improving the dissolution process. The authors demonstrated that the procedure allows the application of LP 129Xe in biomolecular high-resolution NMR under continuousflow conditions at low xenon pressures and can be used to record 2D NMR spectra in solution under continuous flow. O’Neill et al.211 reported measurements of the nuclear magnetic resonance (NMR) spectrum of 129Xe adsorbed on silica gel and Grafoil (R) substrates in a 15 tesla magnetic field and temperatures in the range 10 mK to 1 K. Liquid 3He is used to shorten the spin lattice relaxation time of the 129Xe spins and obtain a high degree of spin polarization of over 40% in around a day. The 129Xe NMR spectrum generally exhibits two lines. They showed that one line corresponds to the monolayer of surface xenon atoms and the other line to the monolayers of bulk solid xenon between the substrate and the surface monolayer. By comparing the spectra and relaxation rates for xenon of different 129Xe concentrations and by adding 4He we were able to investigate the Xe-129 interlayer coupling. The work has important implications in the study of porous materials using hyperpolarized gases, the study of surface atoms by NMR and the production of hyperpolarized species by the brute force technique. Ishikawa et al.212 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, the authors obtained the correlation time of random fluctuations of the local field at the liquid–solid interface. By varying the cell volume, the wall coating, and the surface area of the eicosane, they measured the contribution of the spin–rotation interaction to the relaxation. The use of both deuterated molecules enabled them to distinguish surface relaxation from the magnetic dipole–dipole and spin-rotation interactions in solution. Cleveland 198 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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et al.213 introduced a technique is to study hydrated surfaces using hyperpolarized (hp) 83Kr NMR spectroscopy. The longitudinal T1 relaxation of hp-83Kr is shown to be extremely sensitive to the presence of adsorbed water on hydrophilic borosilicate and hydrophobic siliconized glass surfaces. The krypton surface relaxation was found to be largely independent of the total gas pressure applied to the studied materials, and the presented technique was therefore fairly robust. In contrast to the signal decay of hp-129Xe, the longitudinal relaxation of 83Kr was largely unaffected by paramagnetic impurities, and in some materials, 83Kr and 129Xe showed comparable T1 times that are caused by two completely different relaxation mechanisms. Interest in nuclear magnetic resonance measurements at ultra-low magnetic fields (ULF, similar to mu T fields) has been motivated by various benefits and novel applications including narrow NMR peak-width, negligible susceptibility artifacts, imaging of samples inside metal containers, and possibility of directly imaging neuronal currents. ULF NMR/MRI is also compatible with simultaneous measurements of biomagnetic signals. However the most widely used technique in ULF NMR-prepolarization at high field and measurement at lower field-results in large transient signals which distort the free induction decay signal. This is especially severe for the measurement of signals from samples and materials with short T, time. Volegov et al.214 devised an approach that largely cancels the transient signals. The technique was successfully used to measure NMR signals from liquids and gases with T, in the range 1–4 ms.

5. Self-diffusion in liquids 5.1 Experimental and theoretical aspects There is a continuing, indeed growing, interest in measuring diffusion constants and the literature reveals that a number of methodologies are in use. These include attenuated total reflection infrared spectroscopy (ATRIR),215 capacity intermittent titration techniques,216 long capillary methods217 and, of course, NMR spectroscopy. The use of pulsed field gradient NMR methods to measure diffusion constants dates back more than 40 years218 and has been reviewed periodically.219,220 In the pulsed field gradient spin-echo (PGSE) Stejskal-Tanner experiment, transverse magnetization is generated by the initial p/2 pulse which, in the absence of field gradients, dephases due to chemical shift, hetero- and homo-nuclear coupling evolution, and spin–spin (T2) relaxation. After application of an intermediate p pulse, the magnetization refocuses, generating an echo. Pregosin221 reviewed PGSE diffusion methods. In particular he focused on ion pairing phenomena. In soft condensed matter various motional processes take place on time scales which at a given temperature can differ by many orders of magnitude. A prominent example is the complex dynamics associated with the different tiers in disordered materials such as proteins typically involving changes within the protein backbone, regional reorganizations, as well as local conformational changes.222 Even with the advent of modern broadband spectroscopic methods, which cover ten and more decades in frequency or time,223 the mutual relationship between various dynamical processes has to be inferred indirectly. This is particularly true for the multitude of primary (also called a), secondary (or b), etc., relaxations in amorphous materials. Just above their glass transition the time scales of the a- and of the b-process are typically separated by more than 5 decades.224 The analysis of data from dielectric and other spectroscopies is practically always based on the implicit assumption that the a- and b-relaxations are additive in the frequency or time domains or multiplicative in the latter.225 Both options imply that the time scales of the two processes are independent of one another. This often tacitly made assumption was directly tested by Bo¨hmer et al.226 For the deeply supercooled liquid sorbitol, which exhibits a strong secondary relaxation, the primary relaxation could be modified by suppressing the contributions of those subensembles which are characterized by Nucl. Magn. Reson., 2008, 37, 180–207 | 199 This journal is

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relatively slow secondary relaxations. This was clear evidence for a correlation between primary and secondary relaxation times. It has been observed recently that the finite duration of refocusing r.f. pulses in a multiecho acquisition of the signal formed under the influence of the dipolar field leads to significant signal attenuation.227 Hereto, Wong et al.228 quantify the phenomenon by evaluating analytically the influences of both the distant dipolar field (DDF) and transverse relaxation T2 on the magnetization in a multiecho pulse sequence based on correlation spectroscopy revamped by asymmetric z-gradient echo detection (CRAZED). Analytic expressions for the magnetization were obtained, which demonstrated explicitly the origin of rephased signal in the presence of the finite it pulses in the multiecho train. Cho et al.229 demonstrated a rapid NMR method to measure a full three-dimensional diffusion tensor. This method is based on a multiple modulation multiple echo sequence and utilizes static and pulsed magnetic field gradients to measure diffusion along multiple directions simultaneously. The pulse sequence was optimized using a well-known linear inversion metric (condition number) and successfully tested on both isotropic (water) and anisotropic (asparagus) diffusion systems. Crutchfiled and Harris230 developped a simplified PFG NMR diffusion analysis method was to estimate the molecular mass of small molecules in dilute aqueous and organic solutions. Internal referencing was utilized to improve the experimental robustness and simplify the data analysis. Specifically, tetramethylsilane (TMS) and HDO were chosen for the organic and aqueous reference molecules, respectively. The modulation of spin phase produced by Carr-Purcell-Meiboom-Gill (CPMG) sequence in combination with constant magnetic field gradient is appropriate to probe the displacement power spectrum (DPS). The spin-echo attenuation is directly proportional to the DPS value at the applied modulation frequency. Relaxation and selective excitation effects can be factored out while probing the DPS. The modulation frequency is adjusted by varying the pulse separation time while the gradient strength and the time of acquisition are kept constant. In designing the experiment gradient strength limitations, imposed by off-resonance effects, as well as limitations arising from using Gaussian phase approximation must be considered. Lasic et al.231 presented an effective experimental strategy, supported by experimental results for free and restricted diffusion. Windt et al.232 presented a method for correlated displacement-T2 imaging. A Pulsed Field Gradient-Multi Spin Echo (PFG-MSE) sequence is used to record T2 resolved propagators on a voxel-by-voxel basis, making it possible to perform single voxel correlated displacement-T2 analyses. In spatially heterogeneous media the method thus gives access to sub-voxel information about displacement and T2 relaxation. The sequence is demonstrated using a number of flow conducting model systems: a tube with flowing water of variable intrinsic T2, mixing fluids of different T2’s in an ‘‘X’’-shaped connector. Diffusion-ordered NMR spectroscopy (DOSY NMR) is a highly useful tool for the study of complex mixtures via NMR. Often, spectral overlap limits the ability of obtaining cleanly separated subspectra of the components due to inherently instable multiexponential fits or data inversion procedures. Three-dimensional DOSY variants offer the advantage of separating individual peaks in an additional dimension, such that robust monoexponential fits to cross-peaks may be used to determine the diffusion coefficients with higher accuracy. For sensitivity reasons, methods based on proton nuclei are preferable. Newman and Jerschow233 showed that a doublequantum-filtered COSY-DOSY experiment provides advantages over COSYDOSY, while high signal-to-noise ratios are maintained. Sevilla and Kenkre234 obtained exact solutions of a generalization of the Torrey-Bloch equation for use in nuclear magnetic resonance microscopy. The generalization addresses the motion of the nuclear spins towards an attractive centre with, furthermore, an arbitrary time dependence in the attractive (harmonic) potential. The solutions provide an analytic way to interpret observations made with gradient magnetic fields of arbitrary (finite) pulse duration. Limiting results for infinitesimal pulses are shown to reduce to earlier 200 | Nucl. Magn. Reson., 2008, 37, 180–207 This journal is

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expressions and new effects are described for finite pulses. Hu¨rlimann235 presented a new approach of NMR measurements in the presence of grossly inhomogeneous fields where information is encoded in the echo shape of CPMG trains. The method is based on sequences that consist of an initial encoding sequence that generates echoes with contributions from at least two different coherence pathways that are then both refocused many times by a long string of closely spaced identical pulses. The author demonstrated this approach with different implementations of the measurements of longitudinal relaxation time, T1, and diffusion coefficient, D. It was shown that the method can be used for novel single-shot measurements. 5.2 Selected examples Akpa et al.236 demonstarted that a heteronuclear approach to PFG NMR allows the study of molecular displacement over extended time scales by exploiting the longer relaxation time of 13C. The method presented employs the DEPT technique of polarization transfer in order to enhance both the sensitivity and efficiency of 13C detection. Von Meerwall et al.237 used the 1H pulsed-gradient NMR method to augment earlier diffusion measurements in n-alkane and polyethylene (PE) melts and blends with measurements in 12 additional melts and in three series of blends at T = 150 1C across the full concentration range. Cicuta et al.238 reported diffusion coefficients of micron-scale liquid domains in giant unilamellar vesicles of phospholipids and cholesterol. The trajectory of each domain is tracked, and the mean square displacement grows linearly in time, as expected for Brownian motion. The authors studied domain diffusion as a function of composition and temperature and measure how diffusion depends on domain size. Many naturally occurring fluids, such as crude oils, consist of a very large number of components. It is often of interest to determine the composition of the fluids in situ. Diffusion coefficients and nuclear magnetic resonance (NMR) relaxation times can be measured in situ and depend on the size of the molecules. It has been shown239 that the diffusion coefficient of each component in a mixture of alkanes follows a scaling law in the chain length of that molecule and in the mean chain length of the mixture. Fred et al.240 used these relations to determine the chain length distribution of crude oils from NMR diffusion measurements. Trotzig et al.241 studied the change in structure and mobility of poly(ethylene oxide) (PEO) containing 2 wt% of fumed silica and the water self-diffusion coefficient in concentrated PEO–water systems at room temperature. Cosgrove et al.242 investigated the diffusion constants of solvent in solutions of carboxylated acrylic random copolymers in isopropanol (IPA) using the PFG NMR technique. Noginova et al.243 reported the 1H NMR spectra and spin dynamics of the host system in liquid and solid suspensions of gamma-Fe2O3 nanoparticles. Significant line broadening of 1H NMR spectra and growing relaxation rates were observed with increased concentration of nanoparticles in liquid systems, with the relation T1/T2 depending on the particular host. Sagidullin et al.244 used Pulsed field gradient (PFG) nuclear magnetic resonance to investigate the diffusion of probe molecules into polymer systems. Propagators for the diffusion of propanol and propanol-water mixture into multilayers reveal that there might be selective interaction of probe molecules with the polyelectrolyte system. Germann et al.245 measured the translational self-diffusion constants of 12 amino acids (Ala, Arg, Asn, Asp, Cys, Glu, His, Ile, Lys, Met, Phe, and Ser) by field gradient NMR and extrapolated to infinite dilution. Stjerndahl et al.246 studied the consequences of including amide bonds into the structure of short-chain nonionic surfactants. Of particular interest were the possible effects of the hydrogen bonding ability of the amide group on the micellar shape. The aggregate structure and hydration of two different amide-containing surfactants were investigated using NMR diffusometry as the main technique. Kanakubo et al.247 determined the self-diffusion coefficients (D) of the cation and anion in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) together with the electrical conductivity under high Nucl. Magn. Reson., 2008, 37, 180–207 | 201 This journal is

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pressure. Price et al.248 used multinuclear pulsed gradient spin-echo (PGSE) NMR diffusion and linewidth measurements to probe binding and transport in aqueous Na+-15-crown-5, Na+-18-crown-6, Cs+-15-crown-5 and Cs+-18-crown-6 systems.

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Solid-state NMR spectroscopy A. E. Alieva and R. V. Lawb DOI: 10.1039/b617055m

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 2006 and June 2007. As usual, a large number of papers making use of solidstate NMR techniques have been published during this period, however, only some of these have been included in this report. In choosing sources for this report we have aimed at highlighting publications which use solid-state NMR as the only or the primary technique for structural and/or dynamics studies of solid materials. In selecting references, we have also aimed at illustrating the 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 previous years. Section 2 of the report includes review articles on both general and specific aspects of solid-state NMR spectroscopy and its applications. Experimental developments and novel applications that are of general methodological interest are arranged in Section 3. With regard to experimental aspects, there has been a renewed interest in proton chemical shift measurements in the solid state via natural-abundance CPMAS 2H NMR [Chem. Phys. Lett., (1994), 226, 193],12 recoupling of chemical-shift anisotropy powder patterns [J. Magn. Reson., (1989), 85, 265]14 and new studies of the anisotropy of bulk magnetic susceptibility [Chem. Phys. Lett., (1982), 87, 30].43 Other remarkable developments include: a dipolar recoupling technique for measurements of intermolecular distances and torsion angles in solids by Tycko,15 orientationally encoded ultrafast 2D NMR by Frydman et al.,22 the first threedimensional experiment on quadrupolar nuclei by Massiot et al.,24 high-resolution 1 H and 13C measurements combined with first principle calculations by Emsley et al.,25 improved high-field pulse sequences by Opella et al.28,29 and heteronuclear dipolar decoupling by Madhu et al.33 In addition, the number of publications describing solid-state 17O NMR technique developments and applications has increased significantly in the last two years. With respect to NMR parameter determinations by experimental and computational techniques included in Section 4, some interesting examples comprise of analysis of bulk 1H chemical shifts sensitive to p-stacking and hydrogen bonding by Spiess et al.,45 comprehensive investigation of 77Se chemical shift anisotropy by Wasylishen et al.,50 calculations of 17O parameters using DFT with a planewave basis set by Ashbrook et al.51 and measurements of quadrupolar couplings of 39K by Moudrakovski and Ripmeester.56 Various examples of solid-state NMR applications are collected in the final Section 5. This section is divided into 14 subsections depending on the type of the material studied: (5.1) organic solids; (5.2) inclusion compounds; (5.3) amino acids; (5.4) peptides and proteins; (5.5) lipids and membranes; (5.6) pharmaceutical and biomedical applications; (5.7) cellulose and related materials; (5.8) soils and related materials; (5.9) coals and carbonaceous materials; (5.10) polymers; (5.11) organometallic and coordination compounds; (5.12) glasses and amorphous solids; (5.13) micro- and mesoporous solids; (5.14) surface science and catalysis; and (5.15) inorganic and other related solids. a b

Department of Chemistry, University College London, 20 Gordon Street, London, UK WC1H 0AJ Department of Chemistry, Imperial College London, London, UK SW7 2AY


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Sections 1–5.6 were prepared by A. E. Aliev. The remaining Sections 5.7–5.14 were prepared by R. V. Law.

2. Reviews An introduction to the background principles and applications to inorganic materials of solid-state 17O NMR has been presented by Ashbrook and Smith in their tutorial review.1 The information that the NMR parameters can provide about the local environment is explained through a series of illustrations from different areas of solid state chemistry and structural science of inorganic materials. Berendt et al. have reviewed applications of high field solid state NMR techniques in pharmaceutical research and analysis.2 Applications of solid-state NMR to pharmaceutical polymorphism and related matters have been reviewed by Harris.3 The review article discusses a range of applications, with particular emphasis on information about crystallography, for which NMR can address problems that cannot be readily solved by diffraction techniques (such as dynamic disorder and non-stoichiometric hydration). Several advantages of solid-state NMR are highlighted: (i) unlike diffractograms, NMR spectra yield immediate chemical information; (ii) heterogeneous samples can be investigated; (iii) amorphous content provides no significant barrier to studies, and (iv) NMR can be an effective technique for quantitation (down to the level of ca. 1%). Proton solid-state NMR studies of tunneling phenomena and isotope effects in transition metal dihydrides have been reviewed by Buntkowsky and Limbach.4 The review focuses on transition metal dihydrides and dihydrogen complexes, in which the hydrogens are relatively weakly bound and exhibit fairly high mobility, in particular with respect to their mutual exchange. The first part of this review gives an introduction into the interplay of chemical kinetics and tunneling phenomena in general, rotational tunneling of dihydrogen in a two-fold potential in particular and the Bell tunnel model, followed by a summary of solid state NMR techniques for the observation of these tunnel processes. Then a discussion of the effects of these processes on the 2H NMR line shape is given. The second part of the review reports results of a 2H solid-state NMR spectroscopy and T1 relaxation study of trans[RuD2Cl(PPh2CH2CH2PPh2)2]PF6, in the temperature region from 5.4 to 320 K. The relaxation measurements are analysed in terms of a simple one dimensional Bell tunnel model. Baldus has reviewed investigations of molecular interactions by multi-dimensional solid-state NMR.5 Interactions such as the formation of protein complexes and ligand binding for a large range of molecular sizes and binding affinities were considered. It has been shown that recent instrumental and methodological progress has enabled novel possibilities for using multi-dimensional solid-state NMR to study molecular 3D structures and interactions in noncrystalline systems. Two-dimensional correlation experiments were applied to study ligand binding in globular and membrane proteins and have enabled the investigation of molecular interfaces in the context of protein folding and aggregation. In lipid bilayers, a versatile set of solidstate NMR experiments has been reviewed, which are useful for studies of molecular structure, topology and complex formation in a functional environment. Oligomeric structure, dynamics and orientation of membrane proteins investigated by solid-state NMR has been presented by Hong.6 In particular, the recent progress in determining the orientation, the internal and global protein dynamics, the oligomeric structure and the ligand-bound structure of membrane proteins with both a-helical and b-sheet conformations has been discussed. Examples are given that illustrate the insights into protein function that can be gained from the NMR structural information. Hologne et al. have reviewed the use of deuterated peptides and proteins in MAS solid-state NMR applications.7 Nucl. Magn. Reson., 2008, 37, 208–256 | 209 This journal is

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Rational design of vector and antibiotic peptides using solid-state NMR has been reviewed by Mason, Bechinger and Kichler.8 The application of 2H solid-state NMR in determining structure activity relationships and the mechanism of action of membrane active peptides is discussed. The enhancement of the disruption of anionic lipids in the membrane by new lead compounds is shown to be a key determinant of both DNA vector and antimicrobial activity. A practical guide for solid-state NMR distance measurements in proteins has been presented by Kovacs et al.9 Rotational resonance (R2) and rotational echo double resonance (REDOR) techniques are discussed that can be applied in a site-directed fashion for precise distance measurements in proteins. These tools are well suited for systems in which a few precise distance measurements are needed to understand a mechanism or to map a binding site, particularly if this information is unavailable from X-ray crystallography or solution NMR, as is often the case for membrane proteins. Strategies and challenges in the design and implementation of such experiments are further described and illustrated with experiments probing mechanisms of transmembrane signaling in bacterial chemotaxis receptors. Solid-state NMR studies of molecular recognition at protein–mineral interfaces have been reviewed by Goobes, Stayton, and Drobny.10 Finally, lithium NMR and its applications to the translational dynamics studies in ion conductors have been reviewed by Bohmer, Jeffrey, and Vogel.11

3. Experimental developments 3.1 Indirect measurements of protons An alternative approach for obtaining 1H chemical shifts in solids has been described by Mizuno et al,12 similar to that proposed previously [A. E. Aliev, K. D. M. Harris and D. C. Apperley, Natural-abundance high-resolution solid-state NMR spectroscopy, Chem. Phys. Lett., (1994), 226, 193]. In particular, 2H NMR was examined as an approach to determine proton chemical shifts in solids using a 930 MHz (1H frequency) instrument. For high-resolution observation, the line width due to 2H quadrupole interaction and chemical shift anisotropy was removed by MAS and that due to 1H–2H dipolar interactions by 1H decoupling. It has been shown that the sensitivity can be enhanced by applying 1H to 2H cross polarization and by adding spinning-sideband spectra. These techniques make it possible to obtain 2H naturalabundance MAS spectra revealing highly resolved 2H signals. The second-order quadrupole effects of 2H are also examined. Proton-selective 17O–1H distance measurements in fast MAS solid-state NMR spectroscopy for the determination of hydrogen bond lengths have been described by Brinkmann and Kentgens.13 The method has been applied to determine 17O–1H distances in organic, biological, and biomimetic materials. It enables the estimation of medium-range 17O 1H distances across hydrogen bonds in the presence of shortrange 17O–1H contacts sharing the same 17O site. The method employs the newly developed symmetry-based radiofrequency pulse sequence applied to the protons to achieve heteronuclear dipolar recoupling, while simultaneously decoupling the homonuclear proton dipolar interactions. Fast MAS (50 kHz) and high static magnetic fields (18.8 T) achieve the required proton spectral resolution. 3.2 Recoupling experiments A comparison of three different implementations of the chemical shift recoupling experiment of Tycko et at. [R. Tycko, G. Dabbagh and P. A. Mirau, Determination of chemical-shift-anisotropy lineshapes in a two-dimensional magic-angle-spinning NMR experiment, J. Magn. Reson., (1989), 85, 265] has been presented by Orr and Duerr.14 The method seeks to reduce the effects of artefacts resulting from pulse imperfections and residual C–H dipolar coupling in organic solids. An optimised and constant time implementation are shown to give well-defined and artefact-free 210 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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powder pattern lineshapes in the indirectly observed dimension for both sp2 and sp3 carbon sites. It has been shown that the experimental setup is no more demanding than for the original experiment, and can be implemented using standard commercial hardware. Symmetry-based constant-time homonuclear dipolar recoupling in solid-state NMR has been presented by Tycko.15 Constant-time dipolar recoupling pulse sequences are advantageous in structural studies by MAS NMR because they yield experimental data that are relatively insensitive to rf pulse imperfections and nuclear spin relaxation processes. A new approach to the construction of constant-time homonuclear dipolar recoupling sequences is described by Tycko,15 based on symmetry properties of the recoupled dipole–dipole interaction Hamiltonian under cyclic displacements in time with respect to the MAS sample rotation period. A specific symmetry-based pulse sequence called PITHIRDS-CT is introduced and demonstrated experimentally. 13C NMR data for singly-13C-labelled amino acid powders and amyloid fibrils indicate the effectiveness of PITHIRDS-CT in measurements of intermolecular distances in solids. 15N-detected and 13C-detected measurements of intramolecular 15N–15N distances in peptides with a-helical and b-sheet structures indicate the utility of PITHIRDS-CT in studies of molecular conformations, especially measurements of backbone c torsion angles in peptides containing uniformly 15N- and 13C-labelled amino acids. Tosner et al. have reported the use of optimal control algorithms for tailoring the effective Hamiltonians in NMR spectroscopy through sophisticated rf pulse irradiation.16 Specifically, they address dipolar recoupling in solid-state NMR of powder samples, for which pulse sequences offering evolution under planar double-quantum and isotropic mixing dipolar coupling Hamiltonians are designed. The pulse sequences are constructed numerically to cope with a range of experimental conditions such as inhomogeneous rf fields, spread of chemical shifts, the intrinsic orientation dependencies of powder samples and sample spinning. While the vast majority of previous dipolar recoupling sequences are operating through planar double- or zero-quantum effective Hamiltonians, Tosner et al. present not only improved variants of such experiments but also, for the first time homonuclear isotropic mixing sequences, which transfers all Ix, Iy and Iz polarizations from one spin to the same operators on another spin simultaneously and with equal efficiency. It has been shown that this property may be exploited to increase the signal-to-noise ratio of two-dimensional experiments by a factor of O2 compared to conventional solid-state methods otherwise showing the same efficiency. The sequences are tested numerically and experimentally for a powder of 13Ca,13Cb-L-alanine and demonstrate substantial sensitivity gains over previous dipolar recoupling experiments. Sensitivity enhanced recoupling experiments in solid-state NMR by g-preparation have also been proposed by Khaneja.17 In particular, Khaneja introduces a class of dipolar recoupling experiments under MAS, which use g-dependent antiphase polarization during the t1 evolution period. It has been shown that this helps to design dipolar recoupling experiments that transfer both components of the transverse magnetization of spin S to a coupled spin I in the mixing step of a 2D NMR experiment. Khaneja also shows that it is possible to design such transfer schemes and make them insensitive to the orientation dependency of the couplings in powders. This in turn can be used in the development of sensitivity enhanced 2D NMR experiments of powder samples under MAS conditions. The efficacy of hetero- and homonuclear dipolar recoupling employing adiabatic inversion pulse based rf pulse schemes has been examined at high MAS frequencies via numerical simulations and experimental measurements.18 An approach for minimising the recoupling rf power level is presented, taking into consideration the spinning speed, the range of resonance offsets and 1H inhomogeneities and the available rf field strength. This involves the tailoring of the frequency and amplitude modulation profiles of the inversion pulses. The applicability of the new dipolar


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recoupling schemes to spinning speed regimes where the performance with conventional rectangular pulses may not be satisfactory is demonstrated. A two-dimensional NMR experiment for estimating proton chemical shift anisotropies (CSAs) in solid powders under MAS conditions has been demonstrated in which 1H CSAs are reintroduced with a symmetry-based recoupling sequence while the individual proton sites are resolved according to their isotropic chemical shifts by MAS or combined rotation and multiple pulse (CRAMPS) homonuclear decoupling.19 The experiments were carried out on an ultrahigh-field solid-state NMR instrument (900 MHz 1H frequency), which leads to increased resolution and reliability of the measured 1H CSAs. The experiment is expected to be particularly important for investigating hydrogen bonding in the solid-state.

3.3 Cross polarisation and polarisation transfer A new method for the detection and quantification of a small amount of crystalline material within a liquid solution of solubilized material has been described.20 CPMAS 19F NMR was investigated as a technique to detect low levels (0.2 mg/g) of crystalline sodium 7-{3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy}-2methyl-3, 4-dihydro-2H-chromane-2-carboxylate (1) within a solid mixture with microcrystalline cellulose and a slurry with a liquid vehicle using capric and caprylic acid triglycerides. The results demonstrated that the 19F CPMAS signal obtained in 25 min at 298 K is linearly dependent (r2 = 0.997) on the mass of 1 within the solidstate NMR rotor. Slopes of CP-MAS peak area versus mass of 1 in the rotor were nearly identical for the solid mixture and slurry suspension. Signal-to-noise ratios for the low potency slurry suggest a detection and quantification of 0.1 mg of crystalline 1 in the rotor, corresponding to 2 mg/g of crystalline material within the slurry suspension. A 13C solid-state NMR procedure for extracting structural and dynamical information in organic molecules has been introduced.21 The method combines numerical simulations with two kinds of CP from conventional and remote protons. The former is mostly sensitive to dipolar couplings between directly bonded 13C–1H nuclei, whereas the latter prepares a state of non-uniform polarization, where these particular spin pairs are polarized prior to recording the CP buildup curve. This curve is then expected to quantify the polarization transfer from remote protons only. The method is demonstrated for the specific NH3 group of L-alanine and it shows that the remote protons polarization transfer curve can be used in combination with the conventional CPMAS curve to get additional structure and dynamics related information in molecular systems with relevance to biology and advanced materials.

3.4 Quadrupolar nuclei Among the methods proposed in recent years toward the acceleration of multidimensional NMR acquisitions is an ‘‘ultrafast’’ approach, capable of delivering arbitrary 2D correlations within a single scan.22 This scheme operates by parallelizing the indirect-domain temporal incrementation involved in 2D acquisitions, using as aid an ancillary inhomogeneous frequency broadening acting in combination with a train of frequency-shifted rf pulses. So far, all implementations of this frequency broadening have relied on magnetic field gradients. However, the practical performance of gradient-based approaches is sometimes inadequate, for instance, when applied to solid samples subject to MAS. In order to deal with these cases, an alternative encoding protocol has been introduced by Bhattacharyya and Frydman and experimentally exemplified, based on exploiting the intrinsic anisotropy that spin interactions exhibit in the solid state as the ancillary broadening in charge of encoding the interactions to be measured.22 Principles and preliminary examples of 212 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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the new orientationally encoded ultrafast 2D NMR approach are presented and discussed. Several different amplitude-modulated two-dimensional high-resolution methods, based on MQMAS and STMAS, have been compared.23 These include 3QMAS, 5QMAS, DQ-STMAS, and DQF-STMAS experiments. A new method, called t1-split-STMAS, is also proposed for spin-3/2 nuclei. The comparison is performed in terms of isotropic resolution and spectral width, efficiency, and sensitivity to magic angle offset and spinning speed fluctuations. The first 3D homonuclear/heteronuclear correlation experiment applied to quadrupolar nuclei and making use of the sole scalar J-coupling has been described.24 This experiment, based on the 2D homonuclear-heteronuclear single quantum correlation (H-HSQC) experiment, uses a relayed transfer from the 27Al central transition to neighbouring 31P spins and to the central transition of a second 27Al. It confirms the correlation map characterizing the two 27Al and the 31P NMR signatures of 27Al–O–31P–O–27Al chemically bonded molecular motifs. 3.5 Two-dimensional techniques Mifsud et al. have shown how powder samples at natural isotopic abundance can be assigned to crystal structures by using high-resolution 1H and 13C solid-state NMR spectra in combination with first principle calculations.25 Homonuclear proton double-quantum spectra in combination with through-bond proton–carbon HSQC spectra were used to assign the NMR spectra. They then show that the proton chemical shifts can be included in the process of assigning the spectra to a crystal structure using first principle calculations. The method is demonstrated on the potassium salt of penicillin G. A simple spectroscopic filtering technique has been presented that may aid the assignment of 13C and 15N resonances of methyl-containing amino acids in solidstate MAS NMR.26 A filtering block that selects methyl resonances is introduced in two-dimensional 13C -homonuclear and 15N–13C heteronuclear correlation experiments. The 2D 13C correlation spectra are recorded with the methyl filter implemented prior to a 13C–13C mixing step. It is shown that these methyl-filtered 13Chomonuclear correlation spectra are instrumental in the assignment of Cd resonances of leucines by suppression of Cg–Cd cross peaks. Further, a methyl filter is implemented prior to a 15N–13C transferred-echo double resonance (TEDOR) exchange scheme to obtain 2D 15N–13C heteronuclear correlation spectra. These experiments provide correlations between methyl groups and backbone amides. Some of the observed sequential 15N–13C correlations form the basis for initial sequence-specific assignments of backbone signals of the outer-membrane protein G. A robust sensitivity-enhanced 1H–14N MAS HMQC experiment has been described for proton-detected 14N NMR of solids.27 The sensitivity enhancement is achieved by using dipolar recoupling for coherence transfer with a so-called n = 2 rotary resonance. Rotary resonance occurs when a CW rf field matches certain ratios with the sample spinning frequency, n = o1/or. The theory of rotary resonance for chemical shift anisotropy, heteronuclear and homonuclear dipolar interactions is presented in the irreducible representation. It is shown that the n = 2 rotary resonance decouples the homonuclear dipolar interactions while recoupling the heteronuclear dipolar interaction for proton-detected 14N NMR. The dipolar recoupling, T2 lengthening and 1H–14N HMQC experiment under the n = 2 rotary resonance have been demonstrated. Solid-state NMR experiments benefit from being performed at high fields, and this is essential in order to obtain spectra with the resolution and sensitivity required for applications to protein structure determination in aligned samples. Since the amount of rf power that can be applied is limited, especially for aqueous protein samples, the most important pulse sequences suffer from bandwidth limitations resulting from the same spread in chemical shift frequencies that aids resolution. SAMPI4 is a pulse Nucl. Magn. Reson., 2008, 37, 208–256 | 213 This journal is

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sequence that addresses these limitations.28 It yields separated local field spectra with narrower and more uniform linewidths over the entire spectrum than the currently used PISEMA and SAMMY experiments. In addition, it is much easier to set up on commercial spectrometers and can be incorporated as a building block into other multidimensional pulse sequences. This is illustrated with a two-dimensional HETCOR experiment, where it is crucial to transfer polarization from the amide protons to their directly bonded nitrogens over a wide range of chemical shift frequencies. A quantum-mechanical treatment of the spin Hamiltonians under high-power rf pulses is presented which gives the scaling factor for SAMPI4 as well as the durations of the rf pulses to achieve optimal decoupling. A pulse sequence that yields three-dimensional 1H chemical shift/1H–15N heteronuclear dipolar coupling/15N chemical shift solid-state NMR spectra has been demonstrated on a uniformly 15N labelled membrane protein in magnetically aligned phospholipid bilayers.29 Based on SAMPI4, the pulse sequence yields high resolution in all three dimensions at a 1H resonance frequency of 900 MHz with the relatively low rf field strength (33 kHz) available for a lossy aqueous sample with a commercial spectrometer and probe. The 1H chemical shift frequency dimension is shown to select among amide resonances, which will be useful in studies of larger polytopic membrane proteins where the resonances overlap in two-dimensional spectra. Moreover, the 1H chemical shift, which can be measured from these spectra, provides an additional orientationally dependent frequency as input for structure calculations. It has been shown that weak 2J(71Ga–31P), typically 12 Hz in GaPO4, can be used to efficiently establish heteronuclear 71Ga–31P correlation using a MAS HMQC experiment in gallo-phosphate materials.30 The experiment demonstrated for cristobalite GaPO4 is then applied to Ga(PO3)3, where it allows the differentiation of the signature of three different Ga sites overlapping in the 1D spectrum. 3.6 Multiple quantum spectroscopy A new method for the excitation and detection of high-order 13C multiple-quantum (MQ) NMR signals in solids under MAS condition has been presented.31 In the new experimental scheme, high-order 13C MQ coherences are generated by relaying several sequentially generated 13C double-quantum coherences in dipolar coupled networks. Numerical simulations and experimental implementations are presented to demonstrate the efficiency of this method under a moderate MAS frequency regime. 13C MQ signals up to 10-quantum coherences are observed experimentally on the model compound 1-13C-labelled glycine at an MAS frequency of 12 kHz. A high magnetic field of 16.4 T (700 MHz 1H frequency) has been used together with a specialized high-power rf-resistant probe and 43Ca isotope labelling to measure 43Ca MQ (M = 3, 5) MAS spectra for 43Ca-enriched silicate slags and present the first evidence of the multiple Ca2+ sites in the amorphous structure.32 3.7 Other experimental developments A heteronuclear dipolar decoupling sequence has been introduced.33 The sequence, called swept-frequency two-pulse phase modulation (SWF-TPPM), is based on one of the previously described decoupling sequences, TPPM. The sequence is robust in performance with respect to various experimental parameters, such as, the pulse flip angle, pulse phase, and offset and a comparison is made with other decoupling schemes, namely TPPM, SPINAL and XiX, on a sample of U–13C-labelled tyrosine for MAS speeds up to 14 kHz. A simple approach has been demonstrated for designing optimised broadband inversion pulses for MAS solid state NMR studies of biological systems.34 The method involves a two step numerical optimisation procedure and takes into account experimental requirements such as the pulse length, resonance offset range 214 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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and extent of 1H inhomogeneity compensation needed. A simulated annealing protocol is used initially to find appropriate values for the parameters that define the well known tanh/tan adiabatic pulse such that a satisfactory spin inversion is achieved with minimum rf field strength. This information is then used in the subsequent stage of refinement where the rf pulse characteristics are further tailored via a local optimisation procedure without imposing any restrictions on the amplitude and frequency modulation profiles. It has been shown that this approach constitutes a generally applicable tool for obtaining pulses with good inversion characteristics. At moderate MAS frequencies the efficacy of the method is experimentally demonstrated for generating double-quantum NMR spectra via the zeroquantum dipolar recoupling scheme RFDR. The application of the 31P NMR spectroscopy to large proteins or protein complexes in solution is hampered by a relatively low intrinsic sensitivity coupled with large line widths. Therefore, the assignment of the phosphorus signals by twodimensional 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. For the complex of Ras with the GTPanalogue it has been shown that solid-state 31P NMR methods can be more sensitive by almost one order of magnitude than solution-state NMR.35 Thus, solid-state NMR seems to be the method of choice for obtaining the resonance assignment of the phosphorus signals of protein complexes in solution. Experiments on Ras-GDP complexes show that the microcrystalline sample can be substituted by a precipitate of the sample and that unexpectedly the two structural states observed earlier in solution are also present in crystals. The orientation of membrane proteins undergoing fast uniaxial rotation around the bilayer normal can be determined without macroscopic alignment.36 It has been shown that the motionally averaged powder spectra exhibit their 01 frequency at the same position as the peak of an aligned sample with the alignment axis parallel to the magnetic field. This equivalence is exploited to determine the orientation of a b-sheet antimicrobial peptide not amenable to macroscopic alignment, using 13C and 15N chemical shifts from powder spectra. This powder sample approach permits orientation determination of membrane-disruptive proteins in diverse environments and under MAS. Despite the success of previous studies, high-resolution solid-state NMR of paramagnetic systems has been still largely unexplored because of limited sensitivity/resolution and difficulty in assignment due to large paramagnetic shifts.37 Recently, it has been demonstrated that an approach using very-fast magic angle spinning, VFMAS, with spinning speed Z 20 kHz, enhances resolution/sensitivity in 13 C solid-state NMR for paramagnetic complexes [Y. Ishii, S. Chimon, N. P. Wickramasinghe, A new approach in 1D and 2D 13C high resolution solid-state NMR spectroscopy of paramagnetic organometallic complexes by very fast MAS, J. Am. Chem. Soc., 2003, 125, 3438]. A novel strategy for sensitivity enhancement, signal assignment, and distance measurement in 13C solid-state NMR under VFMAS for unlabelled paramagnetic complexes using recoupling based polarization transfer is demonstrated.37 As a robust alternative of CP, rapid application of recoupling based polarization transfer under VFMAS is proposed. In the present approach, a dipolar based analog of INEPT (dipolar INEPT) method is used for polarization transfer and a 13C signal is observed under VFMAS without 1H decoupling. The resulting low duty factor permits rapid signal accumulation without probe arcing at recycle times (B3 ms/scan) matched to short 1H T1 values of small paramagnetic systems (B1 ms). Experiments on Cu(DL-Ala)2 showed that the fast repetition approach under VFMAS provided sensitivity enhancement by a factor of 8–66 for a given sample, compared with the 13C MAS spectrum under moderate MAS at 5 kHz. The applicability of this approach was also demonstrated for a more challenging system, Mn(Acac)3, for which 13C and 1H paramagnetic shift dispersions reach 1500 and 700 ppm, respectively. It was shown that effective-evolution-time Nucl. Magn. Reson., 2008, 37, 208–256 | 215 This journal is

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dependence of transferred signals in dipolar INEPT permitted one to distinguish CH, CH2, CH3 and CO groups in 1D experiments for Cu(DL-Ala)2 and Cu(Gly)2. Applications of this technique to 2D 13C/1H correlation NMR under VFMAS yielded reliable assignments of 1H resonances as well as 13C resonances for Cu(DL– Ala)2 and Mn(Acac)3. Quantitative analysis of cross-peak intensities in 2D 13C/1H correlation NMR spectra of Cu(DL–Ala)2 provided distance information between non-bonded 13C/1H pairs in the paramagnetic system. A simple approach has been proposed for enhancing the sensitivity of 13C highresolution solid-state NMR for proteins in microcrystals by reducing 1H T1 relaxation times with paramagnetic relaxation reagents.38 It was shown that 1H T1 values can be reduced from 0.4–0.8 s to 60–70 ms for ubiquitin and lysozyme in D2O in the presence of 10 mM Cu(II)Na, EDTA without substantial degradation of the resolution in 13C CPMAS spectra. Faster signal accumulation using the shorter 1H T1 attained by paramagnetic doping provided sensitivity enhancements of 1.4–2.9 for these proteins, reducing the experimental time for a given signal-to-noise ratio by a factor of 2.0–8.4. This approach is likely to be applicable to various other proteins in order to enhance sensitivity in 13C high-resolution solid-state NMR spectroscopy. Scalar couplings between 13C spins can impair both resolution and sensitivity in 13 C-labelled preparations.39 It is demonstrated that deconvolution of MAS NMR data with maximum entropy (MaxEnt) reconstruction allows the removal of splittings due to J-couplings without loss in sensitivity. A combination of MaxEnt reconstruction in t2 with selective pulses in t1 produces fully J-resolved data in both dimensions. The possibility to obtain J-resolved 13C–13C data without compromising the sensitivity is particularly important for solid-state NMR of ‘‘difficult’’ biological samples, like membrane proteins, where sacrifices in signal-to-noise are not desirable. The method is demonstrated using preparations of a-spectrin SH3 domain (62 residues) as a small test system and of outermembrane protein G as an example of a membrane protein with higher molecular weight (281 residues). Both preparations were obtained using [2-13C]-glycerol as the carbon source during the bacterial growth. Experimental and simulated 14N MAS NMR spectra of the NH4+ ions in the two polymorphs, mS60 and mP60, of (NH4)2MoO4 are used to illustrate that a long-term stability of rotor-controlled MAS frequencies to 0.1 Hz can be achieved using commercial instrumentation (MAS speed controller and 7.5 mm MAS probe with a single marked rotor) attached to a highly pressure-stabilized air supply.40 A new modification of the STARS simulation software employs a Gaussian distribution for the experimental spinning frequency around the frequency set for the MAS speed controller. A simulated spectrum is then obtained by summation of several calculated spectra for evenly spaced spinning frequencies around the set frequency with relative weight factors corresponding to the Gaussian distribution. A methodologically interesting solid-state 17O NMR study of local order and crystallinity in amine-templated mesoporous Nb oxide has been reported by Skatchenko et al.41 Advances in solid-state NMR methodology and computational chemistry are applied to the 19F NMR of solid octafluoronaphthalene.42 It is demonstrated experimentally, and confirmed by density functional theory (DFT) calculations, that the spectral resolution in the MAS spectrum is limited by the anisotropy of the bulk magnetic susceptibility (ABMS). This leads to the unusual observation that the resolution improves as the sample is diluted. DFT calculations provide assignments of each of the peaks in the 19F spectrum, but the predictions are close to the limits of accuracy and correlation information from 2D NMR is invaluable in confirming the assignments. The effects of non-Gaussian lineshapes on the use of 2D NMR for mapping correlations of spectral frequencies (e.g. due to the ABMS) are also discussed. RF heating of solid-state biological samples is known to be a destabilizing factor in high-field NMR experiments that shortens the sample lifetime by continuous 216 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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dehydration during the high-power CP and decoupling pulses. Gor’kov et al. describe specially designed, large volume 15N–1H solid-state NMR probes developed for 600 and 900 MHz PISEMA studies of dilute membrane proteins oriented in hydrated and dielectrically lossy lipid bilayers.43 The probes use an orthogonal coil design in which separate resonators pursue their own aims at the respective frequencies, resulting in a simplified and more efficient matching network. Sample heating at the 1H frequency is minimized by a loop-gap resonator, which produces a homogeneous magnetic field B1. Within the loop-gap resonator, a multi-turn solenoid closely matching the shape of the sample serves as an efficient observe coil. Gor’kov et al. compare power dissipation in a typical lossy bilayer sample in the new low-E probe and in a previously reported 15N–1H probe which uses a double-tuned 4-turn solenoid. RF loss in the sample is measured in each probe by observing changes in the 1H 2p pulse lengths. For the same values of 1H B1 field, sample heating in the new probe was found to be smaller by an order of magnitude. Applications of the low-E design to the PISEMA study of membrane proteins in their native hydrated bilayer environment are demonstrated at 600 and 900 MHz.

4. NMR parameters: experimental and theoretical studies 4.1 Spin

1 2

nuclei

An analysis of bulk 1H NMR chemical shifts for a series of biochemically relevant molecular crystals in analogy to the well-known solvent NMR chemical shifts has been presented.44 The term bulk shifts denotes the change in NMR frequency of a gas phase molecule when it undergoes crystallization. NMR parameters were computed from first-principle electronic structure calculations under full periodic boundary conditions and for isolated molecules and compared to the corresponding experimental fast MAS solid-state NMR spectra. The agreement between computed and experimenal lines was generally very good. The main phenomena responsible for bulk shifts are packing effects (hydrogen bonding and p-stacking) in the condensed phase. By using these NMR bulk shifts in well-ordered crystalline model systems composed of biologically relevant molecules, the individual spectroscopic signatures of packing effects can be understood better. These local structural driving forces, hydrogen bonding, p-stacking and related phenomena, stand as a model for the forces that govern the assembly of much more complex supramolecular aggregates. The accuracy of condensed-phase ab initio structure predictions has been assessed. The calculation of nuclear shieldings for paramagnetic molecules has been implemented in the ReSpect program, which allows the use of modern density functional methods with accurate treatments of spin-orbit effects for all relevant terms in the fine structure constant.45 Compared to previous implementations, the methodology has been extended to compounds of arbitrary spin multiplicity. Effects of zero-field splittings in high-spin systems are approximately accounted for. Validation of the new implementation is carried out for the 13C and 1H NMR signal shifts of the 3d metallocenes. Zero-field splitting effects on isotropic shifts tend to be small or negligible. Agreement with experimental isotropic shifts is already good with the BP86 gradient-corrected functional and is further improved by Hartree-Fock exchange in hybrid functionals. Decomposition of the shieldings confirms the dominant importance of the Fermi-contact shifts, but contributions from spin-orbit dependent terms are frequently also non-negligible. Agreement with 13 C NMR shift tensors from solid-state experiments is of similar quality as for isotropic shifts. Novel measurements and calculations of the olefinic 13C chemical shift tensor principal values in several metal diene complexes have been described.46 The experimental values and the calculations show shifts as large as 70 ppm with respect to the values in the parent olefinic compounds. These shifts are highly anisotropic, Nucl. Magn. Reson., 2008, 37, 208–256 | 217 This journal is

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with the largest ones observed in the less shielded principal components and the smallest ones in the most shielded principal components of the tensor. The orientations of the principal components of the tensors remain, within 101, at their directions in ethylene and other olefinic compounds. The calculations, performed using the GIAO method and the LanDZ pseudopotential basis set, show good agreement with the experiments, and were used to establish definite evidence for the existence of a Cl-bridge structure in the bicyclo[2.2.1]hepta-2,5-diene dichlororuthenium(II) polymer. Reaction of RuCl2(PPh3)3 with LiNN 0 (NN 0 = 2-[(2,6-diisopropylphenyl)imino]pyrrolide) affords a single product, with the empirical formula RuCl[(2,6-(Pr2C6H3)Pr-i)NQCHC4H3N](PPh3)2.47 2D COSY and J-resolved solid-state 31P NMR experiments confirm that the PPh3 ligands on each metal centre are magnetically and crystallographically inequivalent, and 31P CPMAS NMR experiments reveal the largest 99Ru–31P spin–spin coupling constant 1J = 244 20 Hz measured so far. Finally, 31P dipolar-chemical shift spectroscopy is applied to determine benchmark phosphorus chemical shift tensors for phosphine ligands in hexacoordinate ruthenium complexes. The first solid state 29Si NMR of a disilyne, RSiSiR, R = Si(CH(SiMe3)2)2(i-Pr), has been measured: d11 = 364 20; d22 = 221 16 and d33 = 350 13; CSA = 643 ppm.48 These measured values, as well as calculations for model disilynes, strongly support the description of the Si–Si bond in bent disilynes as a triple bond, although with weakened s-bonds and a reduced bond order of 2.6. A comprehensive investigation of selenium chemical shift tensors has been presented.49 Experimentally determined chemical shift tensors were obtained from solid-state 77Se NMR spectra for several organic, organometallic or inorganic selenium-containing compounds. The first reported indirect spin–spin coupling between selenium and chlorine is measured for Ph2SeCl2 where 1 77 J( Se, 35Cl)iso is 110 Hz. Selenium magnetic shielding tensors were calculated for all of the molecules investigated using zeroth-order regular approximation density functional theory, ZORA DFT. The computations provide the orientations of the chemical shift tensors, as well as a test of the theory for calculating the magnetic shielding interaction for heavier elements. The ZORA DFT calculations were performed with nonrelativistic, scalar relativistic and scalar with spin-orbit relativistic levels of theory. Relativistic contributions to the magnetic shielding tensor were found to be significant for (NH4)2WSe4 and of less importance for organoselenium, organophosphine selenide and inorganic selenium compounds containing lighter elements. The two NMR active isotopes of xenon, 129Xe (I = 1/2) and 131Xe (I = 3/2), are exploited to characterize the xenon magnetic shielding and quadrupolar interactions for two sodium perxenate salts, Na4XeO6 xH2O (x = 0, 2), at an applied magnetic field strength of 11.75 T.50 Solid-state 129/131Xe NMR line shapes indicate that the local xenon environment in anhydrous Na4XeO6 adopts octahedral symmetry, but upon hydration, the XeO64 anion becomes noticeably distorted from octahedral symmetry. For stationary, anhydrous samples of Na4XeO6, the heteronuclear 129/131Xe–23Na dipolar interaction is the principal contributor to the breadth of the 129/131Xe NMR lines. For stationary and slow MAS samples of Na4XeO6 xH2O, the anisotropic xenon shielding interaction dominates the 129Xe NMR line shape, whereas the 131Xe NMR line shape is completely dominated by the nuclear quadrupolar interaction. The xenon shielding tensor is approximately axially symmetric, with a skew of 0.7 0.3, an isotropic xenon chemical shift of 725.6 1.0 ppm, and a span of 95 5 ppm. The 131Xe quadrupolar coupling constant, 10.8 0.5 MHz, is large for a nucleus at a site of approximate Oh symmetry, and the quadrupolar asymmetry parameter indicates a lack of axial symmetry. This study has demonstrated the extreme sensitivity of the 131Xe nuclear quadrupolar interaction to changes in the local xenon environment. 218 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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4.2 Quadrupolar nuclei The NMR shielding and electric field gradient tensors of three polymorphs of Mg2SiO4, forsterite (a-Mg2SiO4), wadsleyite (b-Mg2SiO4) and ringwoodite (g-Mg2SiO4), have been calculated using a DFT approach with a planewave basis set and pseudopotential approximation.51 These Mg2SiO4 polymorphs are the principal components of the Earth down to depths of 660 km and have been proposed as the hosts of water in the Earth’s upper mantle and transition zone. A comparison of the calculations with single-crystal spectroscopic data in the literature for the a-polymorph, forsterite, shows that both the magnitude and orientation of the shielding and EFG tensors for O and Si can be obtained with sufficient accuracy to distinguish subtle differences in atomic positions between published structures. The authors compare calculated 17O MAS NMR quadrupolar powder lineshapes directly with experimental lineshapes and show the precision with which the NMR parameters may be determined from multi-parameter fitting. The relatively small amount of sample available for the b- and g-polymorphs, arising from the high pressures required for synthesis, has hindered the extraction of NMR parameters in previous work. The application of DFT calculations to these high-pressure polymorphs confirms previous spectral assignments, and provides deeper insight into the empirical correlations and observations reported in the literature. These firstprinciples methods are expected to be highly promising for the determination of local bonding in more complex materials, such as the hydrated forms of Mg2SiO4, by aiding analysis of their multinuclear NMR spectra. Non-covalent cation–p interactions are important in a variety of supramolecular and biochemical systems. A 23Na solid-state NMR study of two sodium lariat ether complexes, 1 and 2, in which a sodium cation interacts with an indolyl group that models the side chain of tryptophan, has been presented.52 Solid-state 23Na NMR spectra of MAS and stationary powdered samples have been acquired at three magnetic field strengths (9.4, 11.75, 21.1 T) and analysed to provide key information on the sodium electric field gradient and chemical shift tensors which are representative of the cation–p binding environment. Triple-quantum MAS NMR spectra acquired at 21.1 T clearly reveal two crystallographically distinct sites in both 1 and 2. The quadrupolar coupling constants, CQ(23Na), range from 2.92 0.05 MHz to 3.33 0.05 MHz; these values were somewhat larger than those reported previously for NaBPh4 [A. Wong, R. D. Whitehead, Z. Gan and G. Wu, J. Phys. Chem. A, 2004, 108, 10551], but very similar to the values obtained for sodium metallocenes [M. J. Willans and R. W. Schurko, J. Phys. Chem. B, 2003, 107, 5144]. From the 21.1 T data it was concluded that the spans of the sodium CS tensors are less than 20 ppm for 1 and 2 and that the largest components of the EFG and CS tensors are non-coincident. Quantum chemical calculations of the NMR parameters substantiate the experimental findings and provide additional insight into the dependence of CQ(23Na) on the proximity of the indole ring to Na+. Taken together, this work has provided novel information on the NMR interaction tensors characteristic of a sodium cation interacting with a biologically important arene. The first 33S chemical shift anisotropy data has been obtained from a combined determination of 33S CSA and quadrupole coupling parameters utilizing the observation of both the 33S (I = 3/2) central and satellite transitions in a natural abundance 33S MAS NMR study aimed at characterizing the two important tetrathiometallates.53 Trends in the chlorine chemical shift tensors of amino acid hydrochlorides are investigated in the context of new data obtained at 21.1 T and extensive quantum chemical calculations.54 The analysis of chlorine-35/37 NMR spectra of solid L-tryptophan hydrochloride obtained at two magnetic field strengths yields the chlorine electric field gradient and CS tensors, and their relative orientations. The chlorine CS tensor is also determined for the first time for DL-arginine hydrochloride monohydrate. The drastic influence of 1H decoupling at 21.1 T on the spectral Nucl. Magn. Reson., 2008, 37, 208–256 | 219 This journal is

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features of salts with particularly small 35Cl quadrupolar coupling constants (CQ) is demonstrated. The chlorine CS tensor spans of hydrochloride salts of hydrophobic amino acids are found to be larger than those for salts of hydrophilic amino acids. A new combined experimental-theoretical procedure is described in which quantum chemical geometry optimizations of hydrogen-bonded proton positions around the chloride ions in a series of amino acid hydrochlorides are cross-validated against the experimental chlorine EFG and CS tensor data. The conclusion is reached that the relatively inexpensive B3LYP/3-21G* method provides proton positions which are suitable for subsequent higher-level calculations of the chlorine EFG tensors. The computed value of span is less sensitive to the proton positions. Following this crossvalidation procedure, |CQ(35Cl)| is generally predicted within 15% of the experimental value for a range of HCl salts. The results suggest the applicability of chlorine NMR interaction tensors in the refinement of proton positions in structurally similar compounds, e.g., chloride ion channels, for which neutron diffraction data are unavailable. A series of alkaline earth chloride hydrates has been studied by solid-state 35/37Cl NMR spectroscopy in order to characterize the chlorine electric field gradient and chemical shift tensors and to relate these observables to the structure around the chloride ions.55 Chlorine-35/37 NMR spectra of solid powdered samples of pseudopolymorphs (hydrates) of magnesium chloride (MgCl2 6H2O), calcium chloride (CaCl2 2H2O), strontium chloride (SrCl2, SrCl2 2H2O, and SrCl2 6H2O), and barium chloride (BaCl2 2H2O) have been acquired under stationary and MAS conditions in magnetic fields of 11.75 and 21.1 T. Powder X-ray diffraction was used as an additional tool to confirm the purity and identity of the samples. Chlorine-35 quadrupolar coupling constants (CQ) range from essentially zero in cubic anhydrous SrCl2 to 4.26 0.03 MHz in calcium chloride dihydrate. CS tensor spans are between 40 and 72 ppm, for example, 45 20 ppm for SrCl2 6H2O. Plane wavepseudopotential density functional theory, as implemented in the CASTEP program, was employed to model the extended solid lattices of these materials for the calculation of their chlorine EFG and nuclear magnetic shielding tensors, and allowed for the assignment of the two-site chlorine NMR spectra of barium chloride dihydrate. This work builds upon current understanding of the relationship between chlorine NMR interaction tensors and the local molecular and electronic structure, and highlights the particular sensitivity of quadrupolar nucleus solid-state NMR spectroscopy to the differences between various pseudopolymorphic structures in the case of strontium chloride. 39 K solid state NMR spectra (static and MAS) on a set of potassium salts measured at 21.14 T have shown that the chemical shift range for K+ ions in diamagnetic salts is well in excess of 100 ppm contrary to previous assumptions that it was quite small.56 Inequivalent potassium sites in crystals can be resolved through differences in chemical shifts, with chemically similar sites showing differences of over 10 ppm. The quadrupolar coupling constants obtained from MAS and solid echo experiments on powders cover the range from zero for potassium in cubic environments in halides to over 3 MHz for the highly asymmetric sites in K2CO3. Although the quadrupolar effects generally dominate the 39K spectra, in several instances subtle but significant contributions of chemical shift anisotropy with values up to 45 ppm were observed. Careful analysis of static and MAS spectra allowed the observation of the various chemical shift and quadrupole coupling tensor components as well as their relative orientations, thereby demonstrating that high-field 39K NMR spectroscopy in the solid state has a substantial sensitivity to the local environment with parameters that will be of considerable value in materials characterization and electronic structure studies. Truflandier et al. have presented the first DFT based calculations of NMR shielding parameters for a transition metal nucleus using periodic boundary conditions.57 These calculations employ the gauge-including projected augmented-wave pseudopotential approach. The quality of this method is discussed by comparing 220 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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experimental and calculated chemical shift tensor eigenvalues for the quadrupolar 51 V nucleus in the diamagnetic solid-state compound AlVO4. Furthermore, the combination of shielding tensor with fast and accurate projector augmented-wave electric field gradient tensor calculations allowed the authors to determine the relative orientation of these two tensors. DFT calculations (6–311+G(2d,p)/B3LYP level of theory) of 51V EFG tensor elements have been performed for embedded and isolated cluster models of orthovanadates.58 The structural models used to calculate the EFGs of 51V are (I) an isolated H4VO4+ cluster, (II) an isolated HnVO4n–3 cluster (n = number of nextneighbour cations) (III) an isolated orthovanadate anion, VO4x, and (IV) a VO4x ion embedded in a finite point-charge array whose electrostatic potential, at the embedded ion, is equivalent to that of the infinite lattice. Models III and IV provided results in good agreement with the experiment. Calculations, employing the embedded and isolated VO4x models, were used to discuss site assignments for AlVO4. Correlations between quadrupole coupling parameters and deviations of the orthovanadate structure from ideal tetrahedral symmetry were found. Finally, central transition 55Mn NMR spectra of several solid manganese pentacarbonyls acquired at magnetic field strengths of 11.75, 17.63, and 21.1 T have been described.59 The variety of distinct powder sample lineshapes obtained demonstrates the sensitivity of solid-state 55Mn NMR to the local bonding environment, including the presence of crystallographically unique Mn sites, and facilitates the extraction of the Mn chemical shift anisotropies, CSAs, and the nuclear quadrupolar parameters. The compounds investigated include molecules with approximate C4v symmetry, LMn(CO)5(L = Cl, Br, I, HgMn(CO)5, CH3) and several molecules of lower symmetry (L = PhCH2, Ph3nClnSn (n = 1, 2, 3)). For these compounds, the 55 Mn CSA values range from o100 ppm for Cl3SnMn(CO)5 to 1260 ppm for ClMn(CO)5. At 21.1 T the 55Mn NMR lineshapes are appreciably influenced by the Mn CSA despite the presence of significant 55Mn quadrupolar coupling constants that range from 8.0 MHz for Cl3SnMn(CO)5 to 35.0 MHz for CH3Mn(CO)5. The breadth of the solid-state 55Mn NMR spectra of the pentacarbonyl halides is dominated by the CSA at all three applied magnetic fields. DFT calculations of the Mn magnetic shielding tensors reproduce the experimental trends and the magnitude of the CSA is qualitatively rationalized using a molecular orbital, MO, interpretation based on Ramsey’s theory of magnetic shielding. In addition to the energy differences between symmetry-appropriate occupied and virtual MOs, the dcharacter of the Mn MOs is important for determining the paramagnetic shielding contribution to the principal components of the magnetic shielding tensor.

5. Applications 5.1 Organic solids The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned.60 The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution. The structures of six N-unsubstituted pyrazoles, three already known and three newly synthesised, have been studied by a combination of X-ray crystallography, multinuclear NMR (solution and solid state), and density functional theory (DFT) calculations.61 In those cases where crystal structure and CPMAS NMR were available, the agreement was almost perfect, allowing a prediction of the tautomer (with certitude) and the tetrameric structure (with high probability) in the case of 5-isopropyl-3-phenyl-1H-pyrazole without knowing the X-ray structure. In the case of the 5-(2-benzylphenyl)-3-trifluoromethyl-1H-pyrazole, the DFT calculations at the B3LYP/6-31G** level justify the great stability of this tautomer by the presence of an intramolecular N–H p interaction, present in solution. Nucl. Magn. Reson., 2008, 37, 208–256 | 221 This journal is

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The calibration of a solid-state NMR spectrometer requires setting the magic angle, setting the reference and decoupler frequencies, ensuring that the magnetic field is homogeneous across the sample volume, optimizing the signal-to-noise ratio, determining the p/2 pulse durations, and optimizing the Hartman-Hahn matching condition. Each task has one or more widely accepted standards, such as potassium bromide for setting the magic angle, adamantane for optimizing magnet homogeneity, and hexamethylbenzene or glycine for measuring the signal-to-noise ratio. It has been shown that all of these tasks can be performed using 3-methylglutaric acid (MGA). In the case of high-power decoupling, the CH2 and CH carbon peaks of MGA provide an opportunity to evaluate the decoupling in a manner that is superior to any of the commonly used standard compounds.62 Thus, MGA can be used as a single solid-state NMR standard compound to perform all calibration steps except for magnet shimming. The components of the nitrogen chemical shift tensor have been examined for a series of para substituted N,N-dimethylaniline derivatives through measurement of the 15N NMR spectra of powder samples and through quantum chemical calculations on the isolated molecules.63 Experiments and calculations show that the isotropic CS, diso, decreases with increasing electron donating ability of the para substituent, in agreement with previous solution studies. More importantly, the study shows that this decrease in the isotropic (solution) CS is due to decreasing values of the CS tensor component d11 and component d33. The component d22 is essentially invariant to the electron donating/withdrawing ability of the para substituent. Through Ramsey’s theory of nuclear magnetic shielding, it has been shown that the variation in d11 and d33, and hence diso, is due to changes in the n–p* and the s–p* energy gaps in N,N-dimethylaniline. This, in turn, is a result of the change in the energy of the p* molecular orbital with change in the p-electron donating ability of the para substituent. The effects of nitrogen inversion on the components of the nitrogen CS tensor components are also discussed. This study also shows the feasibility of performing 15N cross-polarization experiments on nonspinning powder samples at natural isotopic abundance. Methyl brevifolincarboxylate isolated from the herb of Potentilla argentea L. (Rosaceae) is a representative of the naturally occurring polyphenols. The compound is of pharmaceutical interest mainly because of its antiviral and antioxidant properties. 13C NMR spectra of this compound in solution and solid phase have been reported.64 Carbon-13 CPMAS spectra were assigned by comparison with solution data, dipolar dephasing and short contact time experiments. The correctness of assignments was verified by GIAO DFT calculations of shielding constants. The differences between the solution and solid state chemical shift values were explained in terms of orientation of OH groups and intramolecular hydrogen bonds. The splitting of the C1QO resonance shows that there exists a polymorphism in the solid phase, which might be due to the formation of intramolecular hydrogen bond involving carbonyl or methoxy oxygen (i.e. C10–OH OQC or C10–OH OCH3). Kuwahara et al. have presented a new NMR method to clarify the dynamics of proton tautomerism in solid 9-hydroxyphenalenone.65 Two 13C resonance lines influenced by the proton tautomerism have a chemical shift difference between them, which increases with decreasing temperature. To depict the precise potential curve of the proton tautomerism, the chemical shift difference when the proton tautomerism is completely frozen is necessary. For solid 9-hydroxyphenalenone and its derivatives, the freezing temperatures are often under 173 K. When the freezing temperatures are below the temperature range in which standard MAS NMR probes can perform a sample spinning, it is very difficult to obtain the shift difference. The NMR experiments based on this new method are performed at a temperature significantly higher than 173 K at which the proton tautomerism is still active. The new method yields the 13C spin relaxation rates, the rates for the proton tautomerism and the populations of the two tautomers. Using the populations and the 13C chemical shift difference at that temperature, Kuwahara et al. determined the 222 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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chemical shift difference at the freezing temperature. They also obtained several parameters characterizing the potential profile for the proton dynamics in solid 9-hydroxyphenalenone. Latosin´ska et al. have reported the temperature dependencies of the relaxation time T1 (in the ranges: 100–440 K at 60 MHz; 20 K–RT at 24.667 MHz) and the second moment of the NMR line for protons (in the range: 100–350 K at 27 MHz) measured for a polycrystalline sample of 4-chloro-2-furfurylamino-5-sulfamoylbenzoic acid (furosemide), form I.66 The minima in the temperature dependence of the T1 time revealed two activation processes related to the proton transfer in the O–HO hydrogen bond (the low-temperature minimum) and a jumps of the –NH2 group (the high-temperature minimum). The reduction in the second moment value M2 indicated a global motion of the compound molecule, a quasi-isotropic tumbling motion. Kwan et al. have reported solid-state 17O NMR determination of the 17O NMR tensors for the keto carbonyl oxygen (O6) of guanine in two 17O-enriched guanosine derivatives: [6-17O]guanosine (G1) and 2 0 ,3 0 ,5 0 -O-triacetyl-[6-17O]guanosine (G2).67 In G1 2H2O, guanosine molecules form hydrogen-bonded G-ribbons where the guanine bases are linked by O6 H–N2 and N7 H–N7 hydrogen bonds in a zigzag fashion. In addition, the keto carbonyl oxygen O6 is also weakly hydrogen-bonded to two water molecules of hydration. The experimental 17O NMR tensors determined for the two independent molecules in the asymmetric unit of G1 2H2O are: Molecule A, CQ = 7.8 0.1 MHz, ZQ = 0.45 0.05, diso = 263 2, d11 = 460 5, d22 = 360 5, d33 = 30 5 ppm; Molecule B, CQ = 7.7 0.1 MHz, ZQ = 0.55 0.05, diso = 250 2, d11 = 440 5, d22 = 340 5, d33 = 30 5 ppm. In G1/K+ gel, guanosine molecules form extensively stacking G-quartets. In each G-quartet, four guanine bases are linked together by four pairs of O6 H–N1 and N7 H–N2 hydrogen bonds in a cyclic fashion. In addition, each O6 atom is simultaneously coordinated to two K+ ions. For G1/K+ gel, the experimental 17O NMR tensors are: CQ = 7.2 0.1 MHz, ZQ = 0.68 0.05, diso = 232 2, d11 = 400 5, d22 = 300 5, d33 = 20 5 ppm. In the presence of divalent cations such as Sr2+, Ba2+, and Pb2+, G2 molecules form discrete octamers containing two stacking G-quartets and a central metal ion, that is, (G2)4–M2+–(G2)4. In this case, each O6 atom of the G-quartet is coordinated to only one metal ion. For G2/M2+ octamers, the experimental 17O NMR parameters are: Sr2+, CQ = 6.8 0.1 MHz, ZQ = 1.00 0.05, diso = 232 2 ppm; Ba2+, CQ = 7.0 0.1 MHz, ZQ = 0.68 0.05, diso = 232 2 ppm; Pb2+, CQ = 7.2 0.1 MHz, ZQ = 1.00 0.05, diso = 232 2 ppm. The authors also performed extensive quantum chemical calculations for the 17O NMR tensors in both G-ribbons and G-quartets. Their results demonstrated that the 17 O chemical shift tensor and quadrupole coupling tensor are very sensitive to the presence of hydrogen bonding and ion–carbonyl interactions. Furthermore, the effect from ion-carbonyl interactions is several times stronger than that from hydrogen-bonding interactions. The results obtained establish a basis for using solid-state 17O NMR as a probe in the study of ion binding in G-quadruplex DNA and ion channel proteins. The synthesis and detailed structural studies in solid state using X-ray diffraction and 13C CPMAS NMR of new 1,5-bis(4-cyano-2,6-dimethoxyphenoxy)-3-oxapentane and 1,5-bis(4-cyano-2,6-methoxyphenoxy)pentane have been presented.68 Protonation of an azasugar inhibitor inside the active site of a glycosidase has been studied by solid-state NMR spectroscopy.69 By measuring 13C chemical shifts of azafagomine bound to yeast a-glucosidase, almond b-glucosidase, and Aspergillus niger glucoamylase, and 15N chemical shift ofazafagomine bound to b-glucosidase, the authors found evidence for an N1-protonation of azafagomine inside b-glucosidase. For a-glucosidase and glucoamylase the corresponding chemical shifts are similar to those of the non-protonated inhibitor, which shows that charge stabilization at anomeric position is not occurring in these enzymes.


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Tetrazine-based organic species are interesting intermediates for organic synthesis and represent a source of new materials bearing specific properties with potential applications in biology and material science. 1H, 13C, 15N NMR measurements carried out in solution and in the solid-state have been used to characterize a series of 3,6-disubstituted 1,2,4,5-tetrazine/dihydrotetrazine new derivatives.70 Experimental results presented provide data for the assignment of 15N chemical shifts including new organic small molecules; two polymers having the tetrazine ring in the main chain and several previously published compounds. The authors report for the first time 15N experimental chemical shift data for tetrazine systems in the solid state. On the basis of their solid-state NMR characterization of dynamics in two model salts, Traer et al. have drawn the analogy to the fuel cell membrane candidate, phosphoric acid-doped poly(benzimidazole), and concluded that phosphate anion dynamics contribute to long-range proton transport, whereas the mobility of the polymer itself is not a contributing factor.71 This is contrasted with emerging membrane candidates, which rely on fully covalently bonded acid donors and acceptors, and target high-temperature PEM fuel cell operation in the absence of liquid electrolyte. The hydrogen-bonding structures of benzimidazolium phosphate and benzimidazolium methane phosphonate are established using X-ray diffraction paired with solid-state 1H DQF NMR. By comparing the dynamics of the phosphate and methane phosphonate anions with the dynamics of imidazolium and benzimidazolium cations, the relative importance of these processes in proton transport is determined. The imidazolium cation is known to undergo two-site ring reorientation on the millisecond time scale. In contrast, it is shown that the benzimidazolium rings are immobile in analogous salts, on a time scale extending into the tens of seconds. Therefore, Traer et al. chose to study the phosphate anions and demonstrated that the time scale of tetrahedral reorientation is comparably fast (50 ms). Moreover, the 31 P CODEX NMR data clearly indicated a four-site jump process. In contrast, the methane phosphonate was shown to undergoe a three-site jump on a slower time scale (75 ms). A mechanism for a zigzag pathway of proton transport through the phosphonate salt crystallites has been developed based on the 31P CODEX and 1H variable-temperature MAS NMR data. 2,3-Dimethylquinoxaline (DMQ) and dimethylglyoxime (DMGH2) form a 1:1 hydrogen-bonded complex in the solid state, which is completely dissociated in methanol solution.72 There are small differences in solid-state 13C shifts between the separated components DMQ and DMGH2 and the complex. The changes in 15N solid-state chemical shifts are more significant: the hydrogen bond imparting a low frequency shift of ca. 19 ppm. The effect of direct protonation on the DMQ solidstate 15N shifts was measured, and the experimental 15N data correlated with those from GIAO molecular orbital calculations. Sharif et al. have presented a novel series of hydrogen-bonded, polycrystalline 1:1 complexes of Schiff base models of the cofactor pyridoxal-5 0 -phosphate (PLP) with carboxylic acids that mimic the cofactor in a variety of enzyme active sites.73 These systems contain an intramolecular OH N hydrogen bond characterized by a fast proton tautomerism as well as a strong intermolecular OH N hydrogen bond between the pyridine ring of the cofactor and the carboxylic acid. In particular, the aldenamine and aldimine Schiff bases N-(pyridoxylidene)tolylamine and N-(pyridoxylidene)methylamine, as well as their adducts, were synthesized and studied using 15N CP and 1H NMR techniques under static and/or MAS conditions. The geometries of the hydrogen bonds were obtained from X-ray structures, 1H and 15N chemical shift correlations, secondary H/D isotope effects on the 15N chemical shifts, or directly by measuring the dipolar 2H–15N couplings of static samples of the deuterated compounds. An interesting coupling of the two ‘‘functional’’ OH N hydrogen bonds was observed. When the Schiff base nitrogen atoms of the adducts carry an aliphatic substituent such as in the internal and external aldimines of PLP in the enzymatic environment, protonation of the ring nitrogen shifts the proton in the intramolecular OH N hydrogen bond from the oxygen to the Schiff base nitrogen. 224 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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This effect, which increases the positive charge on the nitrogen atom, has been discussed as a prerequisite for cofactor activity. This coupled proton transfer does not occur if the Schiff base nitrogen atom carries an aromatic substituent. The structural studies on the solid state of two benzodiazacoronads that form chiral and achiral crystals have been presented.74 Crystals are considered as a twocomponent system consisting of an organic unit and a water molecule in 1:1 ratio. Both components play an important role in the crystal structure. The strong (O–H O, N–H O) and weak (C–H O) intermolecular hydrogen bonds are responsible for phase organization and, in consequence, formation of chiral or achiral crystals. Formation of chiral cocrystals from two different achiral molecules by self-assembly is well-known. However, the authors of this work have shown that the water molecule can be an important achiral cofactor responsible for chiral crystallization. 5.2 Inclusion compounds The molecular structure and dynamics of novel inclusion compounds (ICs) consisting of n-perfluoroalkane (PFA) guests and b-cyclodextrin (b-CD) host (PFA/b-CD) have been investigated using 19F MAS and 1H - 19F CPMAS NMR spectroscopy with the aid of thermal analyses, FT-IR spectroscopy, and X-ray diffraction method.75 The ICs of C9F20/b-CD and C20F42/b-CD were successfully obtained as precipitates from mixtures of respective PFAs and saturated aqueous solution of bCD. The wide-angle X-ray diffraction (WAXD) revealed that C9F20/b-CD forms a channel-type crystallite, while C20F42/b-CD is nearly amorphous at room temperature. The structural orders in both ICs increase at elevated temperatures. The 19F NMR signals obtained by the direct polarization (DP) method for PFA/b-CD are resonated at higher frequencies than those for original PFA. This can be ascribed to the lower dielectric environment of the b-CD cavity. Above 353 K, 1H - 19F CP/ MAS NMR technique revealed that C9F20 molecules undergo vigorous molecular motion and partly come out of the b-CD channel. However, the guests hardly degrade or evaporate unless the host is pyrolytically decomposed above ca. 573 K. The spin-lattice relaxation times in the laboratory frame for 19F (T1F) are almost identical for all the fluorines in PFA/b-CD at each temperature, while significantly different values were observed for fluorines in neat PFA. This indicated that effective intramolecular spin diffusion occurs within a PFA molecule included in b-CD. The reorientational dynamics of benzene-d6 molecules hosted into the cavity of a cavitand-based, self-assembled capsule was investigated by MD simulations and temperature-dependent solid-state 2H NMR spectroscopy.76 MD simulations were preliminarily performed to assess the motional models of the guest molecules inside the capsules. An in-plane fast reorientation of the benzene guest around the C6 symmetry axis (B1 motion), characterized by correlation times of the order of picoseconds, was predicted with an activation barrier (B8 kJ mol1) very similar to that found for neat benzene in the liquid state. An out-of-plane reorientation corresponding to a nutation of the C6 symmetry axis in a cone angle of 391 (B2 motion, 373 K) with an activation barrier (B39 kJ mol1) definitely larger than that of liquid benzene was also anticipated. In the temperature range 293–373 K correlation times of the order of a nanosecond have been calculated and a transition from fast to slow regime in the 2H NMR scale has been predicted between 293 and 173 K. 2H NMR spectroscopic analysis, carried out in the temperature range 173– 373 K on the solid capsules containing the perdeuterated guest (two benzene molecules/capsule), confirmed the occurrence of the B1 and B2 motions found in slow exchange in the 2H NMR time scale. Line shape simulation of the 2H NMR spectral lines permitted defining a cone angle value of 391 at 373 K and 351 at 173 K for the nutation axis. The T1 values measured for the 2H nuclei of the encapsulated aromatic guest gave correlation times and energetic barrier for the in-plane motion B1 in fine agreement with theoretical calculation. The experimental correlation time Nucl. Magn. Reson., 2008, 37, 208–256 | 225 This journal is

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for B2 as well as the corresponding energetic barrier are in the same range found for B1. A molecular mechanism for the encapsulated guest accounting for the B1 and B2 motions was also provided. Solid-state 2H and 13C NMR studies were performed for the first time on an urea inclusion compound with a doubly branched alkane guest molecule.77 Variable temperature 2H NMR measurements were done on two samples with 2,15-dimethylhexadecane deuterated either at two methylene groups (positions C3 and C14) or at both terminal isopropyl groups (positions C1, C1 0 , C2, C15, C16 and C16 0 ). The 13C NMR data demonstrated that the inner chain segments exist in the trans-conformation. A comprehensive analysis of the experimental 2H NMR data demonstrated that the guest molecules undergo restricted overall rotation (modelled with a degenerate 2-site jump process) around the channel long axis, which is a major source for spin-lattice relaxation. Moreover, it is found that the orientation of the methyl groups is perpendicular to the long molecular axis (i.e., gauche conformation at both chain ends) which gives rise to a better molecular packing and stronger vander-Waals interactions. Activation energies of 24.3 (1.0) kJ/mol were derived for the overall molecular rotation, while for methyl group rotation values of 14.4 (0.6) kJ mol1 (between 210 and 250 K) and 12.0 (1.7) kJ mol1 (between 160 and 200 K) were obtained. For a consistent description of the available 2H NMR data, the overall molecular wobbling of the guest molecules was also taken into account. The molecular properties of 1,6-dibromohexane in its urea inclusion compound have been investigated by means of a multinuclear solid-state NMR spectroscopy.78 Solid-state 13C CPMAS and 1H MAS NMR studies (line shapes, spin-lattice relaxation measurements) were performed for the first time to probe the guest dynamics and conformational order. Variable temperature 2H NMR studies comprising line shape analysis as well as spin-lattice relaxation (T1Z, T1Q) experiments were done on samples with guest molecules selectively deuterated at two different positions. A quantitative analysis of the experimental data proves that the guest dynamics are dominated by mutual exchange between two gauche conformers. It is shown that these guest motions unequivocally can be quantified (type and timescale) by a comprehensive analysis of the T1Z and T1Q data. In addition, there is evidence that other motional contributions, such as overall molecular fluctuations and lateral motions, also contribute to spin relaxation. The molecular behaviour of 1,6-dibromohexane in urea is shown to be completely different from that reported for the long chain analogues or for n-alkanes where typically unhindered overall rotational motions of the guests in their all-trans conformation around the urea channel long axis are discussed. The differences in guest ordering and dynamics are shown to be a direct consequence of the differences of the urea lattice structures (monoclinic vs. hexagonal urea lattice). The structure of supramolecular complexes formed by a naphthalene-spaced tweezer molecule as host and 1,4-dicyanobenzene (DCNB), 1,2,4,5-tetracyanobenzene (TCNB), and 7,7,8,8-tetracyano-p-quinodimethane (TCNQ) as aromatic, electron-deficient guests has been investigated by solid-state NMR and X-ray diffraction measurements.79 Quantum chemical calculations using linear scaling methods are applied to predict and to assign the 1H NMR chemical shifts of the complexes. By combining experiment and theory, insights into intra- and intermolecular effects influencing the proton chemical shifts of the host–guest system have been provided in the solid state. A method has been presented for detecting multiple xenon atoms in cavities of solid-state inclusion compounds using 129Xe double quantum NMR spectroscopy.80 Double quantum filtered 129Xe NMR spectra, performed on the xenon clathrate of Dianin’s compound were obtained under high-resolution MAS conditions, by recoupling the weak 129Xe–129Xe dipole–dipole couplings that exist between xenon atoms in close spatial proximity. Because the 129Xe–129Xe dipole–dipole couplings are generally weak due to dynamics of the atoms and to large internuclear separations, and since the 129Xe CSA tends to be relatively large, a very robust 226 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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dipolar recoupling sequence was necessary, with the symmetry-based dipolar recoupling sequence proving appropriate. The authors have also attempted to measure the 129Xe–129Xe dipole–dipole coupling constant between xenon atoms in the cavities of the xenon-Dianin’s compound clathrate and have found that the dynamics of the xenon atoms (as investigated with molecular dynamics simulations) as well as 129Xe multiple spin effects complicate the analysis. The double quantum NMR method is shown to be useful for peak assignment in 129Xe NMR spectra because peaks arising from different types of absorption/inclusion sites or from different levels of occupancy of single sites can be distinguished. The method can also help resolve ambiguities in diffraction experiments concerning the order/disorder in a material. 5.3 Amino acids Mikhailiuk et al. have reported studies of conformationally rigid trifluoromethylsubstituted a-amino acid designed for peptide structure analysis by solid-state 19F NMR spectroscopy.81 It has been shown that the enantiomeric excess can be determined by solid-state NMR.82 In particular, the use of the solid-state NMR ODESSA experiment for the determination of the enantiomeric excess of valine has been demonstrated. Yamada et al. have presented a systematic experimental investigation of carboxyl oxygen EFG and CS tensors in crystalline amino acids.83 Three 17O-enriched amino acids were prepared: L-aspartic acid, L-threonine, and L-tyrosine. Analysis of twodimensional 17O MQMAS, MAS and stationary NMR spectra yielded the 17O CS and EFG tensors and the relative orientations between the two tensors for the amino acids. The values of quadrupolar coupling constants (CQ) were found to be in the range of 6.70–7.60 MHz. The values of the isotropic chemical shift were in the range of 268–292 ppm, while those of the d11 and d22 components varied from 428 to 502 ppm, and from 303 to 338 ppm, respectively. A significant correlation between the magnitudes of d22 components and C–O bond lengths was found. Since C–O bond length may be related to hydrogen-bonding environments, solid-state 17O NMR was shown to have a significant potential in provision of insights into important aspects of hydrogen bonds in biological systems. Yamada et al. have also presented an experimental investigation of the carboxyl 17 O NMR parameters for four distinct sites in L-valine and L-isoleucine.84 The carboxyl 17O quadrupolar coupling constant, CQ, and isotropic chemical shift, diso, for these compounds were obtained by analysing two-dimensional 17O MQMAS and/or 1D MAS spectra. The values of CQ and diso were found to be in the range of 7.00–7.85 MHz, and 264–314 ppm, respectively. Extensive quantum chemical DFT calculations have been performed for a full cluster of L-valine molecules and a few theoretical models. The calculated results indicated that there was a correlation between the 17O NMR parameters and C–O bond lengths, which was helpful for the spectral assignment. They also demonstrated that the torsion angle of L-valine plays an important role in determining the magnitudes of 17O NMR parameters. Further to two other reports above, Yamada et al. have decribed a highly effective labelling method for 17O-enriched amino acids and peptides at moderate experimental conditions (Japanese Patent 2006–8666), which has enabled the authors to readily carry out solid-state 17O NMR experiments in various amino acids and peptides.85 Finally, Gross and McDermott have demonstrated a novel method to locate hydrogen atoms in amino acids, which involves measuring the CaHa bond vector geometry through orientationally dependent dipolar coupling frequencies measured by Lee-Goldburg cross polarization (LGCP).86 A 2D LGCP experiment was used to measure the polar angle of the CaHa bond vector in a single crystal of the model compound L-alanine. It has also been demonstrated that by coupling the 13Ca1Ha LGCP experiment to a 13Ca15N REDOR experiment, one can determine the Nucl. Magn. Reson., 2008, 37, 208–256 | 227 This journal is

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complete three-dimensional geometry of the CaHa and CaN vectors in a single crystal. These measurements allow for location of hydrogen atoms in crystalline biological macromolecules. 5.4 Peptides and proteins Li+ and Ca2+ binding to the carbonyl oxygen sites of a model peptide system has been studied by Chekmenov et al. using 17O solid-state NMR spectroscopy.87 17O CS and quadrupole coupling (QC) tensors have been determined in four Gly– (Gly–17O)–Gly polymorphs by a combination of stationary and fast MAS methods at high magnetic field of 19.6 T. In the crystal lattice, the carbonyl oxygen of the central glycyl residue in two Gly–Gly–Gly polymorphs form intermolecular hydrogen bonds with amides, whereas the corresponding carbonyl oxygens of the other two polymorphs form interactions with Li+ and Ca2+ ions. This permitted a comparison of perturbations on 17O NMR properties by ion binding and intermolecular hydrogen bonding. High quality spectra were augmented by DFT calculations on large molecular clusters to gain additional theoretical insights and to aid in the spectral simulations. Ion binding was shown to significantly decrease the two 17O chemical shift tensor components in the peptide plane, d11 and d22, and, thus, a substantial change in the isotropic chemical shift. In addition, quadrupole coupling constants were found to decrease by up to 1 MHz. The effects of ion binding were found to be almost an order of magnitude greater than those induced by hydrogen bonding. Lamellar structure of poly(Ala–Gly) or (AG)n in the solid was examined using 13C solid-state NMR and statistical mechanical approaches.88 Two doubly labelled versions, [1-13C]Gly14[1-13C]Ala15- and [1-13C]Gly18[1-13C]Ala19 of (AG)15 were examined by two-dimensional 13C spin diffusion NMR in the solid state. In addition five doubly labelled [15N, 13C]-versions of the same peptide, (AG) 15 and 15 versions labelled [3–13C] in each of the successive Ala residues were utilised for REDOR and 13 C CPMAS NMR measurements, respectively. The observed spin diffusion NMR spectra were consistent with a structure containing a combination of distorted bturns with a large distribution of the torsion angles and antiparallel b-sheets. The relative proportion of the distorted b-turn form was evaluated by examination of 13C CPMAS NMR spectra of [3-13C]Ala–(AG)15. In addition, REDOR determinations showed five kinds of atomic distances between doubly labelled 13C and 15N nuclei which were also interpreted in terms of a combination of b-sheets and b-turns. The statistical mechanical analysis undertaken was in excellent agreement with the Ala Cb 13C CPMAS NMR data strongly suggesting that (AG)15 has a lamellar structure. Elastin is an abundant protein found in vertebrates and is the source of elasticity in connective tissues and blood vessels. The repeating polypeptide sequences found in the hydrophobic domains of elastin have been the focus of many studies that attempt to understand the function of the native protein on a molecular scale. In a new communication, the (LGGVG)6 elastin mimetic has been characterized by solidstate 13C NMR spectroscopy.89 Through the use of a combination of a statistical analysis based on the Protein Data Bank, one-dimensional CPMAS NMR spectroscopy, and two-dimensional off-MAS spin-diffusion experiments, it was determined that this tandem repeat does not form a regular, highly ordered structure. Instead, like the poly(VPGVG) elastin mimetics, the valine has a twofold heterogeneity, although the conformations of these two populations differ from one peptide to the other. To clarify the physical properties of silk yams, cocoons and yams of 12 different silk species were analyzed by solid-state 13C NMR and their amino acid compositions and spin-lattice relaxation time were compared.90 The correlation between these values and physical values of yams obtained by tensile strength measurements were discussed. Mole fraction of glycine (glycine/(glycine + alanine + serine + valine)) and T1 of cocoons and yams were different depending on the silk species. 228 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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Mole fraction of glycine showed high correlation with viscosity and T1 showed high correlation with Young’s modulus. Iwata et al. have reported constraints on the supramolecular structure of amyloid fibrils formed by the 40-residue b-amyloid peptide associated with Alzheimer’s disease (Ab140) obtained from solid-state NMR measurements of intermolecular dipole–dipole couplings between 13C labels at 11 carbon sites in residues 2 through 39.91 The measurements were carried out under MAS conditions, using the constanttime finite-pulse rf-driven recoupling (fpRFDR-CT) technique. Iwata et al. have also presented one-dimensional 13C MAS NMR spectra of the labelled Ab140 samples. The fpRFDR-CT data revealed nearest-neighbour intermolecular distances of 4.8 0.5 A˚ for carbon sites from residues 12 through 39, indicating a parallel alignment of neighbouring peptide chains in the predominantly b-sheet structure of the amyloid fibrils. The one-dimensional NMR spectra indicated structural order at these sites. The fpRFDR-CT data and NMR spectra also indicated structural disorder in the Nterminal segment of Ab140, including the first nine residues. These results place strong constraints on any molecular level structural model for full length b-amyloid fibrils. Bu et al. have reported investigations of the molecular structure of amyloid fibrils formed by residues 14–23 of the b-amyloid peptide associated with Alzheimer’s disease (Ab1423), using solid-state NMR techniques in conjunction with electron microscopy and atomic force microscopy.92 The NMR measurements, which include two-dimensional proton-mediated 13C–13C exchange and relayed proton-mediated 13 C–13C exchange spectra, showed that Ab1423 fibrils contain antiparallel b-sheets with a registry of backbone hydrogen bonds. While the theoretical predictions were not in exact agreement with the experimental results, they facilitated the design of experiments by suggesting a small number of plausible alignments that are readily distinguished by solid-state NMR. Sup35p is a prion protein found in yeast that contains a prion-forming domain characterized by a repetitive sequence rich in Gln, Asn, Tyr and Gly amino acid residues. The peptide GNNQQNY713 is one of the shortest segments of this domain found to form amyloid fibrils, in a fashion similar to the protein itself. Upon dissolution in water, GNNQQNY displays a concentration-dependent polymorphism, forming monoclinic and orthorhombic crystals at low concentrations and amyloid fibrils at higher concentrations. Van der Wel et al. have prepared nanocrystals of both space groups as well as fibril samples that reproducibly contain three (coexisting) structural forms and examined the specimens with MAS solid-state NMR.93 MAS 13C and 15N spectra of both nanocrystals and fibrils revealed narrow resonances indicative of a high level of microscopic sample homogeneity that permitted resonance assignments of all five species. Variations in chemical shift among the three dominant forms of the fibrils were observed which were indicated by the presence of three distinct, self-consistent sets of correlated NMR signals. Similarly, the monoclinic and orthorhombic crystals exhibited chemical shifts that differed from one another and from the fibrils. Collectively, the chemical shift data suggested that the peptide assumes five conformations in the crystals and fibrils that differ from one another in subtle but distinct ways. This included variations in the mobility of the aromatic Tyr ring. The data also suggested that various structures assumed by the peptide may be correlated to the ‘‘steric zipper’’ observed in the monoclinic crystals. MAS solid-state NMR experiments applied to biological solids are still hampered by low sensitivity and resolution. In a new report, Agarwal et al. employed a deuteration scheme in which individual methyl groups are selectively protonated.94 This labelling scheme allowed the acquisition of proton carbon correlation spectra with a resolution comparable to that in solution-state NMR experiments. An increase in resolution by a factor of 10–15 was observed compared to standard heteronuclear correlation experiments using PMLG for 1H, 1H dipolar decoupling in the indirect dimension. At the same time, the full sensitivity of the proton-based Nucl. Magn. Reson., 2008, 37, 208–256 | 229 This journal is

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experiment was retained. In comparison to the heteronuclear detected version of the experiment, a gain in sensitivity of a factor of ca. 4.7 was achieved. Binding of antifreeze proteins to ice surfaces has been studied by Ba and Mao using solid-state 13C NMR spin lattice relaxation measurements.95 The majority of protein structures is determined in the crystalline state, yet few methods exist for the characterization of dynamics for crystalline biomolecules. Recent advances in high-resolution solid-state NMR have enabled the site-specific assignment of 13C and 15N nuclei in proteins. With the use of multidimensional separated-local-field experiments, Lorieau and McDermott have reported the backbone and side chain conformational dynamics of ubiquitin, a globular microcrystalline protein.96 The measurements of molecular conformational order parameters were based on heteronuclear dipolar couplings, and they were correlated to assigned chemical shifts, to obtain a global perspective on the sub-microsecond dynamics in microcrystalline ubiquitin. A total of 38 Ca, 35 Cb and multiple side chain unique order parameters were collected, and they revealed the high mobility of ubiquitin in the microcrystalline state. In general the side chains showed elevated motion in comparison with the backbone sites. The data were compared to solution NMR order parameter measurements on ubiquitin. The solid-state NMR measurements were sensitive to motions on a broader time scale than solution NMR measurements, and the solid-state NMR order parameters were generally lower than the corresponding solution values. Unlike solution NMR relaxation-based order parameters, order parameters for CH2 spin systems were readily measured from the powder line shape data. These results illustrate the potential for detailed, extensive and sitespecific dynamic studies of biopolymers by solid-state NMR. Rapid advances in solid-state MAS NMR have made it possible to probe protein dynamics on a per-residue basis, similar to solution experiments. In a new work, Reif et al. compare methyl 2H relaxation rates measured in the solid and liquid samples of a-spectrin SH3 domain.97 The solution data are treated using a model-free approach to separate the contributions from the overall molecular tumbling and fast internal motion. The latter part forms the basis for comparison with the solid-state data. Although the accuracy of solid-state measurements is limited by deuterium spin diffusion, the results suggest a significant similarity between methyl dynamics in the two samples. This is a potentially important observation, preparing the ground for combined analysis of the dynamics data by solid- and solution-state NMR. As demonstrated by means of the one-dimensional solid-state MAS exchange experiment (CODEX), the rate of the proton driven spin diffusion between backbone 15N nuclei in totally enriched protein depends strongly on the MAS frequency: spin diffusion at MAS frequency 16 kHz is about 4–5 times slower as compared to that at MAS frequency 1 kHz which is due to the averaging of the homo- and heteronuclear dipolar interactions by MAS.98 It has been shown that even at the highest MAS frequencies used the spin diffusion rate is comparable or larger than typical values of the spin-lattice relaxation rates of backbone nitrogens in solid proteins. Thus, the precise quantitative analysis of 15N T1’s in totally enriched solid proteins may lead to wrong quantitative results. On the other hand, the effectiveness of the 15 N–15N correlation and structure determination experiments making use of 15 N–15N distances can be increased by decreasing the MAS frequency as far as possible, which is counter intuitive to the commonly applied fast MAS conditions in order to reduce the dipolar-broadened line widths for increased spectral resolution. Schubert et al. have described the simplification of 13C–13C correlation spectra obtained from a microcrystalline protein sample expressed on a growth medium of 10% fully 13C labelled glucose diluted in 90% natural abundance glucose as compared to a fully labelled sample.99 Such a labelling scheme facilitates the backbone and side-chain resonance assignment of Phe, Tyr, His, Asp, Asn, Ile, Lys and Pro and yields an unambiguous stereospecific assignment of the valine Cg1, Cg2 and the leucine Cd2 resonances.


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Amino-acid selective MAS NMR experiments can aid the assignment of ambiguous cross-peaks in crowded spectra of solid proteins. In particular, for larger proteins, data analysis can be hindered by severe resonance overlap. In such cases, filtering techniques may provide a good alternative to site-specific spin-labeling to obtain unambiguous assignments that can serve as starting points in the assignment procedure. Jehle et al. have presented a simple pulse sequence that allows selective excitation of arginine and lysine residues.100 To achieve this, the authors make use of a combination of specific cross-polarization for selective excitation [M. Baldus, A. T. Petkova, J. Herzfeld and R. G. Griffin, cross polarization in the tilted frame: assignment and spectral simplification in heteronuclear spin systems, Mol. Phys., 1998, 95, 1197] and spin diffusion for transfer along the amino-acid side-chain. The selectivity of the filter was demonstrated with the excitation of lysine and arginine side-chain resonances in a uniformly 13C and 15N labelled protein preparation of the a-spectrin SH3 domain. It was shown that the filter can be applied as a building block in a 13C–13C lysine-only correlation experiment. A method for assigning solid-state NMR spectra of membrane proteins aligned in phospholipid bicelles that makes use of isotropic chemical shift frequencies and assignments has been described.101 The resonance assignments were based on comparisons of 15N chemical shift differences in spectra obtained from samples with their bilayer normals aligned perpendicular and parallel to the direction of the applied magnetic field. Rhodopsin is the visual pigment of the vertebrate rod photoreceptor cell and is the only member of the G protein coupled receptor family for which a crystal structure is available. Towards the study of dynamics in rhodopsin, Werner et al. have reported NMR-spectroscopic investigations of a,e-15N-tryptophan labelled rhodopsin in detergent micelles and reconstituted in phospholipids.102 Using a combination of solid state 13C, 15N-REDOR and HETCOR experiments of all possible 13C 0 i1 carbonyl/15N i -tryptophan isotope labelled amide pairs, and H/D exchange 1H,15N– HSQC experiments conducted in solution, the authors have assigned chemical shifts to all five rhodopsin tryptophan backbone 15N nuclei and partially to their bound protons. 15N chemical shifts were found to be similar when comparing those obtained in the native like reconstituted lipid environment and those obtained in detergent micelles at the membrane interface. The results suggest that the integrated solution and solid state NMR approach can provide highly complementary information in the study of structure and dynamics of large membrane proteins like rhodopsin. The number of structural restraints that can be obtained to solve 3D structures of proteins in the solid state is significantly lower than that in solution, and in relatively few cases, their skillful use has actually produced 3D structures. Paramagnetic metal ions, either as substitutes of diamagnetic metals in metalloproteins or inserted in suitably designed tags, are known to provide a wealth of structural restraints in solution, among which pseudocontact shifts are very precious. Balayssac et al. have shown that pseudocontact shifts (pcs) generated by paramagnetic metal ions with sufficiently large spin quantum number and magnetic susceptibility anisotropy can be easily measured, and in large numbers, in solid-state NMR spectra of proteins.103 The sample used was microcrystalline cobalt(II)-substituted matrix metalloproteinase 12 (MMP-12, 17 kDa). About 250 pcs were observed for nuclei up to more than 20 A˚ from the metal and were found in very good agreement with the calculated ones. A limited number of nuclei were also influenced by intermolecular interactions with paramagnetic metals in neighbouring molecules within the crystal lattice, and these effects were also quantitatively accounted for. These findings open new perspectives for solid-state protein structure determinations, including the use of the intermolecular pcs for solid-state samples with two- or one-dimensional order, such as fibrils. Initial steps in the development of a suite of triple-resonance 1H/13C/15N solidstate NMR experiments applicable to aligned samples of 13C and 15N labelled Nucl. Magn. Reson., 2008, 37, 208–256 | 231 This journal is

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proteins have been described.104 The experiments take advantage of the opportunities for 13C detection without the need for homonuclear 13C/13C decoupling presented by samples with two different patterns of isotopic labelling. In one type of sample, the proteins are B20% randomly labelled with 13C in all backbone and side chain carbon sites and B100% uniformly 15N labelled in all nitrogen sites; in the second type of sample, the peptides and proteins were 13C labelled at only the acarbon and 15N labelled at the amide nitrogen of a few residues. The requirement for homonuclear 13C/13C decoupling while detecting 13C signals was avoided in the first case because of the low probability of any two 13C nuclei being bonded to each other; in the second case, the labelled 13Ca sites were separated by at least three bonds in the polypeptide chain. The experiments enabled the measurement of the 13C chemical shift and 1H–13C and 15N–13C heteronuclear dipolar coupling frequencies associated with the 13Ca and 13C 0 backbone sites, which provide orientation constraints complementary to those derived from the 15N labelled amide backbone sites. 13C/13C spin-exchange experiments identified proximate carbon sites. The ability to measure 13C–15N dipolar coupling frequencies and correlate 13C and 15N resonances provided a mechanism for making backbone resonance assignments. Three-dimensional combinations of these experiments ensured that the resolution, assignment, and measurement of orientationally dependent frequencies can be extended to larger proteins. Moreover, measurements of the 13C chemical shift and 1H–13C heteronuclear dipolar coupling frequencies for nearly all side chain sites enabled the complete three-dimensional structures of proteins to be determined with this approach. Pintacuda et al. have described solid-state NMR of a paramagnetic protein via assignment and study of human dimeric oxidised Cu-II–Zn-II superoxide dismutase.105 Etzkorn et al. have employed two-dimensional solid-state NMR to study structure and dynamics of insoluble folding states of the domain-swapped protein Crh.106 Starting from the protein precipitated at its pI, conformational changes due to a modest temperature increase were investigated at the level of individual residues and in real-time. This study provides direct evidence that protein aggregates of a domainswapped protein retain a significant fraction of native secondary structure and demonstrates that solid-state NMR can be used to directly monitor slow molecular folding events. Despite the considerable biological significance of this membrane binding mechanism for 5–10% of all cellular proteins, to date very little is known about structural and dynamical features of lipidated membrane binding domains. A study of the molecular dynamics of the C-terminus of membrane-associated fulllength lipidated Ras protein determined by solid-state NMR. Fully functional lipidmodified N-Ras protein was obtained by chemical-biological synthesis ligating the expressed water soluble N-terminus with a chemically synthesized 2H or 13C labeled lipidated heptapeptide. Dynamical parameters for the lipid chain modification at Cys 181 were determined from static 2H NMR order parameter and relaxation measurements. Order parameters describing the amplitude of motion in the protein backbone and the side chain were determined from site-specific measurements of 1 H–13C dipolar couplings for all seven amino acids in themembrane anchor of Ras.107 5.5 Lipids and membranes A solid-state deuterium NMR study has shown that polyunsaturated phosphatidylinositol and diacylglycerol substantially modify the fluidity and polymorphism of biomembranes.108 Matsumori et al. have reported studies of large molecular assembly of amphotericin B formed in ergosterol-containing membrane.109 Participation of the surface structure of Pharaonis phoborhodopsin, ppR and its A149S and A149V mutants, consisting of the C-terminal a-helix and E-F loop, in the 232 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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complex-formation with the cognate transducer pHtrII has been studied using sitedirected 13C solid-state NMR.110 Solid-state NMR characterization of the putative membrane anchor of TWD1 from Arabidopsis thaliana has been reported.111 A 2H, 13C and 15N solid-state NMR investigation of the dynamics and orientation of a transmembrane helical bundle has been undertaken to determine the orientation of uniaxially rotating membrane proteins using unoriented samples.112 Membrane composition has been shown to modulate the interaction between a new class of antineoplastic agents deriving from aromatic 2-chloroethylureas and lipid bilayers using a detailed solid-state NMR study.113 Etzkorn et al. have reported secondary structure, dynamics and topology of a seven-helix receptor in native membranes.114 Dvinskikh et al. have described sensitivity and resolution enhancement techniques useful for solid-state NMR spectroscopy of bicelles.115 A structural study of 19F-labelled alamethicin in phospholipid bilayers using solidstate 19F NMR has been presented.116 Structure, dynamics and topology of membrane polypeptides have been studied using oriented 2H solid-state NMR spectroscopy.117 Ramamoorthy et al. have described structure and topology studies of cellsignaling peptides containing nuclear localisation sequences in membrane bilayers using solid-state NMR and molecular dynamics simulations.118 A solid-state 2H, 15N and 31P NMR spectroscopic study of membrane topology of a 14-mer model amphipathic peptide has been presented.119 Durr et al. have reported studies of structural and dynamical properties of a membrane-anchored electron-carrier protein, cytochrome b(5).120 A study combining synthesis, solid-state NMR, TEM and SAXS has revealed that biphenyl bicelle disks align perpendicular to magnetic fields on large temperature scales.121 Surface and dynamic structures of bacteriorhodopsin in a 2D crystal have been investigated by site-directed solid-state 13C NMR.122 Egawa et al. have studied the structure of the light-harvesting bacteriochlorophyll c assembly in chlorosomes from Chlorobium limicola.123 Solid-state NMR studies of two backbone conformations at Tyr185 as a function of retinal configurations in the dark, light and pressure adapted bacteriorhodopsins have been presented by Kawamura et al.124 Doherty et al. have described membrane-bound conformation and topology of the antimicrobial peptide tachyplesin I.125 Signal assignment of a uniformly [13C, 15N]-labelled membrane protein, H+-ATP synthase subunit c has been presented by Kobayashi et al.126 5.6 Pharmaceutical and biomedical applications The synthesis of four new 1,5-bis(4-amidinophenoxy)-3-oxapentane analogs has been described.127 The structures of the obtained bis-amidines and bis-nitriles in the solid state were evaluated on the basis of 13C CPMAS NMR spectra and theoretical calculations at DFT level. A single crystal X-ray diffraction structure has been presented for 1,5-bis(4-amidinophenoxy)-3-oxapentane. A preliminary anticancer assay against three cell lines has also been given. The difference in the molecular conformation packed in the crystal lattice between the meta-stable a-form and stable g-form of indomethacin on the basis of solid-state 13 C NMR spectral patterns has been revealed.128 It was found that solid-state 13C NMR can be a powerful tool for the estimation of the number of molecular conformations as well as configurational differences in the packing of molecules in a unit cell. Solid-state NMR line widths were measured for various ibuprofen preparations, including crystallization from different solvents (acetone, acetonitrile, methanol), meltNucl. Magn. Reson., 2008, 37, 208–256 | 233 This journal is

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quenching, manual grinding, cryogrinding, compacting and by blending with various excipients.129 Ibuprofen recrystallized from acetonitrile exhibited broader lines than ibuprofen recrystallized from either acetone or methanol. Manually ground ibuprofen had NMR line widths that were indistinguishable from the commercial sample, but cryoground ibuprofen had larger line widths than either. Only dilution in talc led to line width increases, which is attributed to the magnetic susceptibility anisotropy of the talc excipient. The results showed that solid-state NMR line widths can be used to understand physical characteristics including particle size and morphology, degree of order in the materials, and physical environment. Crystalline lactose subjected to various forms of pharmaceutical processing including compaction, lyophilization, spray drying, and cryogrinding has been studied by 13C CPMAS NMR.130 Saturation recovery experiments to determine proton spin-lattice relaxation times (1H T1) showed that the a-monohydrate form had a 1H T1 of 243 s, while compaction resulted in a threefold reduction in T1 (79 s), with little change in the spectrum. Lyophilisation and spray drying both produced amorphous lactose, with relaxation times around 4 s. Cryogrinding for various times produced mixtures of crystalline and amorphous material, with the amount of amorphous material increasing with grinding time. Sixty minutes of grinding time produced mostly amorphous material, with some crystalline material remaining. The 1 H T1 of this sample was 2.0 s. Reducing particle size, introducing crystal defect sites, and producing amorphous material all serve to reduce the T1 by creating sites of high mobility. Spin diffusion to the high-energy sites creates a uniform 1H T1 across the sample. The result is shorter relaxation times for the high-energy mixtures. Relaxation measurements performed on dosage forms could potentially be used to predict stability of pharmaceutical formulations. Lange et al. have demonstrated that solid-state NMR methods can be used to rapidly determine the high-resolution 3D structure of Epothilone B in the polycrystalline state.131 The solid-state NMR structures exhibit an average heavy atom RMSD to the mean structure of 0.14 A˚. The 3D structural analysis led to stereospecific assignments and provided insight into the influence of intermolecular interactions upon NMR chemical shifts. A nanostructured matrix, consisting of titania, was designed in such a way that an antiepileptic drug could be encapsulated and released according to a well-defined time release schedule.132 The antiepilectic drugs, phenytoine or valproic acid were added during the gelation stage in order to obtain a homogeneous gel phase. The resulting nanostructured matrix including the drug showed only weak attractive forces, such as London forces, dipole–dipole coupling and in some cases hydrogen bonds. The resulting assembly was characterized using MAS NMR spectroscopic techniques. Sotthivirat et al. have reported studies of the influence of formulation and processing variables on the physical state of prednisolone (PDL) in formulations consisting of PDL, microcrystalline cellulose, and sulfobutylether b-cyclodextrin.133 PDL was used as a model drug in controlled porosity osmotic pump pellet formulations and was characterised using solid-state NMR spectroscopy and other complimentary analytical techniques. Solid-state NMR spectroscopy was shown to be a powerful technique for the analysis of drug formulations and investigations of the effects of processing conditions. Finally, 31P solid-state MAS NMR has been applied for the determination of the phosphorus compounds that occur in dental casting investment material.134 Six commercial products were examined. All products were shown to contain ammonium dihydrogen phosphate as the acid phosphate required for the setting reaction. All set by the formation of struvite and significant amounts of amorphous magnesium orthophosphate. In three products, lesser amounts of newberyite were present and in another the equivalent amorphous compound was formed. Farringtonite was present to a lesser extent with the metaphosphate. Interestingly, compounds that were not detected in earlier X-ray powder diffraction spectroscopy studies were detected by NMR, notably amorphous and glassy compounds. 234 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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5.7 Cellulose and related materials 13

C CP MAS showed the presence of the intermolecular hydrogen bond involving the molecule of water in N-acetyl, N-m-nitrophenyl-2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylamine, none of the glucopyranosylamines studied in this paper form strong hydrogen bonds in the crystal lattice.135 13 C CP MAS dynamics and interactions of a wood/phenol–formaldehyde resin composite were examined using 13C labelled and 2H labelled phenol–formaldehyde resin. The 13C CP MAS of the wood composite and resin were compared.136 17O MAS NMR studies at 19.5 T were performed on 17O-enriched methyl a-D-galactopyranoside (4-17O), methyl P-D-glucopyranoside (2-17O), methyl a-D-glucopyranoside (4-17O), methyl (X-D-glucopyranoside (6-17O), and a-D-glucopyranosyl (1–6) a17 17 D-glucopyranoside (6- O). The O quadrupolar coupling constants and asymmetry parameters measured were predicted with a model based entirely on the firstcoordination sphere around oxygen.137 13C CP MAS studies of a range of fibres were used to show systematic changes in isotropic chemical shifts, which can be related to the influences of physical processing or chemical modification. A constrained curve fitting method was applied, where the C4 spectral envelope is represented as the sum of contributions from polymer in ordered, partially-ordered and disordered environments. The empirical g-gauche effect was used to rationalise the relationship between C4 shifts and conformational order.138 13 C DQMAS NMR was used for the complete assignment of the 13C NMR resonances to the corresponding carbon ring positions for the monoclinic and triclinic allomorphs of 13C-labelled methyl 4 0 -O-methyl-b-D-cellobioside, a cellodextrin model compound of cellulose 13C -perlabelled at the cellobiose core. This allowed for the complete 13C chemical shift assignment, that when combined with the X-ray crystallography data provided a complete characterization.139 Cotton fibers were modified by surface-initiated atom transfer radical polymerization of ethyl acrylate (EA) followed by copolymerization with styrene. 13C CP MAS, 1H relaxation times and other techniques were used to analyse the fibres which showed the grafting and differences in dynamics in the modified fibres.140 An improved method to analyze the 13C NMR spectra of native starches, which considers the contribution of the V-type conformation and the nature of the amorphous component, has been developed. Starch spectra are separated into amorphous and ordered subspectra, using intensity at 84 ppm as a reference point. Relative proportions of amorphous, single, and double-helical conformations are estimated by apportioning intensity of C1 peak areas. Quantitative analysis shows that the single-helical component increases with amylose content of starches.141 MAS NMR was applied to loblolly pine wood samples to identify potential structural changes induced by tree age, milling, lignin extraction, or naturally occurring mutations. Special attention was paid to ketone and aldehyde as well as nonpolar alkyl groups, which could be observed at low concentrations using improved SSB suppression with gated decoupling. These results demonstrate the utility of solid-state NMR as an assay for changes in the lignin structure of genetically modified plants.142

5.8 Soils and related materials Three representative allophanic Andisols soils in Japan were evaluated by 13C, 27Al and 29Si MAS and CP MAS NMR. Aliphatic, O-alkyl, and carbonyl C were relatively abundant in the uppermost horizons, whereas aromatic C was concentrated in the subsurface horizons. 27Al and 29Si MAS NMR of the aluminosilicates revealed that most part of the tetrahedral Al in volcanic glass had already weathered into octahedral Al. Allophanic constituents were determined by 29Si MAS NMR.143 Changes in soil organic carbon (SOC) contents with soil cultivation have been investigated extensively, but information on the influence of land use changes on the Nucl. Magn. Reson., 2008, 37, 208–256 | 235 This journal is

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chemistry of soil organic matter (SOM) and SOM fractions is scarce. The SOM in physical soil fractions of silty soils under different land use (e.g. maize etc.), grassland and forest was examined using 13C CP MAS NMR. The CP MAS NMR spectra showed the large variation in the SOM.144 Two HF-treated soils were prepared with water contents ranging up to 22% by exposing them to a range of atmospheric humidities. 13C CP MAS NMR was used to investigate the effect of hydration on chemical shift distribution and sensitivity. 1H NMR relaxation rates were also used to detect changes in humidity. Proton spin relaxation editing (PSRE) subspectra revealed substantial changes in the nature of these two components with increasing water content. These results indicate the presence of an organic matter component that is very sensitive to water content, transforming from slowly relaxing at a small water content to rapidly relaxing at a greater water content.145 13 C CP MAS NMR and dipolar dephasing were used to measure the condensed aromatic ring structure in seven humic acids extracted from greysoils. There was a good correlation between the amount of semiquinone free radicals measured by EPR and condensed aromatic rings measured by 13C CP MAS DD.146 The dilute acid hydrolysis of samples comprised of varying fractions of crystalline and amorphous cellulose was studied by 13C CP MAS.147

5.9 Coals and carbonaceous materials The chemical pathways for nitrogen and sulfur transformations during coalification are elucidated by comparing the chemical forms of unaltered peats, lignites, and coals and pyrolyzed peats. Nitrogen forms are characterized by 15N CP MAS NMR. In unaltered peats, the 15N NMR spectra are consistent with the presence of amide nitro-en. When peat is pyrolyzed, the main peak in the 15N NMR spectrum broadens and shifts from 260 ppm to 245 ppm, which is consistent with the loss of some amide nitrogen and the appearance of pyrrolic nitrogen forms.148 The average chemical structure of asphaltenes present in a feed is related to the morphology of the coke that is produced in a delayed coker. A combination of solidstate 13C MAS NMR and XPS were used to characterize this structure.149 A combination of 13C MAS NMR and other techniques are used to characterize organic oxygen, nitrogen, and sulfur species and carbon chemical/structural features in kerogens. As expected, the amount of aromatic carbon, measured by 13C MAS NMR increases with decreasing H/C ratio.150 1 H T1r relaxation study, the relaxation times were measured for three whole asphalts at different temperature ranges. These data were used to calculate the apparent activation energies for the molecular motion of the aromatic and aliphatic components found in asphalt. The measured activation energies were attributed to rapid methyl rotation of the terminal and branched methyl groups on the long carbon chain length alkanes. The low barrier to molecular motion observed for the aromatic constituents can be explained by two mechanisms. The first mechanism is spin-diffusion interaction of the aromatic ring hydrogens with the aliphatic hydrogens of the rapidly rotating methyl substituents on aromatic rings. The second mechanism is the in-plane rotation of relatively small polycondensed aromatic molecules and torsional oscillations of pendant phenyl groups as guest molecules within a nanopore matrix of rigid-amorphous aliphatic components.151

5.10 Polymers The polymorphism of poly(vinylidene fluoride) (PVDF) and its nanocomposites was studied by means of solid state nuclear magnetic resonance spectroscopy. 13C CP MAS NMR was recorded using simultaneous high-power decoupling on both the proton and fluorine channels. Both 1H–13C and 13C–19F CP experiments were 236 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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conducted, giving identical results apart from intensity variations due to the CP efficiency.152 Two fluoropolymers, poly(vinylidenefluoride) (PVDF) and a vinylidenefluoride telomer (VDFT), with different molecular weights have been analysed by 19F MAS NMR. Relaxation-filtered proton-decoupled MAS experiments, namely T1r, filter, dipolar filter, direct-polarisation delayed acquisition (DPDA) and discrimination induced by variable-amplitude minipulses (DIVAM), allowed signals in the DP spectra of PVDF and the VDFT to be discussed in terms of rigid and mobile domains. Both samples showed signals, which were multi-componential, but they differ in the nature of the crystalline form present. High-speed MAS at higher magnetic field resulted in an increase in resolution so that signals previously attributed to single-phase characteristics are shown to indicate the possibility of several different mobilities. The results are debated with respect to molecular weight and relaxation parameters.153 Using solid-state NMR methods the morphological behavior of poly[bis(trifluoroethoxy)phosphazene] was studied, employing four nuclei of interest-1H, 19F, 31P and 13C. Measurements on all four nuclei support that at ambient temperature the crystalline and amorphous phases coexist. VT studies showed that at higher temperatures only a single highly mobile phase exists. All four nuclei showed that when heat cycling the polymer an increase in crystallinity occurs. For the first time 13 C MAS NMR spectra, using high power 19F and 1H decoupling, were obtained, which exhibited the same behaviour domain. Filtered 13C{1H,19F} MAS spectra containing signal from the crystalline domain using the discrimination induced by variable amplitude minipulses (DIVAM) sequence were measured.154 The local structure of sodium ions in poly(ethylene–methacrylic acid) ionomer neutralized by sodium hydroxide has been investigated using 23Na MAS and MQMAS NMR techniques at a high magnetic field, 21.9 T. Isotropic chemical shifts and quadrupolar coupling products of three kinds of nonequivalent 23Na ions, i.e., isolated, hydrated, and aggregated were measured.155 Poly(vinyl butyral) (PVB) with different wt% water was studied with 1H MAS NMR. The composition of PVB samples changes during MAS NMR because of the centrifugal force. As MAS time progresses, initially free water was removed fast but bound water also was gradually depleted. More water was diminished at faster spinning speeds, longer spinning time, higher temperatures, and higher initial water contents.156 Oxidatively degraded polypropylene (PP) samples, with selective 13C labelling of the three carbon sites on the PP chain (tertiary, secondary, and methyl carbons), have been analyzed with a suite of 1D and 2D solid-state 13C NMR experiments that have been used to assign several 13C resonances attributed to oxidation-induced functional groups. These NMR techniques, several of which were recently developed, included dipolar dephasing for MAS speeds Z 10 kHz, CSA filtering, SUPER NMR to separate quasi-static CSA patterns, and 1H–13C HETCOR.157 Solid-state NMR techniques have been employed to investigate the domain structure and mobility of the bacterial biopolymeric metabolites such as poly(3hydroxybutyrate) (PHB) and its copolymers poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) containing 2.7 mol% (PHBV2.7) and 6.5 mol% (PHBV6.5) 3hydroxyvalerate. 13C SPE MAS and CPMAS NMR results showed that these biopolymers were composed of amorphous and crystalline regions having distinct molecular dynamics. Under MAS, 1H T1r, and 13C 1T, showed two processes for each carbon. Proton relaxation-induced spectral editing (PRISE) techniques allowed the neat separation of the 13C resonances in the crystalline regions from those in the amorphous ones. The proton spin-lattice relaxation time in the tilted rotating frame, 1 H T1rT, measured using the Lee-Goldburg sequence with frequency modulation (LGFM) as the spin-locking scheme, was also double exponential and significantly longer than 1H T1r. The results indicated that the introduction of 3-hydroxyvalerate into PHB led to marked molecular mobility enhancement in the biopolymers.158 Nucl. Magn. Reson., 2008, 37, 208–256 | 237 This journal is

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Thermal, thermo-oxidative and fire residues of high impact polystyrene/magnesium hydroxide/red phosphorus (HIPS/Mg(OH)2/P) are investigated by solid-state NMR and compared with the results for the binary subsystem Mg(OH)2/P.159 Poly(aminoimino)heptazine, otherwise known as Liebig’s melon, whose composition and structure has been subject to multitudinous speculations, was studied using a variety of techniques including 13C and 15N solid-state NMR spectroscopy, and theoretical calculations revealed that the nanocrystalline material exhibits domains well-ordered in two dimensions, thereby allowing the structure solution in projection by electron diffraction.160 Multinuclear solid-state NMR was used to characterize the molecular structures in nylon 6-montmorillonite nanocomposites in comparison with the two pure components. Both the polymer and the clay were studied. 27Al MQMAS measurements reveal the existence of an additional four-coordinated aluminum site in the nanocomposites compared to in the pure clay. Other solid state NMR techniques showed different mobility of the polymer chain. This site is most probably induced by interactions of the polymer chains with the silicate surface.161 Polypropylene samples, in which the three different carbon atoms along the chain were selectively labelled with 13C, were subjected to radiation under inert and air atmospheres, and to post-irradiation exposure in air at various temperatures. By using solid-state 13C NMR measurements at room temperature, it has been possible to identify and quantify the oxidation products.162 7 Li and 13C solid-state NMR methods were used to study Li+-doped siloxane/ poly(ethylene oxide) hybrid electrolyte materials, where the polymer chains are linked to the inorganic phase through covalent bonds.163 The temperature dependence of molecular mobility and conformational changes of poly(chlorotrifluoroethylene) have been investigated by 19F MAS NMR spectroscopy. The pulse techniques of dipolar-filter and T1r,-filter allow selective observation of the amorphous and crystalline domains, respectively. The temperature dependence of T1r revealed that the segmental motion in the amorphous domain becomes vigorous above the glass transition temperature and more close to the b-relaxation temperature.164 The influence of silica fillers on chemical modifications of diglycidyl ether of bisphenol A/triethylene tetramine epoxy resins induced by electron beam irradiation has been studied by 13C CP NMR.165 5.11 Organometallic and coordination compounds A DQ recoupling sequence POST-C7 was performed to study 31P–31P geometrical constraints for phosphoro-organic model compounds with different CSA and distinct molecular dynamics in the crystal lattice. The results show that with large CSA, POST-C7 gave good efficiency of 31P DQ excitations.166 55 Mn NMR spectra acquired at 21.14 T (nL(55Mn) = 223.1 MHz) are presented and demonstrate the advantages of using ultrahigh magnetic fields for characterizing the chemical shift tensors of several manganese carbonyls: Z5-CpMn(CO)3, Mn2(CO)10, and (CO)5MnMPh3 (M = Ge, Sn, Pb). For the compounds investigated, the anisotropies of the manganese chemical shift tensors are less than 250 ppm except for Z5-CpMn(CO)3, which has an anisotropy of 920 ppm. At 21.14 T, one can excite the entire central transition of Z5-CpMn(CO)3, which has a breadth of ca. 700 kHz. MQMAS experiments are able to distinguish four magnetically unique Mn sites in (CO)5MnMPh3, each with slightly different values of diso, CQ, and ZQ.167 Crystalline N,N-cyclo-pentamethylenedithiocarbamate cadmium(II) complex was prepared and studied by means of 15N, 113Cd CP MAS NMR spectroscopy and single-crystal X-ray diffraction. The unit cell of the cadmium(II) compound comprises two centrosymmetric isomeric binuclear molecules [Cd2{S2CN(CH2)5}4], which display structural inequivalence in both 15N and 113Cd NMR and XRD data.168 238 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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Silver(I) complexes of thiourea (TU), selenourea (SeU), N,N-dimethyl selenourea (DMSeU) have been prepared. These complexes have been characterized by elemental analysis and NMR (1H, 13C, 77Se and 109Ag) spectroscopy. On complexation, an up field shift in 4CQS and 4CQSe resonances of thiones and selenones in 13 C NMR and low-field shifts 77Se NMR are consistent with the sulfur and selenium coordination to the metal ion.169 Crystalline form I (monoclinic) and form II (triclinic) of ferrocene dicarboxylic acid [Fe-Z5-C5H4-COOH)2] have been employed in solid-gas reactions at room temperature with the gaseous bases NH3, NH2(CH3), and NH(CH3)2. Starting materials and products have been investigated by single-crystal and powder diffraction and by 13C, 15N CP MAS and 1H MAS methods.170 Polycrystalline octa-miclear copper(l) O,O 0 -di-i-propyl- and O,O 0 -di-i-amyldithiophosphate cluster compounds, {Cu8[S2P(OR)2]6(m8S)} where R = i–Pr and i–Am, were synthesized and characterized by 31P CP MAS NMR at 8.46 T and static 65Cu NMR at multiple magnetic field strengths (7.05, 9.4 and 14.1 T). The symmetries of the electronic environments around the P sites were estimated from the 31P CSA parameters, daniso and Z.171 A single C–H F–C contact in [(Z5-C5H5)Pd(C6F5)(PPh3)] is strong enough to pair two independent molecules and render them crystallographically different as suggested by its strongest 1H–19F dipole–dipole coupling in a 2-D CP MAS PILGRIM NMR experiment together with solid state 1-D 19F{1H} and 2-D19F RFDR NMR spectroscopy—thereby proving the power of 2-D solid-state NMR for assessing the strength of supramolecular contacts.172 Phosphines, (EtO)3Si(CH2)xPPh2, Cl2Si(CH2CH2PPh2)2, and (EtO)2Si[(CH2)(x)PPh2]2 (x = 7, 11) have been immobilized on silica in a well-defined manner, and the modified silicas have been studied by 31P and 29Si solid-state NMR.173 Cadmium and mercury acetates have been reacted with pyrazole (Hpz) and 3,5dimethylpyrazole (Hdmpz), affording distinct mixed-ligand species, selectively prepared upon slightly modifying the reaction conditions, were characterised by using conventional X-ray laboratory equipment, supported by 13C CP MAS NMR measurements.174 Novel measurements and calculations of the olefinic 13C CSA tensor principal values in several metal diene complexes were presented. The experimental values and the calculations show shifts as large as 70 ppm with respect to the values in the parent olefinic compounds. These shifts are highly anisotropic, with the largest ones observed in the less shielded principal components and the smallest ones in the most shielded principal components of the tensor.175 A new piperazinium dihydrogen orthophosphate, C4H12N2(H2PO4)2 was discovered and characterized by combining information from X-ray diffraction, 31P CP MAS NMR and thermal analysis.176 59 Co NMR spectra of stationary powder samples of salts containing Co(C2B9H11)2(-) and Co(C5H5)2(+) have been acquired at 21.14 T using singleecho stepped-frequency experiments. The resulting central transition line shapes span more than 2.0 MHz and are dominated by the second-order quadrupolar interaction. Analysis of the spectra leads to CQ values of ca. 163 MHz for both ions, among the largest 59Co CQ values reported. In addition, 59Co chemical shift anisotropies are significant for Co(C2B9H11)2() and Co(C5H5)2(+), with values of 4500–4700 and 5650 ppm, respectively.177 Mixed ligand complexes of Ag(I) with triphenylphosphine (PPh3), triphenylphosphine sulfide (SPPh3), triphenylphosphine selenide (SePPh3) and imidazolidine-2thione have been prepared. The solution as well as solid state NMR studies have been carried out to characterize these complexes.178 Silver(I) complexes with four symmetrically substituted O,O 0 -dialkyl derivatives of dithiophosphoric acid of the general formula [Ag{S2P(OR)2}](n) (R = C2H5, i-C3H7, C4H9, and s-C4H9) were obtained. Their structures and spectroscopic characteristics were studied by 13C and 31P CP MAS NMR spectroscopy and Nucl. Magn. Reson., 2008, 37, 208–256 | 239 This journal is

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X-ray diffraction analysis. The parameters of the anisotropy of the 31P chemical shift, daniso and Z, calculated from the diagrams revealed that the (RO)2PS2 groups act as bridging ligands.179 The preparation and characterization of zinc complexes of formula ZnL2X2 (X = Cl and Br), with L = 1,3-diazinane-2-thione, 1,3-diazipane-2-thione, imidazolidine2-thione and its methyl and n-propyl substituted derivatives, are described. Solution and solid state 13C NMR show a significant shift of the CQS carbon resonance of the ligands, while other resonances are relatively unaffected, indicating that most likely the solid state structure is maintained in solution.180 Crystalline adducts of zinc and copper(II) dithiocarbamate complexes with dibutyl-and diisobutylamines of the general formula [M(NHR 0 2)(S2CNR2)2] (M = Zn, 63Cu, and 65Cu; R = CH3 and C2H5; R-2 = (CH2)4O; R 0 = C4H9 and i-C4H9) were synthesized. Their structures and spectroscopic properties were studied by EPR and 13C and 15N CP MAS NMR spectroscopy.181 Silver(l) complexes of several thiolates have been prepared. These complexes have been characterized by elemental analysis and 13C NMR spectroscopy. All the Ag(I)– thiolate complexes are polymeric in nature. Therefore, 13C CP MAS NMR is being used extensively to analyze the binding site of the ligand and the nature of complexation.182 5.12 Glasses and amorphous solids The 29Si MAS NMR spectra of P2O5–SiO2 binary glasses were measured before and after annealing to examine the local structure around Si atoms in the glasses. The glasses were composed of SiO6 octahedra and Q4. By increasing the P2O5 content, the fractions of SiO6 octahedra increased and those of Q4 decreased.183 A range of model fluoro-alumino-silicate glasses that form the basis of glass (ionomer) polyalkenoate cements and five commercial glasses have been characterised by 29Si, 27Al, 31 P and 19F MAS NMR. The 29Si spectra indicate a predominantly Q33Al and Q44Al. Aluminium was found in predominantly four coordinate sites, but glasses with high fluorine contents showed an increasing proportion of five and six coordinate aluminium. In phosphate containing glasses the phosphorus was present as Al–O–PO32 type species indicating local charge compensation of Al3+ and P5+ in the glass structure. 19F MAS NMR MAS NMR indicated the presence of F– Ca(n), Al–F–Ca(n), F–Sr(n), Al–F–Sr(n) and Al–F–Na(n) species where F–M(n) indicates a fluorine surrounded by n next nearest neighbour cations and Al–F–M(n) represents a fluorine bonded to aluminium with the metal, M in close proximity charge balancing the tetrahedral AlO3F species.184 The characterisation of the setting reaction in glass ionomer cements based on experimental ionomer glasses with different fluorine content and a commercial glass ionomer cement liquid using 13C CP MAS NMR, 29Si, 27Al and 31P MAS NMR spectroscopy, in order to receive information specifically about the cross-linking process, was carried out. Different fluorine containing glass compositions based on 4.5SiO2–3Al2O3–1.5P2O5–(5 z)CaO–zCaF2 where z = 0–3, were mixed with a commercially available polymer liquid to form glass ionomer cements. The cements were subjected to 27Al, 13C CP MAS, 29Si, and 31P MAS NMR analysis and the setting reaction determined.185 A series of lithium silicate glasses approaching the orthosilicate composition (66.7 mol% Li2O) were prepared and their 29Si MAS NMR recorded; this significantly extends the compositional range of glasses studied by this technique. The NMR results were compared with the Raman study of Umesaki et al. (J. Non-Cryst. Solids, 1988, 106, 77–80) on the same system. Volumes per mol silica, determined from the experimental densities, were also used to test the structural results from the present NMR observations.186 Fast Li+-ion conducting glasses of LiCl–Li2O–P2O5 system with different glass network structures were synthesized by a twin-roller quenching method. 7Li MAS 240 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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NMR measurements were performed for the glasses in order to obtain information about the microscopic structure and the ion conduction mechanism of the glasses.187 In the present study the results of 29Si, 27Al and 31P and 19F MAS NMR of 4.5SiO2–3Al2O3–1.5P2O5–(5 z)CaO–zCaF2 glasses with z = 0–3 were used to elucidate the effect of fluoride content on the glass structure. The 29Si MAS NMR spectra gave a chemical shift of about 90 ppm corresponding to Q3(3Al) and Q4(3Al). The 27Al MAS NMR showed a large broad central peak around 50 ppm, which is assigned to four-coordinated Al linked via oxygen to P. A shoulder around 30 ppm and a small peak at about 0 to 10 ppm appeared in the 27Al MAS NMR spectra of the glasses on increasing the fluoride content assigned to five-coordinated and six-coordinated Al species, respectively. The 31P MAS NMR spectra indicated the presence of Al–O–P bonds. The 19F spectra indicated the presence of Al–F–Ca(n) and F–Ca(n) species in all the glasses containing fluoride as well as an additional Si–F–Ca(n) species in the glasses with higher fluoride content.188 The various (vitreous and crystalline) components of two fly ashes are quantified in this paper using three techniques: chemical analysis with selective solutions, X-ray powder diffraction combined with the Rietveld method and MAS NMR.189 The hydrothermal alkaline activation of the oil shale fly ash was studied using SEM/EDX, XRD and 29Si and 27Al high-resolution MAS NMR spectra. The silicon in the original fly ashes was completely converted into calcium-alumino-silicate hydrates, mainly into tobermorite structure.190 5.13 Micro- and mesoporous solids A suite of 1D and 2D solid-state NMR methods was used to follow the complex structural changes in different types of phosphorus species in P-ZSM-5 zeolites that were generated upon treatment of H-ZSM5 zeolites with 0–15% P2O5, followed by calcination or calcination and steaming. Through space and through bond 27Al–31P correlations were used for the first time to study the interaction of phosphorus with the aluminum species. In the calcined samples, the 31P resonances were assigned mainly to orthophosphates, short chain polyphosphates and condensed phosphates which evolves into many other species.191 Solid-state 11B MAS NMR studies on novel mesoporous BCN material are described. While the 11B MAS spectrum at 11.7 T shows severe signal overlap as a result of the second-order quadrupolar broadening, the resolution improves significantly at high field, 21.8 T and three distinct peaks are observed, indicating the presence of three sites in the material.192 A two-step postsynthetic functionalization reaction of zeolite HZSM-5 that proceeds with high selectivity at room temperature was shown. The reaction were characterised using 29Si, 1H and 13C MAS NMR.193 Aluminum species in P-ZSM-5 zeolites were identified and quantified using 27Al MAS and MQMAS NMR methods. Samples containing between 0% and 15% P2O5 were studied after calcination or calcination followed by steaming. In addition to the tetrahedral framework aluminum and the octahedral aluminum, also observed were significant quantities of highly distorted aluminum with tetrahedral coordination and octahedrally coordinated aluminum in aluminum phosphate.194 Ibuprofen has been encapsulated in MCM-41 silica matrices with different pore diameters. Its behavior has been investigated by 29Si, 1H and 13C MAS NMR at ambient and low temperature. This study reveals an original physical state of the drug in such materials.195 Using trimethylphosphine and d5-pyridine as the basic probe molecules, the concentrations of Bronsted acid sites on both HY zeolite and dealuminated HY zeolite have been quantitatively determined using solid-state 1H and 31P MAS NMR.196 Large-pore vinyl-functionalized cubic mesoporous silica FDU-12 materials have been synthesized through the room temperature co-condensation of Nucl. Magn. Reson., 2008, 37, 208–256 | 241 This journal is

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tetraethoxysilane and trimethoxyvinylsilane under acidic conditions templated with triblock copolymer Pluronic F127. The materials thus obtained were characterized by a variety of techniques including 1H, 13C and 29Si, solid-state NMR 2D 13C{1H} and 29Si{1H} HETCOR NMR. Direct evidence of the presence of chemically attached vinyl moieties was provided by solid-state NMR.197 The covalent linkages formed during functionalization of MCM-41 mesoporous molecular sieves with five chloroalkylsilanes have been investigated using MAS NMR spectroscopy. Structural information was obtained from 1H and 13C and 1 H–29Si HETCOR NMR spectra. The 1H and 13C HETCOR results provided the assignments of the resonances associated with the surface functional groups. Sensitivity-enhanced 1H–29Si HETCOR spectra, acquired using Carr-Purcell-Meiboom-Gill refocusing during data acquisition, revealed the identity of 29Si sites and the location of functional groups relative to these sites.198 Multinuclear solid-state NMR techniques are employed to monitor the crystallization of AlPO4-5 aluminophosphate prepared in the presence of HF under hydrothermal condition. The appearance of 31P signals was due to the structural P–O–Al unit and the 19F signal, due to the structural F–Al–O–P unit in the NMR spectra of the series gels, indicates that the crystalline framework is starting to form. More information about the local ordering of the gels is obtained 2D 27Al–31P HETCOR and 31P/27Al double-resonance experiments.199 Structural characterization of different silicas (ordered mesoporous silicas MCM41, MCM-48, and SBA-15, amorphous silica gels Si-40, Si-60, and Si-100, and initial and wetted-dried fumed silica A-300) and bio-objects (fibrinogen solution, yeast cells, wheat seeds, and bone tissues) were measured by 1H NMR spectroscopy (180–200 o T o 273 K).200 Solid state 2H NMR has been used to study the molecular motion of d6-isobutyric acid (d6-iBA) in the pure (unconfined) state and confined in the cylindrical pores of two periodic mesoporous silica materials (MCM-41, pore size 3.3 nm and SBA-15, pore size 8 nm), and in a controlled pore glass (CPG-10–75, pore size ca. 10 nm). The line shape analysis of the spectra at different temperatures revealed three rotational states of the iBA molecules.201 The adsorption of water in the mesoporous silica material with cylindrical pores of uniform diameter, controlled pore glass, was studied by 1H MAS solid state NMR spectroscopy. From the NMR spectra it is evident that inside the mesopores of the silica different water environments exist, which are characterized by their individual chemical shift.202 A mesoporous aluminum silicate material has been successfully synthesized and studied by solid-state NMR. These results showed that the aluminum atoms are tetrahedrally coordinated and are stable up to at least 4001C. The double resonance 27 Al–29Si NMR experiment provided the first direct evidence that all At atoms are surrounded by Si atoms forming Al–O–Si bonds in the framework.203 The paramagnetic Si/Al material doped with Mn2+ has been characterized by the 1 H, 13C, 27Al, 29Si MAS NMR spectra and the 1H, 29Si T1 MAS relaxation measurements as a gel dried and calcined. It has been demonstrated that in spite of strong paramagnetic effects, NMR monitoring in combination with 29Si T1 relaxation experiments can be successful for structural descriptions of porous materials.204 19 F–27Al CP MAS and 27Al{19F} 2D HECTOR experiments provide direct evidence of the formation of tetrahedral Al–F species in zeolite by fluorinated by an aqueous solution of ammonium fluoride.205 A solid-state O-17 NMR study of local order and crystallinity in an aminetemplated mesoporous Nb oxide was carried out.206 1 H MAS NMR spectroscopy was used to investigate the H/D exchange behavior of benzene-d6, ethylbenzene-d10, toluene-d8, and p-xylene-d10 with Bronsted acid sites in different zeolite catalysts.207


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A general protocol for the structural characterization of paramagnetic molecular solids using solid-state NMR is provided and illustrated by the characterization of a high-spin Fe(II) catalyst precursor. Good NMR performance can be obtained on a molecular powder sample at natural abundance by using very fast (430 kHz) MAS, even though the individual NMR resonances have highly anisotropic shifts and very short relaxation times.208

5.14 Surface science and catalysis The coordination of OH groups on MgO has been characterized by 1H MAS NMR after appropriate pre-treatment to obtain surfaces free from carbonates and with a controlled degree of hydroxylation.209 Solid-state NMR spectroscopy has been used to determine the structure of the complex formed upon adsorption of the mononucleotide 2 0 -deoxyadenosine 5 0 monophosphate (dAMP) to the surface of a mesoporous alumina. Rotational-echo double-resonance NMR results reveal that the phosphate group of dAMP interacts predominantly with octahedrally coordinated aluminum species at the surface, and therefore, adsorption is modeled with both mono- and bidentate sorption of the nucleotide phosphate group with octahedral aluminum.210 Solid-state NMR analysis and structural characterization of N-doped TiO2 nanoparticle and monolayer materials suitable for visible photocatalysis is reported. The analysis of and 13C and 15N doped TiO2 synthesized using 15N–urea before calcination indicates formation of various amino functionalities of the type NH, NH2, NH3, and probably NH4+, while the NMR spectrum of the yellow powder that results from high-temperature calcination shows that these nitrogen species oxidize to form nitrate.211 The Fischer-Tropsch (F-T) catalyst is the critical component for the F-T synthesis of a variety of hydrocarbons from syngas. The silica aerogel supported F-T catalysts have been investigated using both 29Si and 13C MAS NMR methods. The silica aerogel’s tetrahedral sub-unit structure and the influence of the loaded metal compounds have been observed. Three types of Si tetrahedral unit structure (Q2, Q3 and Q4) are clearly resolved in the silica aerogel samples.212 High surface area, highly acidic catalysts with different weight loadings of ZrO2 were characterized by 1H MAS NMR.213 Multinuclear solid-state NMR techniques e.g. HECTOR, CP MAS, are employed to monitor the crystallization of AlPO4-5 aluminophosphate prepared in the presence of HF under hydrothermal condition. The crystallization process is characterized by the evolution of intermediate gels, in which the long-range ordering arrangement reveals the threshold of the crystallization. The appearance of 31P signals due to the structural P–O–Al unit and 19F signal due to the structural F–Al(V)–O–P unit in the NMR spectra of the series gels indicates that the crystalline framework is starting to form.214 Methanol catalytic oxidation over VOx/Al2O3, VOx/ZrO2 and VOx/MgO catalysts has been studied by solid-state NMR spectroscopy. It was found that the stronger acidic sites in VOx/Al2O3 result in almost the same selectivities for dimethoxymethane, paraformaldehyde and formic acid, and the weaker acidic sites in VOx/ZrO2 favor the formation of paraformaldehyde, while the VOx/MgO catalyst with the base support shows high selectivity for formate.215

5.15 Inorganic and other related solids 7

Li and 13C MAS NMR spectra of three lithium cuprates with known X-ray structures-lithium(12-crown-4) (2) dimethyl and diphenyl cuprate (1, 2) and lithium(thf)(4)-[tris(trimethylsilyl) methyl]2 cuprate (3)-have been measured and analysed with respect to the quadrupolar coupling constants of 7Li, and the Nucl. Magn. Reson., 2008, 37, 208–256 | 243 This journal is

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asymmetry parameters of the quadrupolar interactions, as well as the 6Li, 7Li and 13 C chemical shifts.216 1 H NMR relaxation measurements have been carried out in anti-ferroelectric Betaine phosphate (BP), ferroelectric betaine phosphite (BPI) and the mixed system BPI(1 x)BPx, at 11.4 MHz and 23.3 MHz from 300 K to 80 K for x = 0.0, 0.25, 0.45, 0.85, and 1.0.217 The local environments and dynamics of hydrogen atoms in five samples of protonated forms of ion-exchangeable layered perovskites, Dion-Jacobson-type H[LaNb2O7] and H[LaTa2O7], Ruddlesden-Popper-type H2[SrTa2O7] and H2[La2Ti3O10], and H1.8[(Sr0.8Bi0.2)Ta2O7] derived from an Aurivillius phase, Bi2Sr2Ta2O9, have been investigated by 1H MAS NMR.218 For the first time, 17O NMR studies were performed on 17O enriched crystalline pyrophosphates (magnesium–, sodium– and barium–pyrophosphate) by means of 3QMAS and DOR in the high external field of 17.6 T. Oxygen atoms in bridging positions (f-O-B-P) exhibit a significantly higher quadrupole coupling constant compared to oxygen atoms in terminal positions (P–O–T). With increasing cationic radius a higher value of the chemical shift of the terminal oxygen atoms is observed.219 MAS-NMR spectroscopy was used to probe the crystallographic environment of Si, Al, F and H in 14 natural talc samples originating from different localities and containing various, small amounts of iron (Fe2O3 o 2 wt%). It was shown that iron induces strong variations in the NMR spectra and that even very low quantities can be used as an indirect NMR parameter to characterize in detail the crystal-chemistry of talc.220 Solid-state 17O NMR measurements between room temperature and 973 K were performed for the first time on 17O-enriched yttria-stabilized zirconia samples. Spinlattice relaxation is found to exhibit a strong temperature dependence which can be traced back to motional displacements of the oxygen ions and which is almost unaffected by the actual sample constitution. Analysis of the spin-lattice relaxation data provides the motional correlation times and activation energy.221 The chemical shifts of 7Li MAS spectra in La4/3-yLi3yTi2O6 showed negative values and decreased with increasing lithium concentration. The chemical shifts were interpreted by Pople’s theory in which the 7Li chemical shifts were due to the local paramagnetic currents of the closest oxygen ions.222 Some silica-based solids, prepared by the sol/gel method in the presence of high Mn2+ concentrations, have been characterized by the 29Si, 27Al MAS NMR spectra and 29Si T1 measurements. The single pulse 29Si, 27Al MAS NMR spectra have shown broad spinning sideband patterns that are interpreted in terms of anisotropic bulky magnetic susceptibility (BMS) and dipole-field effects.223 CaHPO4 was obtained by slow evaporation at room temperature. Seven samples, obtained at different annealing temperatures, were characterized by 31P MAS NMR spectroscopy.224 The unique high-resolution feature offered by 14N MAS NMR spectroscopy of ammonium ions has been used to characterize the crystal structures of various ammonium molybdates by their 14N quadrupole coupling parameters, the quadrupole coupling constant, the asymmetry parameter. Two polymorphs of diammonium monomolybdate, (NH4)2MoO4, were recently structurally characterized by 14N MAS NMR spectra. Finally, by a combination of the 14N and 95Mo MAS NMR experiments, it has become clear that a recent report of the 95Mo MAS spectra and data for the polymorphs of (NH4)2MoO4 are erroneous because the sample examined had decomposed to (NH4)2MoO7.225 Two germanium solids with heteroaromatic amines 8-hydroxyquinoline (hqn) and 1,10-phenanthroline (phen), have been prepared. The complex hydrogen-bond networks have been studied by advanced solid-state NMR spectroscopy that combines homonuclear recoupling techniques (2D 1H–1H DQF and 1H–1H RFDR MAS NMR) and combined rotation and multiple-pulse spectroscopy (2D 1H–1H FSLG, 1 H–31P FS-LG).226 244 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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The distorted perovskites NaTaO3 and NaNbO3 have been studied using 23Na MQMAS NMR. NaTaO3 was prepared by a high temperature solid state synthesis and the NMR spectra are consistent with the expected room temperature structure of the material, with a single crystallographic sodium site. Two samples of NaNbO3 were studied. The first, a commercially available sample which was annealed, showed two crystallographic sodium sites, as expected for the room temperature structure of the material. The second sample, prepared by a low temperature hydrothermal method, showed the presence of four sodium sites, two of which match the expected room temperature structure and the second pair, another polymorph of the material.227 Assignments of the protolytic speciation at the calcium hydroxyl surface sites of synthetic fluorapatite and the chemical interactions between fluorapatite–maghemite and fluorapatite–Fe2+ ions have been studied by means of 1H and 31P single-pulse and 31P CP MAS NMR. Three possible forms of calcium hydroxyl surface sites have been suggested and assigned.228 The hexagonal scandium compounds ScAuSi and ScAuGe were synthesized and were charachterised by 45Sc–29Si magnetic dipole–dipole interactions measured in a site selective fashion on an isotopically enriched material by solid state NMR.229 Gallium model systems containing four- and six-coordinate gallium sites have been investigated using solid-state NMR. Measurement of the isotropic chemical shift and electric field gradient (EFG) have been performed at 9.4 T on a-Ga2O3, bGa2O3, LiGaO2, NaGaO2, KGaO2, Ga2(SO4)3, and LaGaO3 using a variety of techniques on both NMR active nuclei (69Ga and 71Ga) including static, high speed MAS, STMAS, and rotor-assisted population transfer (RAPT). The chemical shift is found to correlate well with the coordination number. The magnitude of the EFG is found to be correlated to the distortion of the gallium polyhedra. A plot of chemical shift versus EFG suggests that solid-state NMR of gallium oxyanions can be more discriminating than solution-state NMR chemical shifts alone.230 Phosphorus distribution was observed in calcite speleothems from solid-state NMR.231 The reaction of cubic gallium arsenide (GaAs) with ammonia yielded gallium nitride (GaN) and this reaction was investigated by 71Ga MAS NMR.232 A representative silicophosphate gel was synthesized, starting from orthophosphate groups and pyrophosphate species. Solid state NMR techniques were used, including dipolar based experiments (CP MAS), as well as J-derived techniques, in both homonuclear (31P INADEQUATE-MAS) and heteronuclear (31P/29Si HMQCMAS) experiments to investiagte this system.233 With the development of high-magnetic field spectrometers, 33S solid-state NMR is now clearly feasible but remains complex, especially considering the low sensitivity of 33S NMR. This communication briefly explores the potential of 33S NMR in the field of cement chemistry.234 The surface of LiCoO2 cathodes was coated with various wt% of Al2O3 derived from methoxyethoxy acetate–alumoxane (MEA-alumoxane) by a mechano-thermal coating procedure, followed by calcination. The structure and morphology of the surface modified LiCoO2 samples have been characterized with 27Al MAS NMR techniques.235 The rare-earth tricyanomelaminates, [NH4]Ln[HC6N9]2[H2O]7 H2O (LnTCM; Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy), have been synthesized through ionexchange reactions. They have been characterized by 1H, 13C, and 15N MAS NMR spectroscopy. The presence of [NH4]+ ions, as well as two NH groups belonging to two crystallographically independent monoprotonated tricyanomelaminate moieties, has only been confirmed by subjecting LaTCM to solid-state H1, 13C, and 15 N{1H } CP MAS NMR and advanced CP experiments such as cross-polarization combined with polarization inversion (CPPI). The 1H 2D DQ SQ spectrum and the 15 N{1H} 2D CP HETCOR spectrum revealed the hydrogen-bonded (N–H N)


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dimer of monoprotonated tricyanomelaminate moieties as well as H-bonding through [NH4]+ ions and H2O molecules.236 The fate of the organophosphate nerve agent isopropyl methylphosphonofluoridate (sarin) on granular activated and metal-impregnated activated carbons that are used in gas-mask filters was investigated by means of 31P MAS NMR spectroscopy.237 Partially deuterated Ca3Al2(SiO4)(3 x)(OH)4, hydrates, prepared by a reaction in the presence of D2O, of synthetic tricalcium aluminate with different amounts of amorphous silica were characterized by 29Si and 27Al NMR spectroscopy. The 29Si NMR spectroscopy was used for quantifying the non-reacted silica and the resulting hydrated products. The incorporation of Si into Ca3Al2(SiO4)(3 x)(OH)4 was followed by 27Al NMR spectroscopy.238 The hydrolysis of three alkoxy-silane coupling agents, g-methacryloxypropyl trimethoxy silane (MPS), g-aminopropyl triethoxy silane (APS), and g-diethylenetriaminopropyl trimethoxy silane (TAS), was carried out. The solid homopolycondensated structures, were analyzed by 29Si and 13C solid-state NMR.239 The hexagonal scandium compounds were synthesized. Two crystallographically independent scandium sites, which can be unambiguously distinguished on the basis of 45Sc–29Si magnetic dipole–dipole interactions measured in a site selective fashion on an isotopically enriched material by solid state NMR.240 Wurtzite indium nitride powders synthesized from the reaction of In2O3 with ammonia were characterized by 115In MAS NMR spectroscopy.241 2D 1H DQMAS NMR was used to investigate different proton environments in a series of alkali (Na, K, Rb, Cs) [Nb6O19]8Lindqvist salts, with the water and hydrogen-bound intercluster protons being clearly resolved. Through the analysis of the DQ 1H NMR spinning sideband pattern, it is possible to extract both the mean and distribution of the motionally averaged intramolecular homonuclear 1H–1H dipolar coupling for the different water environments and the intercluster protons.242 207 Pb NMR studies have been conducted on mixed lead(II) halides of the type PbFX, where X = Cl, Br, or I. NMR data for the mixed halides are compared to the solid-state NMR data for the divalent, binary lead halides, PbX2 (X = F, Cl, Br, I).243 Proton mobilities in Nafion and Nafion/SiO2 composites have been studied using high-resolution solid-state MAS NMR. 1H MAS NMR show that low concentrations of tetraethylorthosilane (TEOS) or short permeation times are necessary to allow complete hydrolysis of TEOS in Nafion. 29 Si MAS NMR shows that this composite has a high ratio of Q3/Q4 sites, consistent with a small particle size and many surface hydroxyl groups.244 27 Al MAS NMR and 3Q MAS NMR was employed to study the diluted alkali earth metal-doped lanthanum manganite solid solutions in the lanthanum aluminate ((1 y)LaAlO3–yLa0.67A0.33MnO3 (A = Ca, Sr, Ba) with y = 0, 2, 3, and 5 mol%.245 The synthesis and analysis of sol-gel-derived samples of forsterite (Mg2SiO4) and willemite (Zn2SiO4), doped with paramagnetic Cu2+, Ni2+, and Co2+, at a range of dopant concentrations was carried out. The 29Si MAS NMR T1 relaxation behaviour is well-behaved and is consistent with the stretched-exponential expression.246 Gold nanoparticles capped with 11-mercaptoundecanylphosphonic acid and sodium 10-mercaptodecanesulfonic acid (MDS) were characterized by a range of techniques which included solid-state 31P and 13C NMR spectroscopies.247 A combination of 1D and 2D MAS NMR experiments has been used to investigate the hybrid organic-inorganic interfaces in surfactant templated silicas. Samples prepared with cetyltrimethylammonium bromide under acidic and basic conditions have been compared. The use of sequences based on the 29Si–1H heteronuclear dipolar interactions allows the NMR response of the protons close to the Si surface sites to be selectively filtered, showing directly the difference between the two systems. One objective of this work was also to show that the use of standard solid246 | Nucl. Magn. Reson., 2008, 37, 208–256 This journal is

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state NMR conditions (magnetic field of 7 T and MAS spinning frequency of less than 15 kHz) can be largely sufficient to obtain extremely valuable information regarding the silica-surfactant interfaces.248 93 Nb MAS and 3QMAS NMR experiments have been performed on (1 x)PbMg1/3Nb2/3O3xPb1/2Sc1/2NbO3 [(1 x)PMN–xPSN] ordered samples, for compositions x = 0.6 (a normal ferroelectric) and 0.2 (a relaxor). Deconvolution of the MAS spectra at several temperatures ranging from 245 to 375 K reveals seven narrow peaks, and two broad components that are assigned to specific local Nb5+ environments defined by the identities of the six nearest B-site cations.249 Two novel indium silicates, K5In3Si7O21 (1) and K4In2Si8O21 (2), have been synthesized by a flux-growth method and characterized by single-crystal X-ray diffraction. The 29Si MAS NMR spectrum of compound 1 was recorded; it shows the influence of the indium atoms in the second coordination sphere of the silicon on the chemical shift.250 Organically modified clays are largely employed in the preparation of nanostructured materials. A wide combination of 29Si, 13C and 1H solid-state NMR experiments were used to characteise these materials.251 Organotin(IV) compounds of the type (o-MeE-C6H4)CH2SnPh3nCln were synthesized, E = O, n = 0 (1), n = 1 (2), n = 2 (3) and E=S, n = 0 (4), n = 1 (5), n = 2 (o6). 119Sn CPMAS NMR spectroscopy suggests that the intramolecular Sn-E interactions persist in solution and also facilitated the discovery of a new crystalline form of 4, 4 0 , that contains a Sn–S distance which is 95% the sum of the van der Waals radii.252 The cubic spinel oxides Li1+xTi2xO4 (0 o = x o = 1/3) are promising anode materials for lithium-ion rechargeable batteries. In the paper, Li diffusion in purephase microcrystalline Li4Ti5O12 with an average particle size in the mm range was probed by 7Li solid state NMR spectroscopy using spin-alignment echo (SAE) and spin-lattice relaxation measurements.253 The 1H NMR spectra and spin dynamics of the host system in liquid and solid suspensions of g-Fe2O3 nanoparticles are reported. Significant line broadening of 1H NMR spectra and growing relaxation rates were observed with increased concentration of nanoparticles in liquid systems, with the relation T1/T2 depending on the particular host.254 Multinuclear solid-state NMR was used to characterise the molecular structures in nylon 6-montmorillonite nanocomposites in comparison with the two pure components. Both the polymer and the clay were studied. 27Al 2D MQMAS measurements reveal the existence of an additional four-coordinated aluminum site in the nanocomposites compared to in the pure clay. 1H and 13C MAS NMR spectra of these mobile molecules are recorded and assigned to be a tertiary amine that is formed during the melt extrusion process. 15N CP MAS spectra show an increase of the fraction of the g-crystalline phase at the cost of the a-crystalline phase upon increasing clay content.255 Molecular motion of D2O confined in the activated carbon fiber ACF was investigated using solid-state 2H-NMR. The 2H-NMR spectrum indicated that p-flip motion as well as tetrahedral jump of D2O was active below 190 K, suggesting the formation of nanocrystals of D2O in the ACF nanoslits.256 Quantification of the C–S–H hydrates and anhydrous material in plain and blended cement systems can be performed by deconvolution of 29Si MAS NMR spectra. NMR data are reliable for simple cement systems, but with the incorporation of supplementary cementitious materials, quantification is often uncertain. For example, the overlap of peaks from slag cement and C–S–H in 29Si MAS NMR spectra causes problems with deconvolution. A novel method was developed to address these difficulties. 29Si MAS NMR was combined with a selective dissolution method.257 The new stannide ScAgSn was synthesized by induction melting of the elements in a sealed tantalum tube and subsequent annealing. ScAgSn crystallizes with a Nucl. Magn. Reson., 2008, 37, 208–256 | 247 This journal is

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pronounced subcell structure. Determination of the superstructure was partly based on 119Sn and 45Sc solid-state NMR data. In particular, the observation of three crystallographically inequivalent sites in 45Sc NMR 3QMAS NMR spectra provided unambiguous proof of the superstructure proposed.258 Fluorinated single-walled carbon nanotubes have been characterized by MAS 13C NMR spectroscopy and the results correlated with Raman, IR, and X-ray photoelectron spectroscopy measurements.259 Solid-state NMR studies are reported on the reaction of MeAlCl2 with ‘PhPLi2’ in THF which gives [{MeAl(PPh)3Li4.3THF}(4)(Z4-Cl)]Li–(+) and the Ga-III and InIII analogues.260 Antimony doped SnO2 samples were prepared by a co-precipitation method and characterized by 119Sn MAS NMR.261 The local structural environments in a series of natural and synthetic alunite samples [AAl3(SO4)2(OH)6, A = H3O+, D3O+, Na+, and K+] have been probed by solid-state 1H, 2H, 23Na, 27Al, and 39K NMR spectroscopy. The natural alunite [AAl3(SO4)2(OH)6] and synthetic hydronium alunite samples contain few structural defects, whereas the synthetic natroalunite and alunite samples have ca. 10% Al vacancies based on 27Al NMR. A new 27Al local environment (Al-D) was observed and assigned to Al with one Al vacancy in the first cation sphere. Three different proton environments, Al2OH, Al–OH and H3O+ are detected by 1H and 2H MAS NMR. The NMR results suggest that the common assumption, namely that an A vacancy and an Al3+ vacancy are compensated by adding an H3O+ and 3H+ (creating 3 Al–OH4, groups), respectively, is too simplistic. Instead, a significant fraction of the Al3+ vacancies are compensated for by 4H+ ions, resulting in 4 Al–OH2 groups per vacancy.262 Little is known about the speciation of P in calcite speleothems. Here solid-state 31 P and 1H MAS NMR spectroscopic techniques were employed as a non-destructive method for analyzing the distribution of P in speleothems.263 Multinuclear solid-state NMR spectroscopy are applied to comprehensively characterize a series of pure and lanthanide-doped LaF3 nanoparticles (NPs) that are capped with di-n-octadectyldithiophosphate ligands (Ln(3+) = diamagnetic Y3+ and Sc3+ and paramagnetic Yb3+ ions), as well as correlated bulk microcrystalline materials (LaF3, YF3, and ScF3). Solid-state 139La and 19F NMR spectroscopy of bulk LaF3 and the LaF3 NPs reveal that the inorganic core of the NP retains the LaF3 structure at the molecular level; however, there is a gradual change in the La and F site environments from the NP core to the surface. Measurements of 139La T1 and T2 relaxation constants are seen to vary between the bulk material and NPs and between samples with diamagnetic and paramagnetic dopants. 45Sc NMR experiments confirm that the dopants are integrated into the La sites of the LaF3 core. Solid-state 1H and 31P MAS NMR spectra aid in probing the nature of the capping ligands and their interactions at the NP surface. 31P CP MAS NMR experiments identify not only the dithiophosphate head groups but also thiophosphate and phosphate species which may form during NP synthesis. Finally, 19 F–31P CP MAS and 1H MAS experiments confirm that the ligands are coordinated to the NP surface.264 The mechanism of hydrogen release from solid state ammonia borane (AB) has been investigated via in situ solid state 11B and 11B{1H} MAS-NMR techniques in fields of 7.1 T and 18.8 T at a decomposition temperature, well below the reported melting point. The decomposition of AB is well described by an induction, nucleation and growth mechanistic pathway.265 Single crystals of disilver(I) monofluorophosphate(V), Ag2PO3F (1), were obtained by slow evaporation of a diluted aqueous Ag2PO3F solution. Compound 1 was further characterized by solid-state 19F, 31P and 109Ag MAS NMR spectroscopy. The value for the isotropic one-bond P–F coupling constant in 1 is 1 JPF = 1045 Hz.266


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NMR of proteins and nucleic acids P. J. Simpson DOI: 10.1039/b617128c

1

Introduction

This chapter describes developments and applications of NMR in the study of biological processes involving proteins and nucleic acids at the molecular level. As noted by the author of this review in the preceding years, S. J. Matthews, the role of NMR in the field continues to burgeon and all areas cannot be adequately covered within the constraints of the chapter. The ‘‘New Methodology’’ section this year has two directions. This first of these (Sections 2.1–2.3) details some applications where NMR is providing insights into biological systems at a level of detail not achievable by other biophysical techniques. In particular, paramagnetic relaxation enhancement (2.1) and relaxation dispersion (2.2) have been providing incredible, atomicresolution, understanding of transiently populated species1 and enzyme dynamics.2 A short section on ‘‘in-cell’’ NMR is also included (2.3). The second part of ‘‘New Methodology’’ reviews some practical aspects, this year concentrating on isotopically-labelled sample production (2.4) and software/protocols (2.5). The latter half of the chapter describes some key structural studies, with an emphasis on protein (3.1) and DNA/RNA (3.2) interactions and large systems (3.3). Reports from one laboratory in particular continue to provide astonishing high-resolution descriptions of massive biomolecular systems using NMR. Of these, the detailed study of the dynamics and interactions of proteasome complexes with molecular weights of 0.36–1.1 MDa is highlighted.3

2

New methodology

2.1 Paramagnetic relaxation enhancement (PRE) The properties of intrinsic and extrinsic paramagnetic species, such as lanthanide ions and nitroxide-based radicals, have been studied and exploited in NMR techniques for many years. Recently, however, there has been a surge in the application of PRE to biomacromolecules, in particular utilising the distancedependent effect on the 1H transverse relaxation rate R2 on attachment or binding of an extrinsic spin label.4 A novel application has been providing unprecedented levels of detail in the study of transiently-populated species, demonstrated in studies by Volkov5 and Tang and co-workers1,6 who have used PRE not only to imply the existence of transient encounter complexes in the pathway to the formation of specific protein interactions, but also characterise their potential conformational ensembles. Volkov et al. attached the nitroxide-based paramagnetic spin label MTSL independently to five sites on yeast cytochrome c peroxidase and used PRE effects to guide docking to its electron-transfer partner, iso-1-cytochrome c.5 Whilst the model agreed well with a crystal structure of the complex, some nonrandomly distributed PRE restraints could not be fitted in the docking. The authors provide evidence that these arise due to a dynamic encounter state, which may be important in the mechanism of electron transfer between the two proteins, and further use the PRE measurements to provide a qualitative map of the encounter surface. Tang et al.6 use PRE to study the complex between two protein domains from the bacterial phosphotransferase system, EIN and HPr. They also observe large intermolecular PRE effects which cannot be explained by the static model of Cross-Faculty NMR Centre and Division of Molecular Biosciences, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ


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the complex, whilst intramolecular PREs are consistent. The authors suggest that the large discrepancies must be due to a lowly-populated minor species in fast exchange with the specific complex. They further use the discrepancy between the observed and predicted PREs to guide restrained rigid-body simulated annealing in order to generate a semi-quantitative depiction of the species, which describes the interaction interface and optimum number of conformers required to achieve a best-fit. Interestingly, the surface correlates with the electrostatic potential of the protein surface, suggesting that this may provide a mechanism enabling an initial nonspecific encounter complex which ‘‘funnels’’ the molecules towards the stereospecific complex. The same laboratory also use the PRE methodologies as part of the characterisation of structural and kinetic aspects of the homeodomain HoxD9 binding to a non-specific DNA duplex ligand.7 A first application involved labelling of the DNA independently at two sites via a dT-EDTA motif to allow co-ordination of paramagnetic Mn2+ or Ca2+ (diamagnetic control). Monitoring PRE effects on HoxD9 revealed that the protein interacts non-specifically along the length of the DNA, with rapid movement between both ends of the duplex. A further application involved using a paramagnetic co-solute Gd-DPTA-BMA to compare the buried binding interface used in the non-specific versus specific protein:DNA complex. The ability of PRE measurements to provide information on transiently populated states has been exploited in the study of disordered protein ensembles.8 Marsh et al.9 observe PREs in the unfolded state of the Drosophila drk protein N-terminal SH3 domain, which exists under non-denaturing conditions in equilibrium with the folded state. Using an N-terminal ‘‘ATCUN’’ tag which allows chelation of paramagnetic Cu2+, PREs indicated both non-native and native contacts within the ensemble. The authors further implement the PREs as restraints within their ENSEMBLE software, which generates ensembles of structures consistent with experimental data by assigning population weights to pre-generated conformers. In another study10 a specific aspect of the drk SH3 unfolded state was probed; namely the burial of Trp36, which seems to nucleate a transient non-native hydrophobic cluster. Using a 5-fluoro-Trp mutant the effects of dissolved oxygen on the fluorine and indole proton R1 rates were used to assess relative burial at opposite sides of the conjugated ring system, which apparently differ. The same authors also used the paramagnetic shifts of 13C nuclei by the oxygen to characterise solvent exposure within the folded and unfolded states.11 Francis et al.12 used PRE-derived ensembleaveraged restraints in restrained molecular dynamics simulations of staphylococcal nuclease D131D. This analysis reveals a tendency for the protein to explore transiently native-like conformations, involving clustering of the three main hydrophobic regions in the unfolded state. The SH3 domain of phosphatidylinositol 3kinase exhibits a dynamic amyloidogenic intermediate state under highly acidic conditions. Using the cysteine-linked MTSL system Ahn et al.13 observed long-range contacts not present in the native conformation, which they suggest may be a critical difference between non-amyloidogenic denatured states and amyloidogenic intermediate states. One potential difficulty in analysis of PREs is the need to account for the local correlation time of the paramagnetic centre, which is commonly attached via a flexible linker to the molecule under study. Vlasie et al.14 describe a DOTA-based caged lanthanide chelator ‘‘CLaNP’’ which is attached in a bi-dentate fashion to dicysteine mutants with restricted local motion. Another, mono-dentate, rigidlyattached lanthanide chelator has been designed based on a Ln3+-binding peptide.15 Such motional considerations and other practical aspects of the measurement of 1H transverse PRE are discussed in a useful reference.4 A review of paramagnetic tagging of diamagnetic proteins is noted.16 Other recent studies involving PRE which demonstrate the diverse range of applications include: identification of the divalent metal binding sites in the 30 kDa GAAA tetraloop receptor17 and Varkud satellite ribozyme stem-loop V,18 second-site ligand screening of the orphan nuclear receptor Nurr119 and various 258 | Nucl. Magn. Reson., 2008, 37, 257–273 This journal is

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protein tyrosine phosphatases20 by spin-labelling of the initial lead compound and monitoring broadening of fragment library molecules, determining the orientation of the helical antimicrobial peptide CM15 within DPC micelles,21 and in the determination of the relative orientation of donor and acceptor ligands bound to the 95 kDa N-acetylglucosaminyltransferase V glycoprotein.22 When acquiring NMR data, the use of chelated metal ions to reduce lengthy recycle times between scans by increasing the proton longitudinal relaxation rate, R1, is well established. Optimised systems for both solution-state23 and solid-state24 studies of proteins have been reported, allowing enhancements in sensitivity (up to 2-fold and 3-fold, respectively) through increased scan repetition rates without affecting transverse relaxation and hence causing line broadening. 2.2 Relaxation studies of protein dynamics Whilst PRE is proving a novel tool in the studies of transiently populated species, relaxation studies continue to provide important atomic-resolution data on a range of dynamic processes. The 15N R2 relaxation rate is governed by motion both on the ns-ps and the ms-ms timescales, the latter of which can be deconvoluted using CPMG-based relaxation dispersion experiments. Many biologically relevant conformational exchange processes, such as those involved in catalysis, occur on this timescale.25 In addition, depending on timescale, the populations, kinetic rate constant and magnitude of shift changes (Do) between inter-converting states can be obtained from fitting dispersion curves. Two outstanding examples of the application of relaxation dispersion in the study of the folding/binding of an intrinsically-disordered protein26,27 and in the study of an enzyme catalytic cycle28 have been reported by the same laboratory. Sugase et al. studied the mechanism of coupled folding and binding of the disordered phosphorylated kinase inducible activation domain (pKID) of the transcription factor CREB to the KIX domain of CREB-binding protein.26 Whilst a titration revealed the equilibrium between the free- and bound states to be in the slow-exchange regime, a number of peaks showed initial fast-exchange peak movements at sub-stoichiometric ratios, indicative of formation of a weak encounter complex. Further, 15N relaxation dispersion at varying ligand concentrations revealed a pattern of uniform on-rates across the two helices of pKID, but with differing off-rates, an observation which implies the existence of another intermediate state, distinct from the encounter complex. By extracting the chemical shifts of the intermediate state from Do it was shown to comprise an almost fully-formed N-terminal helix, with a lesser-defined C-terminal helix, the formation of which is presumably correlated with the formation of the final complex. Thus the study illustrates the power of relaxation dispersion in elucidating the nature and kinetics of the four distinct states (free, encounter, intermediate, complexed) in this dynamically-complicated process. Within the same laboratory, Boehr et al.28 measured amide relaxation dispersion data for complexes representing all five kinetic intermediates in the enzyme dihydrofolate reductase (DHFR) catalytic cycle. Fitting to a two-site exchange model allowed the exchange rate, population and chemical shift differences (Do) between the predominant and a transiently-populated state to be measured. A general trend was observed in relaxation dispersion in the DHFR active site and cofactor binding site, with Do correlating with the steady state changes in chemical shift between the next or preceding complex in the cycle. The implication is that the ground state of the enzyme transiently accesses, for example, the conformation of the ligand-bound state to which the ligand can then bind, shifting the energy landscape such that this becomes the new ground state.2 This is distinct from the idea of an ‘induced fit’ mechanism and demonstrates how NMR is able to provide unprecedented insight into biological mechanisms at atomic level. In a more qualitative study, Li and co-workers report the solution conformation and dynamics of the enzyme 6-hydroxymethyl-7, 8-dihydropterin pyrophosphokinase (HPPK) in Nucl. Magn. Reson., 2008, 37, 257–273 | 259 This journal is

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binary and ternary complexes with MgATP- and substrate analogues.29 Whilst a range of motions are observed in the free enzyme and binary complex which could allow a ‘‘population-shift’’ model akin to DHFR, the authors argue that the sealed and inaccessible nature of the ternary complex requires an ‘‘induced-fit’’ mode of substrate binding, suggesting both types of mechanism may be required in HPPK turnover. The dynamics of another enzyme, the prolyl isomerase pin1, in the free state and during catalytic turn-over have been investigated using similar methods.30 Relaxation dispersion within active site residues was again observed which is of the same timescale in the free and catalytically-active states. Whilst Do and relative populations could not be delineated, the authors suggest these data reveal that the enzyme is inherently predisposed to the ms-ms motions requisite for enzyme catalysis. Namanja and co-workers further study the apo- and substrate-bound dynamics of pin1 using both backbone 15N and sidechain 13C and 2D dynamics.31 They also observe ms-ms dynamics in both forms, with the rates of conformational exchange and order parameters S2 in a number of residues showing both increases and decreases upon substrate binding. The increased disorder is postulated to be compensatory to the entropically unfavourable restriction of motion in a number of binding-site residues and of the ligand, something which has been suggested in a different system by MacRaild et al.32 These workers derive changes in conformational entropy at the ns-ps timescale in backbone 15N nuclei of a bacterial arabinosebinding protein. The majority of measurable residues showed an increase in the amplitude of motions upon substrate interaction, with some local restrictions around the binding site, which again may indicate a mechanism of entropic compensation in the free energy of ligand binding. Zhuravleva et al.33 also measure significant changes in ns-ps dynamics spanning a number of residues in barnase upon binding of barstar. Chemical shift and sidechain 2H relaxation measurements reveal an apparent propagation of changes in dynamics not obvious from the static crystal structures of the two species, which the authors speculate may be an alternative mechanism for communication of ligand binding across a protein, distinct from classic conformational allostery. Strong evidence for such ‘‘dynamically driven protein allostery’’ is provided by Popovych and co-workers34 in their study of cAMP binding to the dimeric catabolite activator protein N-domain (CapN). cAMP binding to one monomer causes no significant chemical shift changes in the binding site of the other monomer, suggesting no structural changes, yet causes a drop in Kd of two orders of magnitude. 15N motions measured on a range of timescales reveal that protein fluctuations are enhanced across the domains upon initial binding of cAMP and quenched upon binding of the second molecule, suggesting Cap is poised to trigger a conformational entropic penalty through which the negative cooperativity arises. A similar motional argument has been invoked by Peng et al. to explain substrate specificity in group IV WW domains,35 which contain an additional serine in a key binding region, loop 1. An extensive set of 15N relaxation data were used to show that the ns-ps and ms-ms timescale dynamics inherent in this region are affected by this insertion, whilst the chemical nature of the loop is unchanged. The authors argue that dynamic properties may be as important in determining ligand specificity as the sidechain chemical properties. Vallurupalli and Kay36 studied 15N and 13C relaxation dispersion of an E. coli enzyme complex between NAD(P)H:flavin reductase and flavin adenine dinucleotide. Three distinct groups of residues could be characterised, two of which were associated with the donor and acceptor sites participating in the electron transfer reaction and could be correlated with the rate of electron transfer. The third group, characterised by a minor population (o1%), could be fitted to Do corresponding to random coil chemical shift values demonstrating that, at least in favourable cases, relaxation dispersion can reveal the nature of the minor species (i.e. an unfolded state in this example). 1H relaxation dispersion was used in determining the intramolecular association between the A and B subdomains of the E. coli mannitol transporter, which must transiently contact each 260 | Nucl. Magn. Reson., 2008, 37, 257–273 This journal is

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other to allow phosphoryl transfer.37 The rate constants are such that ca. 80 association/dissociation events occur per phosphoryl transfer event, suggesting the chemistry is the rate-limiting step, as opposed to conformational changes. This provides a paradigm differing from a previous two-domain system where conformational changes limited the reaction rate, something which the authors correlate with differences in which the domains are tethered. Eichmueller and Skrynikov report a novel use of lanthanide ions to amplify relaxation dispersion in the Ca2+-binding cardiac troponin C.38 This modulation of the pseudo-contact shift is long-range and hence could potentially probe dynamics where the local environment, and thus chemical shift, of a group is unaffected, such as upon movement of a helix or other rigid structural unit. Ln3+-binding tags could provide a general applicability of this method. Some astonishing reports from the laboratory of Lewis Kay demonstrate that sidechain relaxation dispersion and order parameters can be extracted from large or even very large macromolecular systems. A detailed study of sidechain dynamics in by far the largest system reported to date is presented by Sprangers and Kay3 who provide quantitative measurements of both ns-ps and ms-ms motions in 13CHD2and Id1/L/V-methyl-labelled samples of the a7a7 360 kDa ‘‘half-proteasome’’ and a7b7b7a7 670 kDa 20 S proteasome core complex. Comparison of S2 values between the two reveals no obvious changes on association of the b-subunits and interestingly no obvious correlation with crystallographic B-factors. Relaxation dispersion was further observed of 1H-13C multiple-quantum methyl-TROSY coherences which fit a single global exchange process in both species. Tugarinov and Kay describe novel intra-methyl 1H–1H cross-correlation experiments on the 360 kDa ‘‘half-proteasome’’, which allow order parameters to be obtained for methyl groups in standard Id1/L/V–13CH3-labelled perdeuterated proteins.39 In a different report40 the same authors extend the suite of experiments able to probe sidechain motions with a measurement of T1-like decay in 13CHD2-labelled proteins, demonstrated on the 82 kDa protein malate synthase G. Whilst the approach of Kay and co-workers provides exquisite detail of sidechain dynamics, Chill et al. have presented experiments for measuring 15N backbone relaxation in relatively large systems, demonstrated on the detergent-solubilised tetrameric KcsA potassium channel (tc E 38 ns).41 Using modified 2D/3D TROSY-HNCO-based sequences the authors were able to measure a full range of 15N relaxation parameters and characterise ns-ps motion in both the membrane-spanning helices and intracellular terminal regions. They also provide useful practical detail on the implementation of such experiments, including considerations for cryogenically-cooled probes. In light of recent insights into 13C’ spin-relaxation, Wang et al. describe a robust method for quantifying Lipari-Szabo modelfree parameters at the carbonyl position, which has differing sensitivity to motional modes in the backbone from the 15N spin.42 Ferrage et al. propose a measurement of the dipolar cross-relaxation rate between C 0 –Ca which circumnavigates a number of technical issues with previous experiments by using 2NzCz two-spin order.43 Finally, a novel, currently limited, approach of studying 15N relaxation in deuterated amide groups has been described using direct 15N detection.44 The ND group is sensitive to different spectral density frequencies than NH and provides a much more sensitive measurement of CSA, the dominant mechanism of relaxation in the absence of protons. 2.3 In-cell NMR In the last few years especially, a number of atomic-resolution studies of the dynamics and structure of proteins contained within living cells have been reported (see perspectives45,46 and review).47 These ‘‘in cell’’ NMR studies are starting to address questions such as whether the properties and behaviour of macromolecules, which NMR is able to probe so elegantly in vitro, differ in the crowded, heterogeneous environment of the cytoplasm. Bryant et al.48 have published the most Nucl. Magn. Reson., 2008, 37, 257–273 | 261 This journal is

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detailed analysis to date of the backbone dynamics of a protein within a cell with their study of apocytochrome b5 overexpressed in E. coli. They find that the pattern of backbone dynamics is unchanged in the cytosol, whilst the general trend is consistent with the expected increase in viscosity affecting tumbling time. Selenko and co-workers49 have made the advance of applying the approach to a protein in the cytoplasm of a higher eukaryotic cell by injecting recombinant GB1 into Xenopus oocytes, an approach which also sidesteps the problem of ‘‘background’’ signals from labelling of endogenous molecules. Whilst in vivo the structure of GB1 was unaltered, some line-broadening effects were observed which could be reproduced in vitro by suspending GB1 in Xenopus cell extracts or in high concentrations of BSA protein, suggesting these are likely to be purely an effect of ‘‘steric crowding’’ within the cell. Independently, Sakai et al.50 used the same approach in their proof-ofconcept in-cell study of calmodulin and ubiquitin, where they were able to observe processing of an ubiquitin mutant apparently by an endogenous ubiquitin hydrolase, UCH. Protocols for in-cell NMR studies in E. coli and Xenopus oocytes have been published.51 2.4 The production of isotopically-labelled samples for NMR The production of isotopically-labelled biomolecules can still often be the bottleneck to NMR studies. Common problems are low expression levels of heterologouslyproduced proteins, leading to prohibitive costs, a lack of appropriate eukaryotic post-translational modification in prokaryotic cells, or the requirement of sitespecific isotope labelling. Although it can suffer from a number of such problems, recombinant protein production in Escherichia coli is still the most common method, largely due to the ease of genetic manipulation, its rapid expression of milligram quantities of material and because it is relatively inexpensive to culture. Peti and Page52 review some recent developments for E. coli protein production at all stages, from construct identification to optimising cell culture density and cell lysis. Paliy and Gunasekera53 provide useful information comparing growth of E. coli strains using different gluceogenic carbon sources, glycerol, succinate, pyruvate and acetate, in differing minimal media. Suzuki et al.54 have developed a new E. coli expression system using cells growth-arrested by the endoribonuclease toxin MazF. Assuming that the gene for the target protein can be engineered without the target endoribonuclease sequence ACA after transcription, high levels can be expressed whilst the host cells are held ‘‘quasi dormant’’ by the action of MazF on the majority of other cellular mRNAs. In this state the cells tolerate high-level incorporation of toxic amino acids, such as fluorophenylalanine, but more impressively can be grown in a fraction of the volume of media (40-fold less without apparent drop in expression level), requiring a fraction of the isotopically-labelled precursors. Although not yet investigated, this also has the potential to be an ideal system for ‘‘in-cell’’ NMR (vide supra) as there is very little background protein synthesis to mask signals from the protein of interest. For incorporation of fluorine labels into proteins, Jackson et al. describe a system for site-specific introduction of trifluorophenylalanine via TAG nonsense codons,55 the trifluoro motif providing higher sensitivity for direct 19 F-detection for both in vivo and in vitro applications. Whilst assignment of small proteins is now generally routine, amino-acid specific labelling can still be of use for rapidly assisting peak identification or where standard triple-resonance experiments fail, for example in larger systems. Takeuchi et al.56 report an approach using protonated 14N, 13C (carbonyl) labelled amino acids added to a background of perdeuterated 15N medium. This exploits the inherent low levels of scrambling at the 13C 0 position, whilst different assignment information can be derived from both the sensitive TROSY-HNCO and TROSY-HSQC experiments. Iwai and Fiaux57 show how 15N, 10% 13C fractionally-labelled samples commonly used for methyl stereospecific assignment can also aid amino acid identification in triple-resonance experiments. Rapid assignment from a minimal number of samples 262 | Nucl. Magn. Reson., 2008, 37, 257–273 This journal is

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using the combinatorial labelling strategy is discussed in a paper from Ozawa and co-workers.58 Here, they describe production of 15N-only samples using cell-free expression, an approach which reduces amide scrambling via transaminases because of the more controlled set of metabolic enzymes present in these in vitro systems. Cell-free expression has a number of other advantages, such as circumnavigating any cytotoxic effects the target protein or precursors might have and the minimal purification/concentration required for rapidly assessing the state of the biomolecule (see perspectives).59,60 Two reviews61,62 and a mini-review series provide an up-todate overview of current developments in cell-free protein production, including an overview of different translation systems,63 their application and advantages over in vivo expression for membrane proteins64 and a description of their implementation within an automated platform for structural genomics screening.65 A useful review with detailed cell-free expression protocols and an emphasis on integral membrane protein production is recommended.66 Very recently, Wu et al. report a method of high-yielding cell-free synthesis directly from PCR products, missing out the timeconsuming step of preparation of plasmid DNA.67 Linear templates are ordinarily degraded through endonuclease activity so the authors generate single-stranded overhangs which are a target for cyclisation by the endogenous ligase activity of E. coli cell extracts. 2.5 NMR software, applications and protocols Automated routines and prediction methods for NMR data continue to improve and this is leading to an increased reliance on, and acceptance of, their application. Structure determination from NMR data with minimal human input is a particularly attractive goal. Cavalli et al. report68 a method using only chemical shift data with impressive results in tests of small proteins (o120 residues). After first using the shifts to generate secondary structure, their ‘‘CHESHIRE’’ approach uses a molecular fragment replacement (MFR) approach akin to Rosetta or previouslypublished RDC-based protocols to generate ensembles of structures from database screening. An important step is the further refinement of the ensembles using all chemical shifts, which contain tertiary structural information in addition to secondary structure. Backbone RMSDs of 1.2–1.8 A˚ from conventionally-determined structures were obtained. This demonstrates the power of the MFR approach over more ab initio methods; for example the use of similar data for guiding folding simulations resulted in much more modest results even when supplemented with additional sparse J-coupling and NOE information, as reported by Latek and coworkers.69 Lo´pez-Meńdez and Gu¨ntert70 amalgamate a number of pre-existing algorithms for peak picking, automated assignment and structure determination into their ‘‘FLYA’’ protocol, which uses a conventional assignment/NOE-based approach. By inputting only standard triple resonance and NOESY spectra, FLYA generated structures for three test proteins of 12–16 kDa within 1 A˚ backbone RMSD of their previously-determined structures without human intervention such as peak-picking. The correlation between protein backbone chemical shifts and secondary structure is well established and commonly provides initial restraints for structure determination. Wang et al. report that using paired deviations from random coil values, such as from C 0 –Ha correlation plots, allows prediction of secondary structure at least as well as existing methods, but with improved definition of extended structure.71 Their 2DCSi secondary structure prediction program is implemented as a web server. The PREDITOR web server has been developed72 which, akin to the TALOS program, predicts backbone f and c dihedrals with surprising accuracy (and significantly improved accuracy if a sequence homology option is used). However, an impressive extension is the prediction of sidechain w1 rotamers with 84% accuracy. A number of options are provided, including automated correction of referencing and direct output as CNS, CYANA or AMBER restraints. More qualitatively, Moreau et al.73 Nucl. Magn. Reson., 2008, 37, 257–273 | 263 This journal is

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report the program PASSNMR which predicts the amount of secondary structure from unassigned 1H, 15N- and 1H, 13C-HSQC spectra with accuracy akin to far-UV CD measurement, which they suggest as a target screen for structural genomics. Asbury and co-workers report an improved algorithm for generating a-helical structures from solid-state NMR PISEMA data of membrane proteins.74 Applying the TALOS/PREDITOR-type methodology inversely, i.e. using triplet-based comparisons of backbone conformations to predict chemical shifts, has been implemented in the program SPARTA.75 Whilst the shift predictions are still not at a level whereby protein assignments can be made from known structures without NMR data, the method provides slightly better predictions than current methods, which the authors suggest make real improvements to MFR-based structure calculations. A number of improvements or additional modules have been reported for established software, including an extension to the Sparky program for assignment of sidechains in relatively large proteins from 4D NOESY and 3D TOCSY spectra,76 automated analysis of NMR titration spectra in NMRView77 and a set of Mathematica notebooks for analysis of 15N relaxation data.78 Rieping et al.79 report the release of the latest version of their highly successful ARIA software for automated NOE assignment. ARIA2.1 includes a new graphical user interface and links directly to CCPN software. In the AUREMOL software suite, a module ‘‘ISIC’’ has been implemented which allows refinement of, for example, NMR structures derived from a limited number of restraints when an homologous structure is available.80 Within the same package, Gronwald et al. present software that calculates an NMR ‘‘R-factor’’ based on back-calculation of NOESY spectra using a complete relaxation matrix analysis and further correlate the R-factor with the RMSD of the model from the actual structure.81 In light of the increasingly rapid and ‘‘hands-off’’ methods for structure determination, tools such as these for the evaluation of NMR-derived structures are of immense importance. Bhattacharya and co-workers82 have integrated a number of commonly-used and in-house analysis software into a single web-server, PSVS, which provides both residue-level and global (Zscore) outputs of structural quality factors. Finally, in a slightly different vein, Fogh et al. have implemented a spectral naming system directed by the information encoded in the spectrum, as opposed to (for example) the coherence pathways used.83 The system is implemented as part of the CCPN data model but also provides a method capable of unifying the naming of biomolecular NMR experiments, which they demonstrate on both commonplace and more exotic experiment types.

3

High-resolution structural studies of biomacromolecules

3.1 Proteins and their interactions An excellent example of the increasingly multi-disciplinary approach being used in the field of Structural Biology is the study of the nuclear import of an influenza virus polymerase subunit from Tarendeau et al.84 The polymerase had proven thus far recalcitrant to heterologous expression, hence the authors designed a novel librarybased protein-expression screen, ‘‘ESPRIT’’, to test 26, 880 random deletion constructs. This yielded a functional PB2 fragment which expressed at multimilligram quantities, the structure of which was solved by NMR in solution and in complex with the human importin a5 protein by X-ray crystallography. Interestingly, a C-terminal segment of PB2 unwinds to bind importin, which in the free protein is stabilised by one of the three residues implicated in adaptation from avian to mammalian hosts. The interaction between two components of the bacterial typeIV secretion system, VirB7 and VirB9, has been elucidated in NMR studies of the homologous TraN bound to the TraO C-terminal domain.85 TraN forms an extended structure which winds around the immunoglobulin-like b-sandwich fold. The authors identify a b-strand appendage from the domain which they were able to 264 | Nucl. Magn. Reson., 2008, 37, 257–273 This journal is

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demonstrate protrudes through the outer membrane into the extracellular environment using cell-based assays. Grace and co-workers86 provide insight into binding of a corticotropin releasing factor G protein-coupled receptor (GPCR) to an antagonist peptide, astressin. Conventional NOE-based structures of the free and complexed GPCR extracellular domain 1 (ED1) revealed a short-consensus-repeat (SCR) motif, which interacts with the helical astressin C-terminal region. Binding is accompanied by quenching of dynamics in free ED1, which the authors suggest may be motion accessing the bound conformation akin to that observed in enzymes such as DHFR (vide supra). The cytoskeletal talin protein binds to the integrin b-subunit cytoplasmic tail and causes integrin activation. Initial NMR titration studies of talin F3 subunit with integrin b3 peptides delineated two distinct regions of the F3/b3 interaction, responsible for binding and activation.87 From this the authors designed a chimeric peptide with properties suitable for an NOE-based structure determination of the F3/b3 complex which, with cell-based functional assays, revealed details of talin’s unique integrin binding/activation activity. NMR of the perdeuterated calcium- and integrin-binding protein 1 (CIB1) from the neuronal calcium sensor (NCS) family was used to resolve discrepancies in X-ray structural data and probe its interaction with platelet integrin aIIbb3.88 1H–15N RDCs of CIB1 fitted well to the individual double EF-hand domains of the two published crystal structures, but poorly to the overall fold of one structure, suggesting the domain orientation did not match that in solution. Interestingly, the N-terminal extension in this structure matched the clearly-defined helical conformation observed in the NMR data, whilst that with the supposedly correct domain orientation exhibited an apparently artefactual extended structure in this region. An identical bi-lobal, double EF-hand topology has been observed in the structure of another NCS family protein, the rhodopsin kinase (RK) inhibitor recoverin bound to an RK peptide.89 In the NMR structure, RK binds within an hydrophobic groove which is exposed upon Ca2+induced flipping out of an N-terminal myristoyl group, which also allows membrane association. Hence the authors propose these structural changes as a mechanism by which recoverin can associate with rhodopsin and RK to form an inhibitory ternary complex. Complexes between E3 ubiquitin ligase itchWW3 domain and peptides from the Epstein-Barr virus latent membrane protein 2A have been determined using an ARIA-based NOE assignment.90 The structures give insight into the more promiscuous binding properties of the WW3 domain and the authors further investigate the effects of phosphorylation at potential regulatory sites on both the peptide and itch domain. Zhang et al. have reported the 34 kDa structure of the complex between a poxvirus CC chemokine inhibitor vCCI and human MIP-1b.91 Assignment and structure determination required both protonated and perdeuterated samples and mixed isotope labelling. The resulting NOE/RDC-based structure reveals a potential mechanism of inhibition of the immune inflammatory response by vCCI, whose binding occludes a region of Mip-1b involved in receptor recognition and homodimerisation. Activation of cytokine genes by the binding of calcineurin to NFATs (nuclear factors of activated T cells) has been investigated by Takeuchi et al.92 The 39 kDa complex of calcineurin (Cn) with an NFAT peptide was determined by NOE-driven docking, revealing an hydrophobic groove making extensive contacts to conserved sidechains of the peptide PxIxIT motif. Cross-saturation and selective NOE experiments using specific Cn/NFAT labelling were used to confirm the docked structural ensemble. 3.2 Nucleic acids and protein–nucleic acid complexes DNA recognition by the Brinker nuclear repressor, an important component of the Drosophila decapentaplegic morphogen signalling pathway, has been investigated by Cordier et al.93 Dynamics and chemical shift measurements reveal that the DNAbinding region is entirely unstructured under a range of conditions, but folds into a Nucl. Magn. Reson., 2008, 37, 257–273 | 265 This journal is

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small helical domain upon DNA binding. The authors attribute this transition to a cluster of positively-charged residues whose destabilising mutual repulsion is overcome by their interaction with the DNA target, as suggested by their structure of the complex. Madl and co-workers have elucidated the structural basis for DNA and toxin recognition of the E. coli controlled cell death antitoxin CcdA.94 NOE/RDCderived structures reveal homodimeric CcdA binds to a single operator-promoter region DNA duplex via a b-strand insertion into the major groove. The authors further use chemical shift mapping, PRE and ITC to demonstrate co-operativity in binding of three homodimers to three sites in the 71 kDa complex formed with a ccd operon fragment. The molecular basis of non-methyl-CpG DNA recognition has been investigated in the context of the leukaemia-associated MLL histone methyltransferase CXXC domain.95 Conventional structure determination revealed a novel Zn2+-stabilised fold with DNA-binding residues, identified by shift mapping, crosssaturation and mutagenesis, including an extended loop which the authors postulate could reach into the major groove to probe the CpG methylation status. Boudet et al. studied the monomeric form of the Bacillus licheniformis BlaI protein, a transcriptional regulator of b-lactam resistance, in complex with its DNA target.96 Due to the relatively weak binding interaction, an NOE/chemical shift-driven docking approach was adopted which revealed a 301 domain-rotation of the DNA binding region with respect to the dimeric form of the complex. The authors postulate a mechanism whereby the high-affinity dimer form is a ‘‘tensed spring’’ primed for conformational change upon conversion to the monomer as part of the regulatory process. A similar docking approach was required to determine a model for the weakly associating ternary complex of RNA-recognition motif 2 (RRM2) from the human splicing repressor PTB with single-stranded RNA (ssRNA) and the regulatory protein raver1.97 Titration and intermolecular NOE data revealed that the RRM2, which exhibits the canonical babbab motif, binds raver1 within an hydrophobic groove on the opposite face to the RNA binding site, allowing the small RRM to interact with both its target RNA and regulatory protein concurrently. The study of systems such as PTB which bind low-complexity, repetitive nucleotide (nt) sequences is complicated by the inherent weak association and potentially by dynamics associated with binding in multiple register. Auweter and co-workers discuss their successful strategy for overcoming such issues by judicious design of nucleotide and protein constructs in their structural studies of RRMs from the same PTB protein in complex with ssRNA.98 Their laboratory have further applied the approach in determining the first structures of two RRMs and an RRM:RNA complex from the serine- and arginine-rich (SR) family of splicing regulators.99 An added complication was low protein solubility, which was overcome using buffer solutions of charged amino acids (for the 9G8 RRM) or a solubilising protein tag (SRp20 RRM). Zhou et al. determined the structure of the Rous sarcoma virus RNA packaging signal complex comprising the nucleocapsid protein (NC) bound to a ca. 80 nt segment of the genomic RNA.100 The RNA exhibited an apparently dynamic structure which folds into a three stem-loop motif and an eight base-pair stem upon binding the tandem zinc-knuckle motif of the NC. Assignment was aided by nucleotide-specifically protonated, 2H-labelled samples to simplify spectra of the complex. A similar labelling approach was required for the study of the 27 nt apical stem-loop from the human hepatitis B virus encapsidation signal.101 The structure was calculated using NOE, RDC and 1H chemical shift data, the latter proving crucial in identifying the pseudo-triloop conformation, a potential proteinrecognition motif. Unambiguous resonance and NOE assignments, especially in sugar protons, are common limiting factors in studies of RNA by NMR. To address this in short RNA sequences, Wenter and co-workers102 report the synthesis of oligonucleotides with 13 C5 -labelled riboses at specific positions. Johnson Jr, et al. describe the biosynthesis of ribonucleotides with alternate-site 13C/12C labelling in the ribose ring.103 This permits the measurement of spin relaxation without complications from 13C–13C 266 | Nucl. Magn. Reson., 2008, 37, 257–273 This journal is

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scalar or dipolar coupling, facilitating much more detailed analysis of RNA conformational dynamics. Such dynamics are likely to play an important role in, for example, ribozyme function. Eldho and Dayie104 measured 13C R1, R2 and heteronuclear NOE enhancements in a 38 nt catalytic region from a Pylaiella littoralis self-splicing group II intron under a range of conditions. Motions on a wide range of timescales were observed in the regions involved in Mg2+ binding and catalysis which, based on this and other observations, the authors suggest are a conserved feature of the ribozyme machinery. Getz and co-workers105 studied the structure and dynamics of the catalytically-important P4 helix from ribonuclease P using C–H RDCs and imino nitrogen relaxation. The two P4 sub-domains had identical R2/R1 ratios, indicative of either a rigid structure or the two units exhibiting similar timescale motions. The authors used a simple but elegant ‘‘domain elongation’’ strategy106 of extending the RNA helix from one domain, a subsequent change in tumbling properties proving the latter hypothesis. Schweiters and Clore107 have probed the amplitude of motions of the Dickerson duplex DNA dodecamer using an extensive set of NMR (RDC, 31P CSA, NOE and 3 J coupling) and X-ray scattering data. Refinement of the NMR structure using a simulating annealing protocol revealed that ensembles of four or eight models are required to account for the data, which the authors suggest provide a physical picture of atomic motions such as sugar puckering. Jonker et al. studied the dynamics and domain rearrangements in the 36 kDa ternary complex formed between the L11 ribosomal protein and the GTPase region of 23S ribosomal RNA when bound to the natural antibiotic thiostrepton.108 Chemical shift mapping, RDCs and NOE data were used to guide docking of a ternary model which, in conjunction with relaxation data, revealed that the antibiotic contacts both protein and RNA, ‘‘trapping’’ the complex in a rigid, inhibitory state. The authors suggest this rigidification is responsible for the subsequent dramatic reduction in protein synthesis by the ribosome. The structure of a novel aminoglycoside analogue bound to the HIV trans-activating region (TAR) RNA has been investigated by Raghunathan and co-workers using NOE- and RDC-restrained molecular dynamics.109 In contrast with other cationic antibiotics of the aminoglycoside family, the compound interferes with both the Tat- and cyclin T1-binding regions of TAR, suggesting it may be a novel inhibitor of formation of the Tat/TAR/Cyc T1 ternary complex, crucial in HIV gene expression. Chu et al.110 report the NOE-derived structure of a short duplex DNA bound to a ‘‘threading bisintercalator’’ compound, designed to bind with high specificity and affinity by interacting with both minor- and major grooves simultaneously. The structure gives insight into a number of factors contributing to the sequence specificity of this class of intercalators, which are being designed as antibiotic and cancer therapy agents. 3.3 Large and/or challenging systems 3.3.1 Large biomacromolecules and complexes. Whilst a number of NMR structures reported this year are in excess of 30 kDa, the majority of these are derived from restraint-driven ‘‘docking’’-type approaches (vide supra). Although it can provide useful and accurate depictions of macromolecular interactions (some recent developments),111–113 the potential for binding-induced structural changes not described by a docking method remains and it is clearly more desirable to fully determine the structure of the complex. Molecular sizes of 30–40 kDa have remained the limit for high-resolution NMR structures, save in exceptional cases. However, Xu and co-workers have reported a protocol for assignment and structure determination of proteins up to at least 65 kDa.114 Incredibly, their method requires only conventional 13C, 15N labelled samples and uses four spectra; two 4D, 13C, 15Nseparated NOESY experiments, an HNCA and a 3D MQ-CCH-TOCSY. The initial approach obtains sequential assignment based on correlating HC–NH NOEs with HNCA connectivities to potential dipeptide sequences, whose spin systems are Nucl. Magn. Reson., 2008, 37, 257–273 | 267 This journal is

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identified using the CCH-TOCSY. Subsequent matching of dipeptides to the amino acid sequence, sidechain assignment and NOE based structure determination were demonstrated for three proteins of up to 65 kDa, with impressive levels of accuracy. Whilst high-resolution structure determination by NMR is still limited to molecular masses of tens of kilodaltons, it is, however, providing unprecedented levels of detailed insight into interactions and dynamics in systems at least an order of magnitude larger (recently reviewed).115 Arguably the most outstanding demonstration to date has been published this year with the study of the Thermoplasma acidophilum 20S proteasome core particle.3 In addition to measuring sidechain dynamics data in the 360 kDa and 670 kDa complexes (vide supra), chemical shift mapping and binding isotherms could be measured quantitatively for the ‘‘halfproteasome’’, and qualitatively for the full core particle, binding to an 11S activator complex (720 kDa and 1.1 MDa, respectively). Useful triple-resonance (at 360 kDa) and NOESY data (670 kDa) were also demonstrated. The ‘‘methyl-TROSY’’ effect exploited in this study requires the specific labelling of Leu, Val and/or Ile 13CH3 groups in highly perdeuterated proteins, but has the advantage of arising purely due to dipolar effects, as opposed to dipolar/CSA interference in 1H–15N TROSY, and hence is independent of field strength and variations in amide CSA. The method has been further demonstrated in other dynamics studies of the 20S proteasome and the 82 kDa malate synthase G39 (vide supra), preliminary spectra of diacylglycerol kinase in detergent micelles116 (ca. 100 kDa) and in monitoring ligand binding to the 306 kDa aspartate transcarbamoylase (ATCase).117 In the latter study, NMR was used to monitor the enzyme, which catalyses an initial step in pyrimidine biosynthesis, binding to various substrates and nucleotides. More importantly, NMR could be used to observe or imply the ‘‘relaxed’’ and ‘‘tense’’ states of the free and ligandsaturated ATCase, allowing equilibrium constants for the allosteric transition to be derived. Given the apparent general applicability and robustness of the methyl-TROSY approach, its application will likely become increasingly common. A limiting factor in this and other approaches is currently the difficulty in obtaining sequence-specific assignments in large (4100 kDa) systems. In an attempt to address this issue, Horst et al. report a number of sequential assignments could be made for the 72 kDa GroES cochaperonin bound to a 400 kDa single-ring GroEL variant using a 3D 15N separated NOESY-CRINEPT-HMQC.118 With additional use of three 15N selectively-labelled samples and prior structural knowledge, sequential HN–HN NOE correlations and assignment could be made for 61/90 residues. Limited structural information from long-range HN–HN NOEs could also be obtained. Another promising preliminary report used a carbon-detected 2D 13C–13C NOESY spectrum.119 Matzapetakis and co-workers analysed 13C–13C NOEs to identify 75% of monomer residue spin-systems in the 480 kDa bullfrog ferritin M complex (24 subunits of 176 amino acids). Sequential assignments could not be made for this system as the requisite correlations to the carbonyl carbon were extremely broad, presumably due to C 0 CSA relaxation. For systems under 100 kDa, whilst the application of 1H–15N TROSY techniques has become routine, NMR studies are still challenging. Some examples where NMR has provided detailed insight into biological systems include; elucidating the residue-specific effects of K+ binding to the 414 residue Pseudomonas putida camphor monoxygenase cytochrome P450,120 the identification of active site loop motions in the 53 kDa chicken triosephosphate isomerase using TROSY Hahn-echo experiments121 and in detecting residual structure in dynamic regions of a 66 kDa dimeric chloride channel (CIC-0) construct at 7 1C.122 In the latter study, NMR was used to complement a crystal structure of the eukaryotic CIC-0 cytoplasmic domain, where large segments of polypeptide potentially important in channel function and regulatory interactions were absent from the electron density. Here, Alioth et al. initially recorded TROSY-HSQC and CRIPT spectra to distinguish dynamic regions of the protein. Chemical shifts, RDCs


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and standard 15N spin relaxation measurements were then used to demonstrate the presence of both residual structure and fast (ns) timescale dynamics in these regions. 3.3.2 Membrane proteins. Solution NMR studies of even modestly-sized membrane proteins are in general challenging because they require mimics of the hydrophobic environment of the cellular membrane, commonly large assemblies of detergent molecules. Despite this, NMR has been successfully applied to a number of systems, most recently reviewed in ref. 116, 123 and 124. In addition to the study of dynamics in the tetrameric KcsA K+ channel in sodium dodecyl sulphate micelles (SDS) discussed above,41 Takeuchi et al. have investigated the conformational re-arrangement arising from pH-dependent gating.125 Using partially- and per-deuterated samples in n-dodecyl b-D-maltoside (DDM), shift changes were observed upon dropping the pH over a range known to cause the open-closed pore transition, exchanging on a slow (o150 s1) timescale. With residue-specific labelling and extensive mutagenesis the authors were able to assign a number of perturbed residues as those near the KcsA intracellular helix bundle, in line with other data. For studies of membrane proteins, judicious choice of solubilising agent is essential, highlighted in the study of a Staphyloccocus aureus multi-drug resistance pump Smr from Poget et al.126 The homologous E. coli protein has been reported in three different conformations, potentially dependent on detergent, so these authors screened a number of systems using drug binding as an assay. Sample perdeuteration and spectra at 900 MHz allowed 55% sequence assignment of the 107 residue dimer, which exists as a ca. 150 kDa species in the bicelle system chosen. Detergent selection, and other practical aspects of production and preparation, has been recently discussed for two families of integral membrane proteins.127,128 The interaction of the anti-aptotic protein Bcl-xL with the mitochondrial voltage dependent anion channel (VDAC) in lauryldimethylamine oxide (LDAO) has been investigated by Malia and Wagner.129 Initially, chemical shift titrations of the 32 kDa VDAC in LDAO with metabolites were used to confirm its functional state. Selective labelling and TROSY-based triple resonance experiments of Bcl-xL allowed 60% backbone assignment, permitting 80% of residues perturbed by VDAC interaction to be mapped onto a model structure. Due to the topology and notorious lack of dispersion in a-helical membrane proteins, useful NOE restraints can be few, and RDC observation is limited by a paucity of suitable alignment systems. Douglas and co-workers130 have developed a DNA nanotube-based medium which they successfully demonstrate induces the right level of alignment in two detergent-reconstituted systems; the integral transmembrane z–z domain of the T-cell receptor and BM2, a soluble protein with a 20-residue membrane anchor. Finally, it is noted that solid-state NMR is providing an ever-increasing wealth of high-resolution data on integral membrane proteins which is beyond the scope of this year’s review (see ref. 131 and 132). The reader is referred to some interesting and/or promising reports, including structure determinations of the bacterial mercury-transport protein MerF133 and the HIV Vpu transmembrane region134 in aligned phospholipid bicelles, the secondary structure, dynamics and topology of a reverse-labelled, seven-helix protein in native membranes (rhodopsin II),135 assignment and secondary structure of the 79-residue double-labelled H+-ATP synthase subunit c from E. coli,136 and an MAS study of the 144 kDa E. coli cytochrome bo3 oxidase in native lipids.137

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NMR of carbohydrates, lipids and membranes Elizabeth Hounsell DOI: 10.1039/b714852f

1. Introduction As in previous reviews in this series (the last being1), the contents reflect my personal research interests. The first of these is structural and conformational analysis of protein glycosylation, particularly O-linked via GalNAc (mucin-type) and GlcNAc (cytoplasmic-type), which is covered in Section 3. Membrane studies (Section 2) comes first, which are of course highly relevant to receptor interactions where all transmembrane proteins are glycosylated (O- and N-linked) and also to my particular interest of the structure and function of N-glycosylation and the glycosylphosphatidyl inositol (GPI) anchor of prions. However Section 2 is extended to a selection of general NMR methodologies for membrane studies. A large number of these studies relate to anti-microbial peptides in lipid bicelles. Lipids are also covered, if rather briefly, as conjugates with carbohydrate (Sections 3–5) and in metabonomic studies (Section 6, highlighting some relevant natural products and mammalian disease-related metabonomic studies). In addition to covering natural product structure as elucidated usually by NMR in combination with MS and LC methods, these findings are increasingly being correlated with genetic studies (Sections 4.3, 4.4, 4.5 and 5.4) to understand microbial and plant biochemistry.

2. Membrane studies 2.1 General Various aspects of sample preparation and recent progress in establishing high resolution conditions of MAS SS NMR of globular and membrane-associated proteins is reviewed.2 A review on SS NMR of integral membrane proteins3 highlighted MAS and sample alignment (using magnetically aligned phospholipid bilayers (bicelles) that spontaneously align in the magnetic field) to increase sensitivity. Franzin et al.4 point out that as all membrane proteins adopt 3D structures with a unique direction in space defined by the membrane environment it is highly desirable to carry out structure determination within the context of bilayer lipid membranes (i.e. SS NMR of uniaxially oriented planar bilayers) and for the FXYD proteins, a family of auxiliary regulatory subunits of the Na/K ATPases, they highlight recent developments in sample preparation, recombinant bacterial expression systems for preparation of isotopically labelled membrane proteins, pulse sequences and structural indices that guide the structure assembly process. Baldus et al.5 review recent progress to obtain sequential resonance assignments under MAS conditions to study multiple isotope labelled membrane proteins. MAS SS NMR of phospholipid bilayers (DMPCd54 and 2H MAS) supported in cylindrical nanopores of aluminium oxide was shown to permit access to the geometrical arrangements of the lipids.6 Individual lipid headgroup mobility in raft-forming lipid mixtures could be distinguished with 31P MAS NMR on a model membrane of sphingomyelin (SM) and DOPC.7 The issue of Progress in NMR spectroscopy 48(4) has several reviews on NMR of membrane proteins e.g. Zhang et al.8 on the use of 1H, 13C, 15N, 19F, 31P and 2H NMR methods for structure and dynamics of proteins in membrane bilayers; Tamm et al.9 on triple resonance methods, Me protonation, long-range distances by paramagnetic relaxation enhancement and refinement with RDCs; Hologne School of Biological and Chemical Sciences, Birkbeck University of London, Malet Street, London, UK, WC1E 7HX


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et al.10on improvements in proton detection in MAS SS NMR, methods of 1H, 1H distance determination, the detection of water molecules in the SS, and investigations of protein dynamics for membrane proteins, peptides, lipids, oligonucleotides, polymers and inclusion bodies. Sanders and Sonnichsen review applications of solution NMR methods to multispan integral membrane proteins11 and Koglin et al.12 methods of cell free expression of membrane proteins for NMR in the same, special issue of Magn. Reson. Chem. Insights into the interactions of synthetic amphipathic peptides (14–21 amino acids) in DMPC micelles in the absence and presence of cholesterol, DMPG vesicles and oriented bicelles were given by 31P and 2 H NMR.13 A new computational approach developed14 to determine the spatial arrangement of proteins in membranes by minimizing their transfer energies from water to the lipid bilayer, could, for example, reliably distinguish transmembrane and integral monotopic proteins from water soluble proteins (the coordinates of studied proteins can be found in http://opm.phar.umich.edu/). Lindblom and Groebner15 review NMR of lipid membranes and proteins. 2.2 Peptide-membrane studies As described by Wang et al.16 anti-microbial peptides are key components of innate immunity of all life forms and understanding their structure-activity relationships is essential for developing them into novel therapeutics to substitute for traditional antibiotics. Their approach was to use solution NMR of short chain phosphatidylglycerol (PG) micelles as a novel bacterial membrane-mimetic to provide insights into membrane targeting of both natural abundance 15N and 13C peptides, offering a practical approach for the refinement of distance-based structures, whereas isotope labelling in combination with SS NMR depicts a more complete picture of how antibacterial peptides perturb bacterial membranes. Liang et al.17 point out that a major challenge for the structure determination of integral membrane proteins by solution NMR is the limited number of NOE restraints in these systems stemming from extensive deuteration. They have introduced a method of parallel spin-labelling with paramagnetic and diamagnetic labels for paramagnetic relaxation enhancement (PRE) by nitroxide spin-labels of the integral membrane protein OmpA. The paucity of distance information available from highly deuterated proteins was also pointed out by Cierpicki et al.18 who demonstrated that significant improvement in the structural accuracy (to 1 A˚ rms deviation) for OmpA could be achieved by refinement with residual dipolar couplings (RDCs). 31P and 2H SS NMR of peptides incorporated into POPC and POPG oriented lamellar bilayers elucidated the membrane disrupting mechanism (and hence the anti-microbial action) of peptides MSI-78 and MSI-594 derived from magainin and melittin.19 MD simulations of bee venom melittin in aqueous solution, in methanol and in DMPC bilayers were compared with available NMR data.20 The structure and dynamics of the magainin antimicrobial peptides in micelles and bilayers using solution NMR in dodecylphosphocholine (DPC) micelles and MAS SS NMR, showed that one forms an antiparallel dimer with a Phe zipper holding together two highly helical protomers.21 DPPC/water H2O and D2O)/pyridine reverse micelles have been studied by SANA, FT-IR and 1H NMR.22 A SS NMR method for observing the signals due to 13C spins of peptides in close vicinity of 31P and 2H spins in deuterated phospholipid bilayers was developed.23 The orientation of a b-sheet membrane protein in lipid bilayers was determined24 using 2D 15N SS NMR, by 15N–1H dipolar coupling with 15N chemical shift determination of 15N-labeled retrocyclin-2 (a diS-stabilised cyclic peptide with antibacterial and antiviral activities) in uniaxially aligned PC bilayers (dilauroyl or 1-palmitoyl-2-oleoyl-sn-glycero-s-PC). Helical b-peptides were studied as self assembled lyotrophic liquid crystals.25 Marcotte et al.26 explored the effect of gramicidinA (gA) on bicelle orientation in the absence and presence of Eu3+ by 31 P and 2H NMR and demonstrated time-dependent flipping of the bilayer normal Nucl. Magn. Reson., 2008, 37, 274–292 | 275 This journal is

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alignment at high temperatures and high concentrations of gA explained in terms of lipid chain disorder and bilayer size. Isoflavones were shown to increase gramicidin channel life times from studies of 7-O-glucosyl genistein in SDS micelles: the 1H NMR line widths as a function of Mn++ concentration indicated that genistein is quite mobile and buried within the hydrophobic membrane core.27 Biotinylated gramicidins were investigated by 2H SS NMR in oriented phospholipid bilayers28 due to their importance in the AMBRI ‘‘ion channel switch’’ biosensor linked via amino-caproyl groups. Binding of the antibiotic amphotericin B, an anti-fungal drug, to PC membranes was shown to restrict molecular motion of the choline fragment in the hydrophilic region at the surface of liposomes, but to increase the segmental motional freedom of the hydrophobic core.29 The thermodynamics and interactions of the glycopeptide antibiotic, vancomycin correlated to the recently determined NMR structure for the peptidoglycan 4.30 NMR in detergent (LDAO) has shown that the membrane protein, Mistic, from Bacilus subtilis is a four a-helix bundle which may undergo a conformational change upon interaction to autonomously enable folding and insertion into lipid bilayers which does not resemble other membrane proteins.31 Cylcotides, a family of plant peptides with a circular protein backbone and three conserved tightly packed diS bonds (knottins) have antimicrobial activity; one of these, kalata B1, was studied in DDPC micelles.32 The effects of dapsone, an antileprosy sulfone drug, on the phase transition and dynamics of the model membrane DPPE–water/buffer was studied by 1H and 31P NMR.33 As explained by Matsumori et al.,34 bicelles with a small diameter allow for measurements of liquid NMR due to fast tumbling in solution and they characterised the conformation of the non-peptide drug erythromycin in bicelles from coupling constants and NOEs. 2.3 Membrane studies in pathogenesis A review35on the analysis of Vpu, and an HIV specific virus protein with ion channel activity included structural information from SS and solution NMR. SS NMR of 15 N-labeled Vpu in oriented phospholipid bilayers was studied36 to elucidate how the cytoplasmic domain is involved in the binding and degradation of viral receptors such as CD4 and MHC class I. SS NMR studies were carried out in order to determine whether changes in conformation occur in the Ly49 natural killer (NK) receptor on binding to MHC to explain how the Ly49 family regulates NK cell function by sensing MHC class I on target cells.37 The NMR structure of echistatin and the crystal structure of integrin av b3 were used to design a potent peptide antagonist of integrin binding.38 SS NMR spectra with single site resolution of CXCR1, a G-coupled receptor (GPCR), in magnetically aligned phospholipid bicelles were reported to have potential to elucidate drug–receptor interactions.39 The cannabinoid receptor subtype 2 (CB2), is a member of the GPCR superfamily where 13C/15N double labelled first and second transmembrane helices were studied.40 A 31P and 2H SS NMR and relaxation study was used to provide insights into the interaction of peptides (Helix VII) of cannabinoid receptors with the membrane bilayer by investigating the headgroup and acyl chain dynamics.41 The binding to synthetic human insulin of LGR8, a member of the Leu rich repeat (LRR)-containing GPCR family, was studied by NMR using Ala-substituted analogues.42 In studies vital in cancer research, of the molecules involved in programmed cell death (apoptosis) and cell survival, NMR showed that water molecules in apoptotic mitochondria (induced by Baxa) exhibit an accelerated translational motion of structured water common with that induced by the opening of the permeability transition pore (PTP), but limited in amplitude.43 The BH3 motif of the pro-survival family of proteins, BCL, is also present in pro-apoptotic proteins like BID and BAX, and an extended BH3 motif of BID was shown to specifically bind BCL-XL.44 Also in cancer studies, SS NMR was used to determine the backbone of the lipid anchor 276 | Nucl. Magn. Reson., 2008, 37, 274–292 This journal is

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of membrane-bound N-Ras protein.45 Particularly relevant to the efficacy of anticancer drugs, is the first discovered and best characterised primary efflux pump found in humans, the ABC transporter P-glycoprotein (PGP), which shows very broad substrate specificity for mainly lipophilic molecules suggesting binding takes place in the membrane:46 the authors report a systematic study of seven substrates (phenazine, doxorubicin, cephalexin, ampicillin, chloramphenicol, penicillin G and quercetin) with two modulators (quinidine and nicardipine) and 1,2-dimyristoyl-snglycero-3-phosphocholine (DMPC) model membranes. All the tested substances were found to have their highest concentration between the phosphate of the lipid head group and the upper segment of the lipid hydrocarbon chains. In a separate study on PGP, SS NMR was used to study the structural changes induced by verapamil, a Ca++ ion influx inhibitor, in phospholipid bilayers and determined the affinity of interaction with PGP in the lipid matrix.47 2.4 Prions and amyloid In order to study the role of the membrane in the difference in the normal cellular form (PrPC) and the Scrapie or pathological form (PrPSc) of the prion that are normally both GPI-anchored, a recombinant protein lacking the GPI anchor, but with a GPI anchor mimetic reconstituted in PC and raft membranes, was analysed.48 The peptide fragment muPrP 89–123 of the prion is biologically active in transgenic mice in fibrillar form giving rise to neurodegenerative disease: NMR showed that the 112–124 segment adopts an extended b-sheet conformation though not in parallel but in register alignment.49 Conformational intermediates of huPrPC were characterised by a combination of hydrostatic pressure (up to 200 MPa) with 2D NMR and the most pressure-sensitive region found to be aa139–141, indicating that this region might be the first entry point for the infectious conformer to convert the cellular protein.50 Amyloidogenic proteins Ab in Alzheimer’s disease (AD), a-synuclein (a-Syn) in Parkinson’s disease (PD) and Lewy bodies in DLB, suggested to be responsible for the overlap of clinical and neuropathological features of these three diseases, were studied51 using multidimensional NMR to elucidate the molecular interactions between Ab and a-Syn which may lead to the onset of DLB (the second most common form of dementia after AD). A metabonomic study of rat cerebrospinal fluid after infusion of Ab was used to correlate levels of Ab with learning difficulties.52 A review on SS NMR methods on the supramolecular organisation of amyloid fibrils and the conformation of peptides within amyloid fibrils is given in.53 The following are a handful of many other studies reported for Ab: the conformational path that can lead the Ab(1–42) peptide from the native state, which is represented by an a-helix embedded in the membrane, to the final state, which is characterised by sheet structures, was monitored by CD and NMR.54 Peptide inhibitors of amyloid formation based on the aaGxFxGxF framework were designed and characterised by NMR55 which showed inhibition of b-sheet packing of Ab40 and Ab42 via Met3 packing against Gly33 in the C-terminus of Ab40 and against Gly37 in the C-terminus of Ab42. The conformational space accessible to the Ab(21–30) peptide was investigated using replica exchange MD simulations in explicit solvent and found to be in good agreement with NMR suggesting that the persistence of structure in the denatured state may account for the resistance of this peptide to protease degradation.56 Pulsed field gradient NMR technique was applied to measure the self-diffusion coefficients of Ab(1–40) peptide in trifluoroethane/D2O mixtures.57 In studies of metal ion interactions: the mode of Cu++ binding to Ab(1–16) was explored by ESIMS, CD, fluorescence spectroscopy and NMR to explore copper chelators as anti AD drugs;58 the binding of Cu++ and Zn++ to 15N-uniformly labelled Ab(1–40) was studied by 1H–15N HSQC and NMR titration experiments;59 Nucl. Magn. Reson., 2008, 37, 274–292 | 277 This journal is

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31

P MAS SS NMR showed that Ab and Ab-Cu++ complexes with an intermolecular His bridge at the surface of a lipid membrane, but in this study60 Cu-mediated toxicity of Ab did not correlate with the ability to form amyloid or perturb the acylchain region of the lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy.

3. Glycoconjugates 3.1 Conformational studies The oligosaccharides conjugated to all membrane proteins, including Ab and prions, in general can have three levels of importance: intermolecular carbohydrate-toprotein recognition by carbohydrate binding proteins (lectins, selectins and adhesions); roles in the intramolecular conformation, biosynthesis and stability; and, recognition as antigens. Characterisation of all of these functions require good 3D structures and interaction studies. In this Section, conformational methods, synthesis of recognition motifs and some enzyme studies are discussed. Carbohydrate antigens in anti-bacterial vaccines is discussed in Section 4.1, but there is also a general review published61 on antibody–carbohydrate complexes. A review62 describes saturation transfer difference NMR (STD NMR) using a complete relaxation and conformational exchange matrix-saturation transfer (CORCEMA) protocol for ligand receptor complexes. Vliegenthart and Woods have edited a proceedings of the ACS on recent advances in NMR and computer modelling of carbohydrates.63 The effective assignment of glycosidic linkages in oligosaccharides was achieved by 13C labelled O-acetylation of all free hydroxyl groups and 4D carbon correlated 1H–1H ROESY.64 By combining MD simulations with NMR, the rotational preferences for the o angle in Me 2,3-D-methyl-a-D-Glc and -D-Gal65 have been elucidated. Mackeen et al.66 discuss the reliability of conformational studies and advise inclusion of local correlation time in the calculation of inter-proton distances from NMR measurements. Single X-ray diffraction and 13C NMR are reported for two acetylated, glucofuranosido-lactones which show interesting conformational preferences.67 An improved multiplicity-edited MBC experiment that leads to better J cross talk suppression in subspectra68 may have potential in carbohydrate-to-protein binding studies. Selective detection of methane (CH), methylene (CH2) or methyl (CH3) signals in NMR subspectra by editing methods were used to reduce complexity in crowded spectra such as those of natural products and glycoconjugates.69 3.2 Oligosaccharide conjugates The concepts of GLYCOSCIENCES.de portal, an open access repository for glycorelated experimental data, are described70 and data collections of carbohydrates and their use, reviewed.71 The conformational changes induced by reciprocal O-GlcNAcylation and O-phosphorylation of Ser and Thr residues in proteins was studied by NMR techniques, CD and MD simulations of the murine oestrogen receptor.72 The a-helical hairpin peptide (a-helix/turn/a-helix) was used as a model system to explore how glycosylation (O-linked b-GlcNAc) and (single) phosphorylation affected conformation, folding stability and rate of fibrillogenesis.73 NMR was studied for the structural and conformational analysis of a synthesised trisaccharide of the chaperone down-regulator, versipelostatin.74 Pulsed field gradient spin echo NMR was used to measure the a-helical type I antifreeze glycoprotein.75 The structural basis of the inhibition of Golgi a-mannosidase II by mannostatin was studied.76 All developmental stages of the zebrafish from fertilised eggs to hatched embryos synthesise oligomannosyl types of glycans as well as complex types with additional (b1-4)-galactosylated, Neu5Ac/Neu5Gc monosialylated Lewis x termini and CIDMS/MS and NMR also identified an abundant and unusual mucin-type O-glycosylation Fuc(a1-3)GalNAc(b1-4)[Neu5Ac/Neu5Gc(a2-3)Gal(b1-3)]GalNAc which 278 | Nucl. Magn. Reson., 2008, 37, 274–292 This journal is

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may be further oligosialylated, but exclusively in the earlier development stages indicating amongst other information a complex pattern of regulation of sialyltransferase activity during zebrafish development.77 Mendoza et al.78 report the synthesis of O-linked oligosaccharides of the mucin-like glycoproteins of Trypanosoma cruzi that are acceptors for sialic acid in the trans-sialidase reaction with NMR of the resulting product to elucidate the enzyme specificity. Conotoxins are small conformationally constrained peptides found in the venom of snails of the genus Conus which have many post translational modifications (PTMs) such as C-terminal amidation, hydroxylation, carboxylation, bromination and epimerisation, as well as glycosylation.79 These authors report on their characterisation by NMR and Kang et al.80 report on the conformational characterisation of the peptide backbones. The structure and conformation of a sialidase inhibitor polypeptide isolated from the marine sponge, Asteropus simplex, was shown to belong to the 4-loop class of cystine knots similar to those of some conotoxins and spider toxins and may be an important lead for antibacterial and antiviral drug development.81 For other forms of oligosaccharide conjugate (besides protein glycosylation): the conformational properties about the anomeric C-1-N bonds and the sugar C-5-C-6 bonds studied in urea-, thiourea-, and guanidine-linked glycooligomers was described82 and water soluble fluorescent fluorine-based conjugated copolymer bearing Glc pendants with tri(ethylene glycol) tethers.83 Hydroxylated fatty acids excreted in human urine as glucuronide conjugates were synthesised84 and characterised by NMR and HPLC MS/MS experiments. A mimic of the tetrasaccharide structure of the ganglioside GQiba was synthesised having biphenyl replacement for the core Gal(b1-3)GalNAc which, according to saturation transfer difference (STD) NMR, has the correct orientation of the terminal sialic acid(s) for interaction with myelinassociated glycoprotein.85 A series of aminoglycoside-capped macrocyclic structures was synthesised by bis-tethering of neomycin86 on three aromatic platforms (phenanthroline, acridine, quinacridine) and with a tetrasaccharide; the quinacridine platform gave the best DNA binding and was a potent and selective telomerase inhibitor with an IC50 in the submicromolar range (200 nm). A range of N-glycosyl– thiophene-2-carboxamides have been synthesised, conformationally analysed and tested for their effects on DNA synthesis.87 In other synthesis studies: regioselective reductive radical fragmentation of b-Dmannopyranosides to b-D-Rhap was carried out using [1-cyano-2-(2-iodo-phenyl)]ethylidene group as an acetal protecting group for carbohydrate thioglycoside donors where variable temperature NMR studies for the glycosylation step helped define an optimal protocol.88 Stereoselective synthesis of chiral piperidene derivatives using arabinopyranosylamine as the carbohydrate auxillary was proven by NMR and X-ray structure analysis as well as by synthesis of the alkaloids (+)coniine and (+)-dihydropinidine.89 Several novel fluorinated carbohydrates were synthesised as mechanistic probes for glycosyl processing enzymes for inhibitors of UDP-galactopyranose mutase (UGM) key in mycobacterial cell wall by phosphonylated exo-glycals.90 Thione and thiadiazines with glucopentitol groups were synthesised.91 Bis(carbohydrate)zirconcene complexes of bis(2-propenolato)ZdCp2 and tetra-O-methyl-Glcp were characterised by NMR and X-ray diffraction.92 For quercetin and other members of the flavone/flavanoid class of compounds, which are radical-scavenging polyphenols, NMR showed template self association for the recognition of imprinted polymers.93 3.3 Glycosaminoglycans (GAGs) Blundell and Almond present methods for generating mgm quantities of unusual odd- and even-numbered oligosaccharides from hyaluronan (HA) followed by analysis with high-field NMR.94 The same authors have used 15N-labeled oligosaccharides obtained from HA to carry out 1H–1H–15N NOESY-HSQC experiments to Nucl. Magn. Reson., 2008, 37, 274–292 | 279 This journal is

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measure properties of the acetamido group pertinent to a conformational controversy between NMR and simulation data.95 The interactions of HA-based polymers with phospholipid (DPPC and DPPG) liposomes, albumin and fibrinogen were studied using diffusional NMR techniques (PFG NMR).96 Heterodimerisation of CCR2 chemokine ligands MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (CCL7), MCP-4 (CCL13) and eotaxin was shown to be regulated by heparin binding.97 Dromedary camel lung HS, important in water retention and homeostasis, was compared to human and porcine liver heparin and HS and shown to be either a highly sulphated HS, a mixture of heparin and HS or an undersulphated heparin.98 The structures of a series of large oligosaccharides derived from acharan sulphate, an unusual GAG isolated from the giant African snail, Achatania fulica, was shown by ESI-MS and NMR to have 4-linked a-D-GlcNAc and 4,5-unsaturated pyranosyluronic acid 2-sulphate.99 1H and 13C NMR of DP2-DP8 oligomers formed from enzyme digested l-carrageenan extracted from Gigartina skottsbergii, characterised for example a heptasulphated tetrasaccharide.100 The influence of the microstructures of different k-carrageenan gels on the self-diffusion behaviour of poly(ethyleneglycol) (PEG) was determined by NMR diffusometry and TEM.101 Low field NMR methods, such as ex situ NMR probes, on line sensors, new ultrafast analysis methods and multidimensional approaches to relaxometry and diffusometry in food science are reviewed.102 The backbone b-D-(1–3, 1–6)-glucan from the marine diatom, Chaetoceros debilis named chrysolaminaran was assigned by 1H NMR, 13C-DEPT, TOCSY, COSY, and HMQC with partial characterisation of (b1-6)-linked branches connected to the main chain.103 A novel polyhydroxyl linear carbon chain metabolite of the marine dinoflagellate Amphidinium sp., exhibiting a modest inhibitory activity against DNA polymerase-a, was characterised by 2D NMR as having a THF ring, two tetrahydropyran rings and 21 hydroxyl groups on a C60-linear aliphatic chain with one exo-methylene and one Me branch.104 Fucoidan of the brown seaweed Hizikia fusiforme, showed the absence of sulphate in either the b-D-GlcpA or a-D-Xylp; overall sulphate was 22% of a-D-Fucp, a-D-Manp and b-D-Galp where about 2/3rds of the Fuc and Xyl were at the nonreducing ends of a Manp(a1-2) backbone.105 Characterisation by 1D and 2D NMR of the tetraprenyltoluquinols from the brown alga Cystophora fibrosan suggested that this organism should be removed from the genus Cystophora into the Cystoseira.106 Alginate oligosaccharides were characterised by NMR obtained from long strictly alternating sequences of ManA and GulA prepared by the action of recombinant epimerase AlgE4 in studies of its specificity.107

4. Microbial polysaccharides 4.1 Bacterial CPS/OPS antigens An Escherichia coli database (ECODAB) containing structures, NMR chemical shifts and to some extent cross-reactivity relationships has been established http:// www.casper.organ.su.se/ECODAB/ for serotyping of E. coli based on somatic (O), but not flagellar (H) or CPS (K) antigens.108 NMR was used to confirm the chemical structure and purity of pneumococcal capsular PS after RP-HPLC with fluorescence detection used in formulating conjugate vaccines.109 NMR was used110 to follow the purification using a new method of CPS from Neisseria meningitides serogroup C, an important antigen against meningococcal infection (WHO). Niedziela et al.111 report the complete structure of Plesiomonas shigelloides LPS (OPS and core) revealing the trisaccharide repeat [-2-D-Quip3NAcyl(a1-3)-L-Rhap2OAc(a1-3)-D-FucNAc(a1-)] in which Quip3NAcyl is 3-amino-3,6-dideoxy-D-Glc acylated with 3-hydroxy-2,3-dimethyl-5-oxopyrrolidene-2-carboxylic acid and a core novel non-phosphorylated octasaccharide. Hexa- to tridecasaccharides of the OPS of Shigella dysenteriae type I were synthesised and characterised by 1H and 13C NMR carrying the 280 | Nucl. Magn. Reson., 2008, 37, 274–292 This journal is

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5-(methoxycaronyl)pentyl aglycon for attachment to immunogenic carriers in a vaccine production strategy.112 Other studies include: OPS of a strain of Proteus mirabilis containing an amide of D-GalA with L-Ala;113 the OPS of Vibrio salmonicida strain C2 from Atlantic cod having L- and D-glycero-a-D-manno heptopyranoses, 5-acetamidino-7-acetamido-3,5,7,9-tetradeoxy-L-glycero-a-D-galactononulosonic acid and PEA;114 OPS of the Shiga-toxin producing E. coli O171 having a pentasaccharide repeat unit with one equivalent of O-acetyl over two positions of (-4)Neu5Ac7,9Ac(a2-6)-D-Galp(b1-6)-D-Glcp(b1-3)-D-Galp(b1-3)-DGalpNAc(1-).115 The OPS of Providencia alcalifaciens O30 was shown to have a linear repeating pentasaccharide structure.116 The branched tetrasaccharide repeating unit of the OPS of P. alcalifaciens O29 was characterised by 1H and 13C NMR including COSY, TOCSY, ROESY, HSQC and HMBC.117 In the O-chain of the LPS of haloalkaliphilic bacterium Halomonas pantelleriensis (which compared to H. magadiensis showed that both contain a high number of carboxylate groups whose salification might be a protective buffer against extreme life conditions) the 4-O[(S)1-carboxyethyl]-D-GlcA has been found for the first time.118 1H NMR of Cryptococcus capsular glucuronoxylomannans that link cellular apoptosis susceptibility genes to positioning residues on the mannose backbone is reviewed.119 The extracelluler and cell wall lipoteichoic acids (LTA) of Staphylococcus aureus MN8m, a biofilm-forming bacterium were found by NMR to be a mixture of two polymers, a (1-5)-linked poly(ribitol phosphate) substituted at C-4 of ribitol with b-GlcNAc and a (1-3)-linked poly(glycerol phosphate) partially substituted with 120 D-Ala at C-2. In a separate study, the LTA of Staphylococcus was shown by NMR to have no structural differences in lipoprotein (LP) in a LP diacylglycerol transferase deletion mutant (Dlgt) which lacks immunostimulating activity, suggesting that it is the LPs and not LTA that is important in activating TLR2.121 A deletion mutant of the dlta gene encoding the enzyme incorporating D-Ala into D-Ala LTA of Enterococcus faecalis, among the predominant causes of nosocomial (hospitalborne) infections, produced significantly less biofilm when grown in 1% Glc with increased susceptibility to several cationic antimicrobial peptides (polymixinB, colistin and nisin).122 The LTA of E. faecalis was confirmed as 1,3-poly(glycerol phosphate) non-stoichimetrically substituted at C-2 of the glycerol residues with D-Ala, kojibiose and a novel substituent [D-Ala-6]-D-Glcp(a1-2)[D-Ala-6]-D-Glcp(a1-), but opsonic antibodies to E. faecalis are primarily directed to nonalanylated epitopes on the LTA molecule.123

4.2 Bacterial LPS cores (lipid A) and extracellular PS (EPS) Pseudomonas aeruginosa was shown to have highly phosphorylated core oligosaccharides.124 The LPS, PS and core of the fish pathogen, Francisella victoria was characterised using a novel H2BC pulse sequence, the PS being suggested as the largest oligosaccharide elucidated by NMR.125 Analysis of the core-lipid A backbone from the LPS of an organic solvent resistant (e.g. grown in phenol and benzoic acid) gram-negative bacterium, Acinetobacter radioresistens S13, showed novel oligosaccharides containing a trisaccharide of 3-deoxy-manno-octulopyranosonic acid in the inner core region and a Glc rich outer core.126 A benzene resistantlike127 EPS important for the benzene-tolerance of the bacterium Rhodococcus sp.33 was characterised by 2D DQF-COSY, TOCSY, HMQC, HMBC and NOESY experiments and shown to have a tetrasaccharide repeat sequence of a 1:1 ratio of Gal, Man, Glc, GlcA and a stoichiometric amount of pyruvic acid. The EPS produced by R. rhodochrous has potential128 in the bioremediation of oil-contaminated environments: SAR of this showed the EPS was composed of 1:1 ratio of D-Man, D-Gal, D-Glc and D-GlcA with 0.8% (wt/wt) of octadecanoic acid and 2.7% (wt/wt) hexadecanoic acid. Nucl. Magn. Reson., 2008, 37, 274–292 | 281 This journal is

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4.3 Genetic studies of bacterial natural product biosynthesis HR MAS NMR was applied to probe and quantitate the N-linked glycan in Campylobacter jejuni129 in studies which helped correlate molecular biology and biochemistry. The deepest rough C. jejuni 81–176 obtained by mutation of waaC encoding heptosyltransferase I, that catalyses the transfer of the first L-glycero-Dmanno-heptose residue to 3-deoxy-D-manno-octulosonic (Kdo)-lipid A.130 1H NMR of the culture supernatants of a mutant in the C. jejuni gene encoding PEB1a, an adhesin, homologous with periplasmic-binding proteins associated with ABC transporters, had greatly impaired transport of glutamate and aspartate.131. HR-MAS NMR of 15N-labeled cells confirmed the structure of the O-methyl phosphoramidate modification at C-3 of the GalfNAc residue of the CPS of C. jejuni and gave insights into its biosynthesis.132. Characterisation was achieved of the flagellar glycosylation locus in C. jejuni 81–176 using a focused metabolomics approach consisting of correlated biochemistry and genomics of specific targets, in this case novel pseudoaminic acids.133 The effect of lpd gene knockouts was studied with respect to the metabolism of E. coli using 13C-labeling experiments and 1H–13C-NMR spectra showed intracellular metabolic flux-distribution in the absence of lipoamide dehydrogenase.134 The O-repeating unit biosynthesis is the first committed step in LPS biosynthesis in a variety of gram-negative bacteria; in E. coli O86:H2 wbnH encodes an N-acetylgalactosaminyl transferase (GalNAcT) that catalyses the transfer of GalNAc from UDP–GalNAc to the GalNAc–pyrophosphate–lipid acceptor and the resulting product GalNAc(a1–3)GalNAc(a1-PP)–O–(CH2)11-OPh analysed by NMR and LC-MS.135 The structural and functional characterisation of PseC, an aminotransferase involved in the biosynthesis of the sialic acid-like nonulosonate, pseudaminic acid, an essential flagellar modification in Helicobacter pylori, showed that in the enzyme binding site the AltNAc sugar ring adopts a 4C1 chair conformation which is different from the 1C4 form in solution.136 NMR analysis of ‘‘real time’’ enzyme– substrate interactions indicated that the enzyme FlaA1 of H. pylori which is essential for pathogenesis is a UDP–GlcNAc inverting 4,6-dehydratase catalysing the first step in the biosynthesis of a pseudaminic derivative.137 The substrate specificity and transglycosylation catalysed by a thermostable b-glucosidase from a marine hyperthermophile eubacterium Thermotoga neapolitans subcloned and expressed in E. coli was characterised by NMR of products which indicated that glucose from cellulose was transferred to the C-3, C-4 and C-6 of Glc substrate.138 A unique mode of acetylation of oligosaccharides (at C-3 of the nonreducing termini of Glc, Xyl and Man and at equatorial C-2 of Glc and Xyl only) was established by NMR and ESI-MS on the basis of resistance to glucosidases.139 The substrate specificity of an engineered xylanase from Cellulomonas fimi was characterised.140 Characterisation of mutants from Rhizobium sp. NGR234 with defective EPS synthesis elucidated acetyl transferase enzyme specificities.141 The common structure that a lipochito-oligosaccharide must have so that the Rhizobium that produces and excretes it is able to nodulate plants of Phaselus vulgaris was established by following the extracellular signals of a linear backbone GlcNAc, with a non-reducing terminal N–Me group, different N-acyl substituents and terminating alditol, sulphated GlcNAc–ol.142

4.4 Mycobacteria Mycobacterial lipoarabinomannan (LAM) e.g. of M. tuberculosis (M.tb) is a lipidated polysaccharide, the mycoyl–arabinogalactan–peptidoglycan (mAGP) complex, which plays a key role in the survival of the organism, but as found via expression in E. coli and NMR analysis of products, relies on a single enzyme, galactofuranosyltransferase (glfT), to synthesise both glycoside linkages at the core of the mAGP and of D-Gal attached via alternating (b1-5) and (b1-6) linkages.143 282 | Nucl. Magn. Reson., 2008, 37, 274–292 This journal is

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mAGP is also a potent modulator of the immune response which may correlate with novel sugars such as 5-deoxy-5-methylthio-xylofuranose (MSX) found144 in the D-configuration (a1-4)-linked to a Manp residue in the mannan portion. NMR was used to characterise LAM from a mutant of M.tb. lacking the mannosyltransferase responsible for capping with (a1-2)Man: in M.tb the non-reducing termini of LAM is capped but in some other species LAM is not capped or is capped with inositol phosphate and the nature and extent of the capping plays a role in disease pathogenesis.145 The detailed conformation was studied of mycothiol, composed of a glycoside linkage between myo-inositol and D-GlcN with an N-acetyl–Cys linked to the 2 0 amino group of GlcN is thought to replace glutathione as the major intracellular thiol in eukaryotes and to be important as having a role in anti-mycobacterial drug resistance.146 4.5 Fungus Bioconversion of D-psicose to D-tagatose and D-talitol by Mucoraceae fungi (e.g. Rhizopus oryzae) was characterised by NMR.147 Four azaphilines from the fungus Annulohypoxylon cohaerens (named cohaerens C–F), with moderate activity of nitric acid production in RAW cells and strong and non-selective antimicrobial effects, were characterised by 2D NMR, IR, UV and CD spectroscopy.148 Colonization of roots by the arbuscular mycorrhizal fungus Glomus intraradices induced accumulation of apocarotinoids, mono-, di- and branched triglycosides of blumenol C, 13-hydroxyblumenol C and 13-nor-5-carboxy blumenol C.149 The repeating structure of the soluble polysaccharide (PS-1) of a hot aqueous extract of the wild edible mushroom Termitomyces striatus was established by methylation analysis, periodate oxidation and 1D and 2D NMR spectroscopy.150 Structural elucidation of novel fucogalactans of the mycelium of Coprinus comatus identified a pentasaccharide repeating unit.151 Glucans were characterised from the fruiting bodies of the fungus Hericumerinaceus, with backbone (b1-3)-linked-D-Glc and (b1-6)-D-Glc branches152 and in a second study153 found to be terminated in 3O-Me-Rha. Sakamoto154 reviews the characterisation of the specificities of two Apergillus niger exo-polygalacturonases (exo-PG1 and exo-PG2) and a Penicillium chrysogenum exo-arabinanase and its recombinant form ‘Abnx’ (which also has trans-arabinosylation activity) via NMR of products. A novel (b1-3), (b1-6)-oligoglucan elicitor that induces chitinases in tobacco cells was isolated from the fungus Alternaria alternata and shown to cause the cells to transiently express a Phe–ammonia lyase gene and a coumaryl-O-CoA O-methyltransferase gene.155

5. Plants 5.1 Leaves/fruits/seeds The NMR of arabinogalactan and pectin from Silene vulgaris (M.) G. callus showed that the core of the former was a (b1-3)-D-galactopyran with some Gal branched at C-6 and side chains of 3-O-substituted b-Galp, terminal a-Araf and a-Rhap, and 2O-substituted a-Rhap.156 A PS from a tea infusion of Maytenus illicifolia leaves with anti-ulcer protective effects was shown to be a type II arabinoglalactan with a (b1-3)linked Galp main chain substituted at C-6 by (b1-6)-linked Galp chains which were mainly substituted at C-3 by (a1-5) and (a1-3) Araf chains and with non-reducing end units of a-L-Araf and 4-O-Me–GlcpA.157 The alkali extractable PS from the seeds of Retama raetam ssp. Gussonei consisted of a backbone (b1-4)-linked D-Xylp with branches of [4-O-Me–GlcpA]-2-O-Glcp(a1-2)Glc.158 Leucanthoside, a new allose-containing triterpenoid saponin isolated from the aerial parts of Cephalaria leucantha having a tri- and di-saccharide at either end, respectively, was completely assigned by DQF-COSY, NOESY, TOCSY, HSQC, DINE-HSQC, HMBC, 13C–1H–2D-J-resolved spectroscopy and 1,1-ADEQUATE Nucl. Magn. Reson., 2008, 37, 274–292 | 283 This journal is

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NMR.159 Triterpene glycosides were isolated from Cussonia paniculata leaves.160 Antioxidants from the fruits of Luffa cylindrical (sponge gourds) were identified as: p-coumaric acid, 1-O-feruloyl-b-D–Glc, 1-O-coumaroyl-b-D-Glc, 1-O-caffeoyl-b-DGlc, 1-O-(4-hydroxybenzoyl)-Glc, diosmetin-7-O-b-D-glucuronide, apigenin- and lueolin- 7-O-b-D-glucuronide Me ester.161 The structural characterisation of pollen allergens is reviewed.162 5.2 Stems/bark Six new apiosyl-(1-6)-glucosylisoflavones and four known ones were characterised by NMR and chemical methods from the stems of Glycosmis pentaphylla.163 Flavone glycosides from the whole plant of Andrographis alata were established from 1D and 2D NMR experiments.164 Two benzoic acid allopyranosides, pseudoarolsides A and B, from the bark of Pseudolarix kaempferi were determined by MS and 1D and 2D NMR.165 Quinones were characterised from teak, one of which, deoxylapachol, induced fungal cell wall stress.166 In studies on plant polysaccharides: complete assignment of chemical shifts was achieved by HSQC, HMBC, DQF-COSY and NOESY of lignans from the bark of Pinus sylvestris.167 Grass hemicelluloses extracted by alkali peroxide were shown by 13 C NMR to have galactoarabinoxylan, 4-O-methyl galactoarabinoxylan and bglucan structures.168 The complex feruloylated heteroxylan side chains from maize bran were shown169 to have Xylp(a1-3)- and Galp(a1-3)- Galp(a1-2)Xylp(b1-2)-5-Otransferoyl-Araf and dehydrotriferulic and dehydrotetraferulic acids were identified from insoluble maize bran fibre170 which have roles in cross-linking PS in plant cell walls. Inulin and a high methoxy pectin, were shown to constitute the two PS from Echinacea angustifolia radix: the backbone structure of the smooth region of the pectin was an (a1-4)-polygalacturonan partially Me esterified and acetylated with the hairy regions containing 2-O and 2,4-O-Rhap, 5-O- and 3,5-) Araf, 3,6-O-Galp and terminal Rhap, Araf, Arap, Galp and GalAp with a novel Gal–GalA alternating sequence.171 13C CP-MAS NMR spectra were recorded172 for amylose B. Many plant polysaccharides are also expressed in bacteria. Hence, the SS NMR assignments of the 13C resonances of cellulose Ia from Acetobacter xyylinum were reinvestigated by INADEQUATE experiments on uniformally enriched samples and the principal chemical shift tensor components of each 13C-labeled site determined by a 2D iso-aniso RAI (recoupling of anisotropy information) to distinguish the H-bonding pattern.173 5.3 Roots The analysis of root extracts from Deguelia longeracemosa gave 15 prenylated metabolites which were structurally characterised and screened for anti-microbial activity.174 Methanol extracts of the tubers of Gastrodia elata blume were shown to contain n-butyl-b-D-fructopyranosides.175 Stilbene glycosides isolated from the ethanol extracts of the roots of Polygonum multiforum were characterised by NMR and MS and their antioxidant activities (o20 mg/ml) tested.176 3 0 -hydroxy4 0 -methoxy isoflavanoids were isolated from A. membranaceus var. mongholicus.177 A new oleanane glycoside from roots of Astragalus caprinus was characterised as, 3O-Rhap(a1-2)-b-D-GlcpA22-O-b-D-Apif-soyasapogenol B, triterpene saponin.178 Several new rhamnosylated triterpene saponins were characterised from Eryngium campestre179 and complete 1H and 13C assignment of saponins from roots of Gypsophila trichotoma wend achieved.180 Phenolic glycosides and saponins in Primula elatior and Primula veris had the highest content of primulaverin and primeverin.181 A novel diterpenoid from the roots of Semiaquilegia adoxoides was established as 3b, 11-dihydroxy-12-O-b-D-Glcp-8,11,13-abietatrien-6-one.182 Steroidal saponins from the roots of Asparagus officinalis with a unique aglycon moiety and b-D-Glcp, b-D-Xylp, a-D-Rhap containing di-trisaccharides were fully 284 | Nucl. Magn. Reson., 2008, 37, 274–292 This journal is

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characterised by NMR.183 Two new non-plant bioactive triterpene tetraglycosides (the core saccharide unit being sulphated) were isolated from the sea cucumber, Pseudocolochirus violaceus.184 The saponin fraction of Quillaja saponaria, which is used as an adjuvant for an anti-leishmaniasis vaccine, was characterised by 1H and 13 C NMR as containing a mixture of two deacylsaponins, sucrose, glucose, rutin and quercetin.185 5.4 Genetic studies in plants The glycosylation of flavanoids, mediated by the glycosyltransferase (GT) family 1, affects solubility, stability and bioavailability: a GT cloned from Arabidopsis thalania was expressed in flower, leaf and root, but not in the stem.186 It was subcloned in E. coli and the products characterised by NMR to establish the specificity as a probable kaempferol-3-O-UDP GT. 1H NMR analysis of the stereochemistry of the hydrolysis of pyridylaminated Man(a1-6)Man(b1-4)GlcNAc(b1-4)GlcNAc showed that cabbage endo-b-mannosidase is a retaining glycoside hydrolase as are other family 2 enzymes.187

6. Libraries and metabonomics 6.1 Natural product metabonomics Recent advances are reviewed of various hyphenated techniques (GC-MS, LC-PDA, LC-MS, LC-FTIR, LC-NMR, LC-NMR-MS, CE-MS) in online detection of natural products, chemotaxinomic studies, chemical fingerprinting, quality control of herbal products and metabonomic studies.188 The same authors present a general overview of the processes involved in natural product research leading up to the methods detailed above, starting from extraction to determination of the structures of purified products and their biological activity.189 Screening and identification of antioxidants in methanolic extracts of pharmaceutically used plants by hyphenated chromatographic techniques with online DPPH and ABTS radical scavenging, LCMS and LC-UV-SPE-NMR are reviewed.190 Preparative isolation and purification of chemical constituents from the root of Polygonum multiforum by high sped counter-current chromatography (HSCCC) with characterisation by 1H NMR and ESI-MS established the rules of solvent system selection and the systematic pattern to screen for bioactive glycosides.191 Principal component analysis of 600 MHz 1H NMR spectra of commercial formulations of St. John’s wort (Hypericum perforatum) acquired in MeOH-d4 and DMSO-d6 was shown to be able to differentiate between plant extract variability.192 A book edited by Robertson, Lindon and Nicholson on Metabonomics in Toxicity Assessment (ISBN 0-8247-2665-0)193 has several useful reviews crossing the divide between plant and animal studies: such as Bundy setting out the advantages and disadvantages of NMR-based metabonomic profiling as applied to ecotoxicology;194 Griffen et al. on 1H MAS NMR of tissues;195 Lindon et al.196 and Reily et al.197 on NMR spectroscopy of biofluids. 6.2 Lipid/carbohydrate metabonomics in health and disease 600 MHz HR MAS NMR of breast tissue biopsies was used to map the relative intensities of glycerophosphocholine (GPC), phosphocholine (PC) and choline and eight metabolites (choline, creatine, b-Glc, GPC, glycin, myo-inositol, PC and taurine) to show that GPC, PC and choline could distinguish small tumours from non-involved tissue.198 Quantification of PC and GPC using 31P edited 1H NMR confirmed the correlation with the development and progression of cancer.199 A comparison of assessment techniques for related concentrations of plasma lipid and lipoproteins was also achieved in the metabolic syndrome.200 Blood Glc, serum-free fatty acids, serum triglyceride levels and intramyocellular lipids were found to be Nucl. Magn. Reson., 2008, 37, 274–292 | 285 This journal is

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elevated in a mouse model (alloxan-induced) of diabetes and correlated with accelerated atherogenesis and up-regulation of growth factors and their receptors.201 The combination of 600 MHz NMR with thiol spin-labeling of apoB and following Me head group signals of sphingomyelin and PC in the 1H NMR spectrum of LDL indicated that fragments of apoB involved in receptor binding are directly in contact with the solvated phospholipid head groups of the lipid matrix.202 Solution NMR confirmed the products of a-chloroaldehydes, including 2-chlorohexadecanal, produced by myeloperoxidase, and as adducts with ethanolamine glycerophospholipid which were substrates for phospholipase D of relevance in inflammation and atherosclerosis.203 1H NMR-based metabonomics was applied to (a) lumbar cerebrospinal fluid samples collected from patients with bacterial fungal and viral meningitis and (b) ventricular cerebrospinal fluid from patients with ventriculits, each being clearly distinguished by this method.204

7. Drug design and delivery 7.1 Cyclodextrin (CD) inclusion complexes The energetic and conformational preferences involved in the chiral discrimination of ibuprofen isomers in b-CD inclusion complexes was studied205 using NMR and atomistic molecular mechanics simulations (MM/GBSA). Complexation of diazinion, an organophosphate pesticide, with a-, b- and g-CD was followed using NMR and computational studies.206 Host guest interactions were characterised of b–CD with : paeonol;207 free radical scavenger 5-alkoxycarbonyl-5-methyl-1-pyrroline-Noxide EMPO-type nitrone adducts;208 several sub-phthalocyanine derivatives that contain an alkoxy substituent as an axial ligand (characterised in DMSO at the toluene/water interface by UV/VIS spectroscopy, induced circular dichroism (ICD) and NMR).209 Diffusion measurements versus chemical shift titration were compared for camphor-CD (a, b and g) complexes and ppm values found to be more sensitive to diastereomic complex formation.210 The kinetics of the self assembly of a series of dinuclear Pt(II) complexes with b–CD and rotaxanes were investigated by 1 H NMR211 and the interaction between b-CD and a Gemini surfactant in aqueous solution.212 Carboxymethylated (but not native) a-, b-, and g-CD derivatives are all equally effective water-soluble chiral NMR discrimination reagents for cationic substrates.213 7.2 Non CD applications PS such as cross-linked amylose starch are used as excipients (delivery formulation) in controlled release devices for drugs—the effect of formulation, size, compression forces and temperature on the diffusion of water were studied by NMR imaging.214 PS-stabilised iron complexes have numerous applications, such as iron supplementation in anaemia, MRI contrast agents and magnetic separation of cells and proteins.215 Characterisation of glycosyl chitosan (investigated as a material for biomedical and pharmaceutical applications) by 1H NMR identified potentially deleterious modifications.216 However research into chitosan-mediated gene delivery continues to gain interest-for target specificity e.g. folic acid was covalently conjugated to chitosan, characterised by 1H NMR and evaluated in human epithelial ovarian cancer OV2008 cells and human breast cancer MCF-7 cells which, like tumours themselves, overexpress folic acid receptors.217 Protein loading of hexanoylmodified chitsan nanoparticles was studied218 and acid hydrolysis of commercial chitosans was followed by 1H NMR to correlate size and viscosity.219

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Synthetic macromolecules Hiromichi Kurosua and Takeshi Yamanobeb DOI: 10.1039/b617227j

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. Wolter reviewed the applications of hydrogen NMR as a direct method for determination of the hydrogen content. The one-sided access NMR technique is introduced for outside laboratory application in plastic and foodstuff industry.1 Hologne et al. summarized the investigations of protein dynamics on the basis of 1D- and 2D NMR and the improvement of proton detection in MAS NMR with the examples of applications proteins, membrane proteins, peptides, lipids, oligonuleotides and polymers.2 White et al. introduced their work about the biocompatible nanocomposites and the use of 2D solid-state HETCOR NMR study to interrogate length scales of mixing in poly(lactic acid)/poly(caprolactone) blends.3 Foster et al. described the methodological advances of NMR spectroscopy for large macromolecules and a perspective on the wide range of applications of NMR to biochemical problems.4 Bargon and Kuhn presented the principles of CIDNP and the applications to both low molecular weight systems as well as macromolecular systems. The advantages of this method for investigation of the intermediate free radicals are emphasized.5 2H NMR studies about the order and dynamics of rod-like and banana-shaped liquid crystals are reviewed by Domenici. The recent developments about the molecular dynamics of the smectic phases of rod-like molecules and the unusual orientational and dynamics properties of the new liquid crystalline mesophases formed by banana-shaped molecules are reviewed.6 Works associated with MRI and drug delivery, especially concerning about the transport theory in porous media in advancing the progress in biomedical applications by Khanafer. The road for the researchers in the area of MRI and drug delivery to develop comprehensive models based on porous media theory is compared to other approaches.7 Recent developments in the diffusion of soft polymer systems, such as gels and liquid crystals, as studied by field-gradient NMR spectroscopy are reviewed.8

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 Poly(ether ester) is synthesized from 4 0 -hydroxybiphenyl-4-carboxylic acid and two different spacer diols (2-methyl-1,3-propanediol and R-1,3-butanediol).332 The thermotropic phase behavior of the poly(ether ester) is analyzed by DSC, X-ray a

Department of Textile and Apparel Science, Faculty of Human Life and Environment, Nara Women’s University, Kitauoyahigashimachi, Nara City, Nara 630-8506, Japan b Department of Chemistry and Chemical Biology, Gunma University, Kiryu, Gunma 376-8515, Japan


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Table 1 Polymer, monomer

Nucleus

(poly(glycidyl methacrylate)-graft-poly(methyl methacrylate))-graft-polystyrene,((poly(glycidyl methacrylate)-graft-poly(methyl methacrylate))graft-polystyrene)-graft-poly(butyl methacrylate) Poly[(triphenylmethyl)methacrylamide] Bis(dimethylsilyl)-m-carborane-siloxane polymer

H H,B,Si

C60-end-capped poly(Me methacrylate) Cellulose-cyclic ester, cellulose-L-lactide, cellulose-e-caprolactone Chitosan-graft-polyethylenimine Chondroitin-graft-poly(L-lactide)

C

H

Copolyester, L-lactic acid,bis-2-hydroxyethyl terephthalate Ethyl cellulose, silyl ether of ethyl cellulose Humin Hydroxyethyl cellulose-graft-poly(hexadecyl acrylate-co-styrene) Hydroxyethyl starch Lignin Lignite humic acid Methyl cellulose Methylcellulose N,N-di-Me-N-Et chitosan Nafion Nafion Natural rubber Poly (methyl methacrylate), poly (2-methylene-1,3dioxepane),poly (methyl methacrylate-co-2methylene-1,3-dioxepane) Poly (m-phenylene isophthalamide),terephthaloyl chloride Poly 3-(hydroxyalkanoates) Poly((9-ethyl-carbazol-6-yl)methyl methacrylate-comethyl acrylate)

H H

Poly((R)-2-(4-phenylazophenoxy)-n-prop-2-ynylpropionamide) Poly(1,8-octanediol-co-adipic acid-co-L-malic acid) Poly(1,3-diyne) Poly(1,4-bis(hydroxydiphenylsilyl)benzene), poly(4,4 0 -bis(hydroxydiphenylsilyl)biphenyl) Poly(1,5-dioxepan-2-one-co-e-caprolactone) Poly(1H,1H,2H,2H-heptadecafluorodecyl acrylate-co-2-hydroxyethyl acrylate) Poly(1-hexene) Poly(1-hexene) Poly(1-methylpropargyl alcohol), poly(1-methylpropargyl hexanoate), polyacetylene Poly(2-(dimethylamino) ethylmethacrylate), poly(2-(dimethylamino) ethylmethacrylate)-block-polystyrene, poly(2-(dimethylamino) ethylmethacrylate)-blockpoly(methylmethacrylate)

H

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

H

H

H C

H H,C H,F,C H H


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Contents

Ref.

Graft

9

Tacticity Composition, end group Tacticity, end group Regioselectivity

10 11

Composition Graft, composition Degradation Composition Composition Graft

14 15 16 17 18 19

Composition Composition Degradation Degradation Composition Composition Degradation Degradation Cross link Branch

20 21 22 23 24 25 26 27 28 29

Composition

30

Composition Composition, sequence distribution Configuration

31 32

Composition Configuration Cross link, degradation Composition Sequence distribution Tacticity Tacticity Configuration

34 35 36

Block, end group

12 13

33

37 38 39 40 41 42

Table 1 (continued ) Polymer, monomer

Nucleus

Contents

Ref.

Poly(2,5-bis[(4-methoxyphenyl)oxycarbonyl]styrene-co-2,5-di(n-butoxycarbonyl)styrene) Poly(2,6-dimethyl-1,4-phenylene oxide)

H

43

Poly(2-[3-(6-tetralino)-3-methylcyclobutyl]-2ketoethyl methacrylate-co-acrylonitrile), poly((2-[3-(6-tetralino)-3-methylcyclobutyl]-2ketoethyl methacrylate-co-styrene) Poly(2-{[(diphenylmethylene)amino]oxy}-2-oxoethyl methacrylate-co-styrene),poly(2-{[(1-phenyl-ethylidene)ami no]oxy}-2-oxoethyl methacrylate-co-styrene) Poly(2-aminoethyl methacrylate), poly(2-aminoethyl methacrylate-co-2-(diisopropylamino)ethyl methacrylate) Poly(2-formyl-4-vinylphenyl ferrocenecarboxylate) Poly(2-hydroxy ethyl methacrylate-co-methyl acrylate) Poly(2-hydroxyethyl methacrylate)-graft-poly(L-lactide), Poly(2-hydroxyethyl methacrylate)-graft-polystyrene Poly(2-hydroxyethyl methacrylate-co-acrylamide), poly(2-hydroxyethyl methacrylate-co-N-vinyl-2-pyrrolidone), poly(2-hydroxyethyl methacrylate-co-butyl methacrylate) Poly(2-isopropyl-2-oxazoline-co-2-ethyl-2-oxazoline) Poly(2-methacryloyloxyethyl methacrylate) Poly(2-methacryloyloxyethyl phosphorylcholine) Poly(2-methoxy ethyl acrylate-co-acrylonitrile)

H,C

Sequence distribution End group, regioregularity Composition

45

H,C

Composition

46

H

Degradation, cross link

47

H H H

End group Composition Molecular weight Composition

48 49 50

Composition Composition Composition Sequence distribution Reactivity ratio Composition

52 53 54 55

Regioregularity Branch Sequence distribution Sequence distribution, composition Composition Composition

58 59 60

62 63

Tacticity Regioregularity

64 65

H,C,F

Composition

66

H,C H

Composition End group

67 68

H

Composition

69

Poly(3-(2-cyano-ethoxy)methyl-methyoxetane-co-3(methoxy-(triethylenoxy))methyl-3-methyloxetane) Poly(3,5-dimethoxyphenyl methacrylate-co-methyl methacrylate) Poly(3-alkylthiophenes) Poly(3-ethyl-3-hydroxymethyloxetane) Poly(3-hydroxybutyrate-co-3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) Poly(3-hydroxybutyrate-co-3-mercaptopropionate-co3-hydroxypropionate), poly(3-hydroxybutyrate-co-3mercaptobutyrate) Poly(3-hydroxyoctanoate-co-3-hydroxy-9-carboxydecanoate) Poly(3-methacryloyloxystyryl-4 0 -methylphenyl ketone-co-methyl methacrylate) Poly(3-methyl-1-butene) Poly(3-octylthiophene-2,5-diyl-co-3-decyloxythiophene2,5-diyl) Poly(4-[oxy(tri(ethylene glycol))bromoisobutyryl]2,3,5,6-tetrafluorostyrene), poly(4-[oxy(tri(ethylene glycol))bromoisobutyryl]-2,3,5,6-tetrafluorostyreneco-2,3,4,5,6-pentafluorostyrene) Poly(4-biphenyl methacrylate-co-glycidyl methacrylate) Poly(4-bromostyrene),poly[(4-phenylethynyl)styrene]co-poly(4-bromostyrene),poly[(4-hexynyl)styrene]-copoly(4-bromostyrene) Poly(4-chloromethylstyrene-co-2-ethylhexyl acrylate), poly(4-chloromethylstyrene-co-1,1-dichloroethylene), poly(4-chloromethylstyrene-co-N-vinyl-2-pyrrolidone acrylonitrile), poly(4-chloromethylstyrene-co-methacrylonitrile)

H,C

H H H,C H H,C

H

H,C

H,C H,C

44

51

56 57

61


c



Nucleus

Contents

Ref.

Poly(4-methyl-1-pentene) Poly(4-nitro-3-methylphenyl methacrylate), poly(4-nitro-3-methylphenyl methacrylate-coglycidyl methacrylate) Poly(4-nitro-3-methylphenyl methacrylate-co-methyl methacrylate) Poly(5-(2,5-dimethyl-1,4-phenylene)penta-2,4dienylideneammonium chloride-co-N-2,5-dimethyl1,4-phenylene diaza[12]annulenium dichloride) Poly(5-(methacryloyloxyethylaminocarboxylmethyl)bicyclo[2.2.1]hept-2-ene) Poly(5,6-Benzo-2-methylene-1,3-dioxepane-co-2,3,4,5,6pentafluorostyrene) Poly(5-benzyloxy-trimethylene carbonate-co-1,4dioxan-2-one) Poly(8- and 9-(4-oxatricyclodecane-3-one) acrylate-co-2-ethyl-2-adamantyl methacrylate), poly(a-hydroxy-g-butyrolactone methacrylate-co-2methyl-2-adamantyl methacrylate-co-1-hydroxy-3adamantyl methacrylate) Poly(9,9-dioctylfluorene-co-1,1-dimethyl-3,4-diphenyl2,5-bis{7 0 -bromo-2 0 -(9,9-dioctyl)fluorene} silole) Poly(9,9 0 -dioctylfluorene-co-3,6-dimethoxy-9,9dimethyl-9-silafluorene)

C H,C

Stereoselectivity Composition

70 71

H,C

Composition

72

H

Composition

73

H

Configuration

74

Composition

75

H,C

Composition

76

H

Composition, sequence distribution

77

78

Poly(9-ethyl-3-hydroxymethylcarbazolyl acrylateco-methacrylonitrile) Poly(acrylamide tert-butyl acrylate), polyethyleneimine Poly(acrylamide-co-(3-acrylamidopropyl)trimethyl ammonium chloride-co-N-acryloyl valine), poly(acrylamide-co-(3-acrylamidopropyl)trime thyl ammonium chloride-co-N-acryloyl alanine), poly(acrylamide-co-(3-acryl-amidopropyl)trimethyl ammonium chloride-co-N-acryloyl aspartate) Poly(acrylamide-co-butylstyrene-2-acrylamid-2methylpropane sulfonate) Poly(acrylic acid) wrapped multi-walled carbon nanotube Poly(acrylonitrile-co-2-methoxyethyl acrylate)

H,C

Sequence distribution Composition, sequence distribution Reactivity ratio

80

C H,C

Cross link Composition

81 82

H

Composition

83

H

Composition

84

H

85

Poly(acrylonitrile-co-acrylic acid)

C

Poly(acrylonitrile-co-isobornyl-acrylate), poly(acrylonitrile-co-isobornyl methacrylate)

H

Composition, reactivity ratio Sequence distribution Reactivity ratio, composition, sequence distribution Composition Cross link Branch Composition, tacticity Branch

Poly(alkoxyamine ester) Poly(allyl methacrylate) Poly(allyl methacrylate), poly(undecenyl methacrylat) Poly(allyl methacrylate-co-butyl acrylate) Poly(amido amine), 1,3,5-triacryloylhexahydro-1,3,5triazine,n-butylamine Poly(amidoamine) Poly(a-olefin)

H

H,C

H,C


c


Cross link Irregularity

79

86 87

88 89 90 91 92 93 94


Nucleus

Contents

Ref. 95

H H,F

Branch, composition Composition Composition

96 97

H,C

Configuration

98

Composition

99

H

Composition, end group

100

Poly(aryl ether) Poly(arylene ether sulfone) Poly(arylene ether),2,8-dihydroxynaphthalene-6sulfonated salt, hexafluorobisphenol A, decafluorobiphenyl Poly(bis(4-pentenyl)diethylgermanium), poly(bis(4-pentenyl)dimethylgermanium), poly(bis(3-butenyl)diethylgermanium) Poly(butyl methacrylate)-block-poly[2-(acetoacetoxy)ethyl methacrylate] Poly(butyl acrylate-co-vinyl acetate), poly(methyl methacrylate-co-vinyl acetate), poly(buyle acrylate-comethyl methacrylate) Poly(butyl methacrylate-co-2-(dimethylamino)ethyl methacrylate), poly(butyl methacrylate-co-butyl acrylate), poly(butyl methacrylate-co-styrene) Poly(butylene adipate-co-butylene terephthalate)

H

composition

101

H

102

Poly(caprolactone)-block-poly(ethylene glycol) Poly(carbon monoxide-co-ethylene-co-styrene)

H C

H H,C H H

Composition, sequence distribution Composition Sequence distribution Sequence distribution Tacticity Composition Composition End group Composition End group Block

C H,C,P H H H

Composition End group Branch Degradation Molecular weight

113 114 115 116 117

H

Block

118

Degradation Sequence distribution, degradation Sequence distribution, composition Branch

119 120

Tacticity Composition Composition Sequence distribution

123 124 125 126

Poly(carbon monoxide-co-vinyl acetate) Poly(cyclohexyl methacrylate) Poly(cyclopropylidine-co-methylidine) Poly(D,L-lactide) Poly(dithiocarbamate), poly(xanthate) Poly(DL-lactide-co-RS-benzyloxyethyl-b-malolactonate) Poly(e-caprolactone) Poly(e-caprolactone)-block-chitooligosaccharideblock-Poly(ethylene glycol) Poly(e-caprolactone-co-L-lactide) Poly(e-caprolactone) Poly(e-caprolactone) Poly(e-caprolactone) Poly(e-caprolactone), silsesquioxane-based hybrid star polymer Poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone) Poly(ester amide) Poly(ester amide),poly(L-lactide),1,3-cyclohexylbis(methylamine), and sebacoylchloride

C

H

Poly(ester imide ketone),p-hydroxybenzoic acid

Poly(ester-amide), dicarboxylic acid, multihydroxyl primary amines Poly(ethyl 2-ylidene-acetate) Poly(ether ether ketone ketone) Poly(ether ether ketone) Poly(ether sulfone-co-ether ether sulfone)

H,C

H H C

103 104 105 106 107 108 109 110 111 112

121

122


c



Nucleus

Contents

Ref.

Poly(ether urethane)

C

Branch, end group End group End group

127

Poly(ethylene ethyl phosphate) Poly(ethylene glycol acrylate),poly(ethylene glycol acrylate)-block-poly(butyl acrylate) Poly(ethylene oxide) Poly(ethylene oxide)-2-hydroxypropylcellulose (PEO-HPC) Poly(ethylene succinate-co-trimethylene succinate)

H H,C

Poly(ethylene terephthalate),poly[ethylene 5,5 0 isopropylidene-bis(2-furoate)] Poly(ethylene terephthalate-co-butylene terephthalate)

C

Poly(ethylene) Poly(ethylene-1-dodecene)

C C

Poly(ethylene-co-1-hexene) Poly(ethylene-co-1-hexene)

C H,C

Poly(ethylene-co-1-octene), LLDPE

C

Poly(ethylene-co-4-methyl-1-pentene)

C

Poly(ethylene-co-butyl acrylate-co-13C-carbon monoxide) Poly(ethylene-co-norbornene)

H,C

Poly(ethylene-co-norbornene), poly(ethylene-co1-butene) Poly(ethylene-co-propylene)

H

C C C

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

C

Poly(ethylene-co-propylene)

C

Poly(ethylene-co-vinyl alcohol)

H

Poly(ethylenedioxyhiophene-co-dihexylfluorene)

H

Poly(ethylene-vinyl acetate)-graft-poly(maleic anhydride) Poly(ethylenimine) Poly(fluoroacrylate-co-lauryl methacrylate), poly(fluoroacrylate-co-methyl methacrylate) Poly(fluorooxetane),poly(fluorooxetane-co-THF)

H,C H


c


128 129

End group Composition Sequence distribution, Composition Sequence distribution Sequence distribution Branch Composition, sequence distribution composition Polymerization kinetics Sequence distribution Tacticity, regioregularity, sequence distribution Sequence distribution Composition, tacticity Configuration

130 131 132

Sequence distribution, reactivity ratio Branch, end group Sequence distribution Sequence distribution Composition, esterification Sequence distribution, composition Graft

144

150

Degradation Composition

151 152

Molecular weight, end group

153

133 134 135 136

137 138 139 140

141 142 143

145 146 147 148 149


Nucleus

Contents

Ref.

Poly(glycidyl methacrylate) Poly(glycidyl methacrylate-co-methyl acrylate), poly(glycidyl methacrylate-co-ethyl acrylate), poly(glycidyl methacrylate-co-buyle acrylate, poly(glycidyl methacrylate-co-methyl methacrylate, poly(glycidyl methacrylate-co-ethyle methacrylate), poly(glycidyl methacrylate-co-butyl methacrylate) Poly(glycolide-co-trimethylene carbonate)

H H

End group Composition

154 155

H

156

C H

End group, degradation Composition Branch Branch Composition Sequence distribution Composition Composition Degradation Composition Tacticity Composition, polymerization kinetics End group Sequence distribution Sequence distribution Tacticity, sequence distribution Composition Cross link, composition End group Tacticity End group End group End group End group, composition Tacticity Tacticity Composition Composition

H

Composition

184

H,C,P

Composition

185

H

Composition

186

Poly(hyaluronic acid)-graft-poly(adipic acid) Poly(isoprene) Poly(isoprene) Poly(lactide-co-glycolide)-grafted pullulan Poly(lactide-co-trimethylene carbonate)

H H H H

poly(L-glutamic acid), folic acid Poly(limonene-co-N-vinyl pyrrolidone) Poly(L-lactic acid), poly(DL-lactic acid), polyglycolide) Poly(L-lactic-co-glycolic acid) Poly(L-lactide) Poly(L-lactide-co-e-caprolactone)

H H H H H,C H,C

Poly(L-lactide-co-glycolide) Poly(L-leucine-co-L-aspartic acid-co-L-valine)

H C

Poly(maleic anhydride-alt-hexen-1) Poly(methacrylic acid)

H,C

Poly(methacrylic acid)-graft-poly(ethylene oxide) Poly(methacrylic acid-co-methyl methacrylate)

H H

Poly(methyl Poly(methyl Poly(methyl Poly(methyl Poly(methyl Poly(methyl

H

methacrylate) methacrylate) methacrylate) methacrylate) methacrylate) methacrylate)

H H H

Poly(methyl methacrylate) Poly(methyl methacrylate) Poly(methyl methacrylate) brush graft Poly(methyl methacrylate-co-1-(phenyl)-3-(2-acryloyloxyethyl)-3-Me triazene-1), poly(methyl methacrylate-co-1-(p-nitrophenyl)3-(2-acryloyloxyethyl)-3-Me triazene-1) Poly(methyl methacrylate-co-2-hydroxy4-(3-methacryloxy-2-hydroxylpropoxy)benzophenone) Poly(methyl methacrylate-co-2-methacryloxyethyl phenyl phosphate) Poly(methyl methacrylate-co-dodecafluoroheptyl methacrylate)

157 158 159 160 161 162 163 164 165 166 167

168 169 170 171

172 173 174 175 176 177 178 179 180 181 182 183


c



Nucleus

Contents

Ref.

Poly(methyl methacrylate-co-ethylene glycol dimethacrylate) Poly(monomethyl maleic ester)

H

Branch

187

H,C

188 189 190

Poly(N-(1-phenyldibenzosuberyl)methacrylamide) Poly(N-(4-bromophenyl)-2-methacrylamide-co2-acrylamido-2-methyl-1-propanesulfonic acid) Poly(N-(4-methoxy-3-chlorophenyl) itaconimide-comethyl methacrylate), poly(N-(2-methoxy-5-chlorophenyl) itaconimide-co-methyl methacrylate) Poly(N-(triphenylmethyl)methacrylamide),poly(N-[di(4-butylphenyl)-phenylmethyl]methacrylamide) Poly(N-acryloylcarbazole-co-methacrylonitrile)

H H,C

Sequence distribution Tacticity Composition

H

Composition

191

H

Tacticity

192

H,C

193

Poly(N-acryloylcarbazole-co-vinyl acetate) Poly(N-isopropylacrylamide) Poly(N-isopropylacrylamide) Poly(N-isopropylacrylamide-co-allylamine) Poly(N-isopropylacrylamide-co-dimethyl-cbutyrolactone acrylate) Poly(N-isopropylacrylamide-co-methoxy polyethyleneglycol monomethacrylate) Poly(norbornene-co-styrene)

H,C H H

Composition, sequence distribution Composition End group End group Composition Composition

194 195 196 197 198

H,C

Composition

199

H,C

Sequence distribution End group Molecular weight Sequence distribution Branch Sequence distribution

200

Poly(norbornene-co-styrene) Poly(N-tert-butyl acrylamide-b-N-acryloylmorpholine)

H

Poly(N-vinyl-2-pyrrolidone-co-methyl methacrylate)

C

Poly(p-chloromethyl styrene), poly(methyl methacrylate) Poly(p-dioxanone-co-caprolactone)-block-poly(ethylene oxide)-block-poly(p-dioxanone-cocaprolactone) Poly(perfluoroisopropenyl vinylacetate) Poly(phenylacetylene)-graft-poly(methyl methacrylate)

H H

Poly(phthalazinone ether sulfone ketone)-graft-poly(ethylene glycol) Poly(p-n-alkoxyphenylacetylene) Poly(p-phenylene vinylene)

F H H,C H

Poly(p-phenylenevinylene) Poly(propylene oxide)-block-poly(aryl ether sulfone)-poly(propylene oxide) Poly(propylene-co-1-hexene) Poly(propylene-co-disubstituted diallylsilane) Poly(propylene-co-hexacosene)

H H,C

C C

Poly(propylene-ran-1-butene) Poly(ricinoleic acid)

H,C H

Poly(sebacic anhydride-co-caprolactone)

H


c


201 202 203 204 205

Composition Configuration, graft Graft

206 207

Configuration Polymerization mechanism Composition Composition

209 210

Branch Stereoregularity Composition, branch End group Molecular weight Sequence distribution

213 214 215

208

211 212

216 217 218


Nucleus

Contents

Ref.

Poly(silyl ester) Poly(sodium N-undecanoyl leucylvalinate) Poly(styrene-block-caprolactone)

H

219 220 221

Poly(styrene-co-2-ethylhexyl acrylate) Poly(styrene-co-acrylonitrile) Poly(styrene-co-butadiene),poly(butadiene),polyisoprene Poly(styrene-co-butadiene-co-styrene)-graftpoly(maleic anhydride) Poly(styrene-co-butyl acrylate)

H C C C

Branch Stereoregularity Block, sequence distribution Composition Composition Composition Graft

Poly(styrene-co-divinylbenzene) Poly(styrene-co-itaconic acid) Poly(tetrahydroindene) Poly(trialkoxysilane-co-methyldialkoxysilane) Poly(trimethylene terephthalate-co-ethylene terephthalate) Poly(trimethylene-co-butylene terephthalate)

H H H Si C

Poly(trimethylolpropane-co-1,8-octanediol-coadipic acid) Poly(urea-urethane)-functionalized multiwalled carbon nanotubes Poly(urethane urea)

C

C

Poly(vinyl alcohol-co-vinyl levulinate)

H,C

Poly(vinylcarbazole-ran-styrene) Poly(vinylene-phosphine) Poly(vinylene-stibine),poly(vinylene-arsine)-alt(vinylene-stibine) Poly(vinylidene fluoride),poly(styrene-alt-maleic anhydrid) Poly(vinylidene fluoride)-b-poly(styrene)

H H,C,P H

Poly(vinylidene fluoride)-graft-poly(ethylene glycol) Poly(vinylidene fluoride-co-chlorotrifluoroethylene) Poly(vinylphosphonic acid) Poly(o-pentadecalactone-co-p-dioxanone)

H,C H,F H H,C

Poly[(9,9-bis(6 0 -bromohexyl)-2,7-fluorenylene)-alt1,4-phenylene], poly(2,7-fluorenylene-ethynylene)-alt1,4-(2,5-dimethyoxyphenylene-ethynylene) Poly[3-(4-alcoxyphenyl)thiophene] Poly[4-(phenylazophenoxymethyl)styreneco-4-(2-hydroxybenzophenoxymethyl)styrene-covinylphenol]-block-polystyrene, poly(vinylphenol)-blockpoly[4-(phenylazophenoxymethyl)styrene-co-4(2-hydroxybenzophenoxymethyl)styrene-co-styrene] Poly[cyclotriphosphazene-co-(4,4 0 -sulfonyldiphenol)] Poly[styrene-co-(4-vinylbenzyl alc.)]-graft-poly(caprolactone)

H

Sequence distribution Sequence distribution, tacticity Composition Configuration Sequence distribution Composition Molecular weight Graft Composition Regioregularity Sequence distribution Composition

H,C H

Regioregularity Composition

247 248

Cross link Graft, composition Configuration

249 250

H

H,C

F

H

Poly{5-[(5-ethynyl-1-naphthyl)ethynyl]-N,Ndimethylnaphthalen-1-amine}

Branch, composition Branch Composition End group Composition Sequence distribution Composition, sequence distribution Sequence distribution Graft

222 223 224 225 226 227 228 229 230 231 232

233 234 235 236

237 238 239 240 241 242 243 244 245 246

251


c



Nucleus

Contents

Ref.

Poly{6-[4-(4-ethoxyphenylazo)phenoxy]hexyl methacrylate}block-poly(ethylene glycol)-block-poly{6-[4(4-ethoxyphenylazo)phenoxy]hexyl methacrylate} polyacetylene, poly(1,2-methylenedioxybenzene)

H

Block, sequence distribution Configuration, composition Composition End group Branch Polymerization mechanism Composition Composition

252

H,C

Polyacrylamide Polyacrylonitrile Polyamide Polyamine

H,C H

Polyamine,silica polyamine composite Polyampholyte, acrylamide, 3-acrylamidopropyl)trimethyl ammonium chloride, N-acryloyl valine, N-acryloyl alanine, and N-acryloyl aspartate Polybutadiene Polybutadiene, poly(butadiene-co-styrene) Polybutadiene,epoxidation Polycaprolactone,2-decalone,e-caprolactone Polycaprolactone-graft-poly(glycidyl methacrylate)

C, Si H,C

H H H H

Polycarbonate, liquid crystalline Polycarbosilane Polycarbosilane,polydimethylsilane Polydimethylsiloxane Polydimethylsiloxane Polyester, poly(ethylene terephthalate), 5-tertbutylisophthalic acid, 1-3/1-4 cyclohexanedimethanol polyesteramides, diethanolamine, maleic anhydride, ethylene glycol Polyesters, 2,2-bis(hydroxymethyl)propanoic acid, tetra(hydroxymethyl)methane Polyether Polyether,3-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}methyl-3 0 -methyloxetane,3-hydroxymethyl-3 0 methyloxetane Polyethoxysiloxane Polyethylene Polyethylene Polyethylene Polyethylene Polyethylene Polyethylene

H,C H,Si H,Si

Polyethylene glycol, amino dendrimer Polyethylene, polypropylene, poly(ethylene-co-propylene)

H C

Polyethylene-block-poly(methyl methacrylate)

H

Polyfluorene Polyglycerol-chitosan Polyhexene, poly(4-methylpentene), poly(3-methylpentene) Polyimide,bicyclo[2,2,2]oct-7-ene-2,3,5,6tetracarboxylic dianhydride

Si H

c

254 255 256 257 258 259

260 261 262 263 264 265 266 267 268 269 270 271

Branch

272

H C

Branch Branch

273 274

H,Si C C C

Branch Branch Branch Branch Branch Branch Molecular weight Configuration Sequence distribution End group, composition Branch Branch Composition Composition

275 276 277 278 279 280 281

C

H,C


Molecular weight Molecular weight Reaction kinetics Composition Composition, graft Stereoregularity Composition Composition Cross link Composition Composition, molecular weight

253


282 283 284 285 286 287 288


Nucleus

Contents

Ref.

Polyisobutylene Polyisobutylene methacrylate-block-poly(2-(dimethylamino)ethyl methacrylate)-blockpolyisobutylene methacrylate Polylactide-block-poly(ethylene glycol), polylactideblock-poly(ethylene glycol)-block-polylactide

H,C H

End group Composition

289 290

H,C

Block, sequence distribution Graft, graft Tacticity Tacticity Branch Composition Composition Conformation

291

Polylactide-functionalized polyoxanorbornenes Polynorbornene Polynorbornene Polyphenylene Polyphenylene Polyphosphazene Polyphosphoester, bis(1,2-propylene glycol) fumarate, ethyl dichlorophosphate Polypropene Polypropylene

H,C C H,C H

C C

Polypropylene Polypropylene

C C

Polypropylene Polypropylene

H,C C

Polypropylene Polypropylene, poly(butylene), poly(hexene) Polypropylene, poly(ethylene-co-propylene)

C

Polypropylene,4-carboxybenzene sulfonyl azide

H

Polypropylene,poly(3-methyl-1-butene)

H,C

Polypropylene-block-polyethylene Polysaccharide Polysaccharide Polysaccharide Polysaccharide, Chlorella pyrenoidosa

C H,C,N

H,C

Polysilane

H,C,Si

Polysilsesquioxanes Polystyrene

C, F, Si H

Polystyrene Polystyrene Polystyrene Polystyrene and poly(t-butyl acrylate) Polystyrene, poly(a-methylstyrene), poly(4-methylstyrene), poly(4-methoxystyrene), poly(4-trimethylsilylstyrene), star branched polymer Polystyrene, poly(methyl methacrylate)

H C H

H

Tacticity Tacticity, oxidation Tacticity Oxidation, composition End group Degradation, oxidation Tacticity Tacticity Tacticity, composition Graft, composition Tacticity, regioregularity, end Group Composition End group Branch Branch Molecular weight, molecular weight distribution Configuration, conformation Composition Tacticity, conformation End group Tacticity End group End group Composition

End group

292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309

310 311 312 313 314

315 316 317 318 319 320 321 322

323


c



Nucleus

Polystyrene-block-poly(butyl acrylate)-block-polystyrene, poly(tert-butyl acrylate)-block-polystyrene-block-poly(tert-butyl acrylate) Polystyrene-block-poly(chloromethylstyrene)

H

Polytriazole,triphenylamine Polyurethane Polyurethane, isophorone diisocyanate, 1,4-butanediol Polyurethane-block-polystyrene Sulfonated poly(arylene ether)

C H H H

Sulfonated poly(phenylene oxide)

H

Contents

Ref.

End group

324

Molecular weight Configuration Cross link Composition Composition Sulfonation, composition Composition

325 326 327 328 329 330 331

and solid state 13C NMR. From NMR results, the solid state 13C NMR line shapes and TH1r are the same for the quenched and annealed samples, which indicates that the ordered phase (annealed sample) is not a three dimensional crystal, but mesophase which has a considerable degree of conformational disorder. The formation mechanism of a biaxial nematic phase of a polymer with laterally attached book-shaped molecule is investigated by deuterium NMR.333 Of the several parameters which affect the formation of the liquid crystal, it was found that the most important parameter is the dynamics of the polymer backbone. The liquid crystalline conducting polymers are synthesized with Ziegler-Natta, methathesis and rhodiumbased catalysts.334 Orientation behaviors of the polymers as well as the monomers were investigated using fused-state 13C NMR measurements with proton dipolar decoupling. From the analysis of chemical shift tensors, the order parameter and shielding anisotropy in the liquid crystalline phase indicate that liquid crystallineconjugated polymers uniaxially aligned due to the magnetically forced alignment of the liquid crystalline side-chain, giving rise to a monodomain structure.

4. Imaging and diffusion NMR microimaging was applied to investigate the diffusion of styrene into LLDPE in supercritical CO2.335 The concentration profiles of the styrene penetrants are measured in real time, and the results were fitted to a Fickian model for diffusion. Different oral delivery systems based on the thiolated polymer polycarbophilcysteine are compared. Magnetic resonance imaging was used to localize the point of release of the thiolated polymer from the application forms via the positive magnetic resonance signal from a gadolinium complex.336 Results showed that in comparison to conventional application forms the Eutex capsules led to 1.9-fold higher mucoadhesive properties of polycarbophil-cysteine when compared to application with a conventional enteric-coated capsule. The swelling of the compressed polymer and water penetration in the polymer matrix was studied by NMR imaging.337 The effects of formulation, size, compression force, and temperature on the diffusion behavior of water in tablets of crosslinked amylose starch were studied by NMR imaging. Gas-phase MRI experiments were carried out to investigate the structure of EPDM.338 The results indicate that a strong correlation between EPDM crosslinking and T1 of embedded SF6. The structure of foams and filled polymers can be analyzed by means of MRI.339 Average distances between particles are estimated by the use of the autocorrelation function and the spectrum of the autocorrelation function and the obtained information is important for the evaluation of the mechanical strength of filled polymers. 3D image patterns of phaseseparated poly(methyl methacrylate)/poly(styrene- ran-4-bromostyrene) blends were observed by 3D NMR microscopy and 3D X-ray microscopy.340 The phase304 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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separated structure of polymer blends by 3D NMR images was quantitatively consistent with that by 3D X-ray images. The relation between the performance of a self-humidifying H2/O2 polymer electrolyte membrane fuel cell and the amount and distribution of water by using 1H NMR microscopy was studied.341 The potential of using 1H NMR microscopy to obtain the absolute water content of the polymer electrolyte membrane is discussed and several recommendations for future research are provided. The effect of irradiation, in the wavelength range of 310–800 nm, on the diffusion of poly(oxyethylene) of different molecular weight embedded in various alginate matrixes has been investigated.342 The photochemcally induced cleavage of poly(oxyethylene) depends on the polymer concentration. The microstructural and diffusive properties of surfactant-containing poly(vinyl alcohol) cryogels have been characterized.343 The experimental data show that the polymer-poor phase contains more polymer than expected, suggesting that the spinodal decomposition during the freezing step of cryogel preparation is not complete or prevented by ice formation. NMR and ESR techniques are applied to study the effect of diffusion of fluids used as blowing agents for polyurethanes inside selected HIPS materials.344 Experimental results provided a clear demonstration of consistent solvent penetration inside the rubbery phase of the composite polymers. Membrane permeability of dispersed block copolymer vesicles is studied in the equilibrium state.345 It is found that the permeability for water strongly depends on the ethanol content in the dispersion. The effect of some amphiphilic diblock-copolymers and comb-polymers on a microemulsion system is investigated.346 NMR diffusometry yields the self-diffusion coefficients of all the components in the system. The diffusion experiments provide information about the microstructure of the bicontinuous microemulsion changes upon addition of the polymers. The preparation and properties of the multiple hydrogen-bonded complexes between polyamide dendrons and poly(4-vinylpyridine) are described.347 Both T1 and diffusion constant values suggest that the mobility of the dendron and P4VP in the complex is restricted by the formation of multiple hydrogen bondings in solution. Self-diffusion NMR spectroscopy and relaxometry have been employed to study fragrance encapsulation in water-soluble, amphiphilic star block copolymers.348 Diffusion coefficients of four different fragrance molecules in the free form and in the presence of the polymer have been determined and used to calculate the effective degree of encapsulation. 1H NMR spectroscopy has been applied to study the temperature and concentration-induced micellization of a poly(ethylene oxide) and poly(propylene oxide) triblock copolymer, Pluronic P105, in D2O solution.349 The hydrodynamic radius of the unimers and the micelles are determined to be 1.8 and 5.0 nm. The diffusion constants of the solvent and carboxylated acrylic copolymers in isopropanol have been investigated for a range of compositions of butyl methacrylate and methacrylic acid random copolymers have been studied.350,51 Polymer diffusion studies at different diffusion times showed that the diffusion constant decreased with increasing diffusion time. The structural influence on translational diffusion of 2,2,4-trimethylpentane through poly(styrene)-block-poly(ethene-co-but-1-ene)- block-poly(styrene) was studied using pulse field gradient (PFG) NMR coupled with lattice model simulation.352 Diffusion coefficients of Li ion353–355 and the diffusion behaviors of Nafion.356–357 are investigated. A lot of contrast agents for MRI were developed.358–381

5. Characterization of the synthetic macromolecules Using solid-state NMR methods the morphological behavior of poly[bis(trifluoroethoxy)phosphazene] was studied, employing four nuclei of interest—1H, 19F, 31P and 13C. Measurements on all four nuclei support that at ambient temperature the crystalline and amorphous phases coexist. Variable temperature studies showed that above T(1) = 90 1C only a single highly mobile phase exists, which is presumed to be the 2D mesophase. All four nuclei showed that when heat cycling the polymer, Nucl. Magn. Reson., 2008, 37, 293–326 | 305 This journal is

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repeatedly above T(1), an increase in crystallinity occurs with each cycle. For the first time 13C MAS NMR spectra, using high power 19F and 1H decoupling, were obtained, which exhibited the same behavior domain. Filtered 13C{1H, 19F} MAS spectra containing signal from the crystalline domain using the discrimination induced by variable amplitude mini pulses (DIVAM) sequence were measured. Heat treated and solvent cast material showed differences in these 13C spectra, that were consistent with a decrease in backbone conformations upon heating, suggesting an increase in the extended chain form corresponding to the g form. Analogous sensitivity to variations in crystal phase composition has not been seen previously using 1H, 19F and 31P methods, emphasizing the importance of 13C MAS methods to morphological studies of phosphazenes.382 The crystal structure and crystallization behavior of a series of poly(ester amide)s derived from L-tartaric acid, 1,6-hexanediamine, and 6-amino-1-hexanol were examined. The study included aregic polymers containing 5, 10, and 20% of ester groups in addition to the syndioregic polymer containing equal amounts of amide and ester groups. X-ray diffraction data revealed that all the aregic poly(ester amide)s adopt the same crystal structure as the parent polyamide made of L-tartaric acid, and 1,6-hexanediamine. In this structure, chains are slightly compressed and arranged as in the a-form of nylon 66. Solid-state NMR (NMR) revealed that ester groups are excluded from the crystal phase except for the case of the syndioregic polymer. Isothermal crystallization kinetics was analyzed according to the Avrami theory. Crystallization rates were found to decrease regularly with increasing contents in ester groups and with increasing crystallization temperature. Avrami exponent values close to 2 were found whereas spherulitic morphologies were observed by optical microscopy.383 (9-Ethyl-carbazol-6-yl)methyl methacrylate-methyl acrylate (E/A) copolymers of different compositions were prepared by solution polymerization by varying the molar feeding ratio using AIBN as initiator at 60 1C. The reactivity ratios calculated by Kelen-Tudos (KT) method were found to be rE = 1.16 0.02 and rA = 0.69 0.01 whereas those calculated from RREVM method were found to be rE = 1.18 and rA = 0.68. The molecular weights (Mw) and polydispersity index (PDI, Mw/Mn) were determined using GPC. Glass transition temperatures (Tg) for different compositions of E/A copolymers were determined using DSC. Copolymer molar outfeed ratio (FE) was calculated from 1H NMR spectra. The a-methyl, methine, backbone methylene, and quaternary carbon resonance signals of the copolymers were distinguished using 13C {1H}, DEPT-45, -90, and -135 NMR techniques. The a-methyl and b-methylene showed compositional and configurational sensitivity up to pentad and tetrad level, respectively, whereas methine showed only compositional sensitivity up to pentad level. Unambiguous assignments for 1H and 13C {1H} NMR spectra were done by correlating 1D (1H, 13C {1H}, DEPT) and 2D (HSQC, TOCSY) NMR data. The spectral assignments for carbonyl region were done by studying higher bond order couplings by heteronuclear multibond correlation (HMBC) spectra.384 Five elastomeric bis(dimethylsilyl)-m-carborane-siloxane polymers with methyl, Ph, and 2cyanoethyl ligands were characterized by 1H, 11B, 13C, and 29Si NMR (NMR) spectroscopy. All relevant chemical shifts are reported, whereas signal assignment was confirmed by 2D NMR spectroscopy. The chemical composition of the polymers was calculated from the 1H and 29Si NMR spectra. Only 29Si NMR spectroscopy was able to quantify the methoxy end group, from which the average molecular weughts were calculated. The copolymer Dexsil 300 turned out to have a regular microstructure, while the terpolymers Dexsil 400 and Dexsil 410 have only partly regular sequences. 11B NMR spectroscopy confirmed the m-carborane structure and revealed some low molecular weight impurities.385 The microstructure of poly(vinyl alcohol-co-vinyl levulinate) (VOH-VLA copolymer) was studied by 1H NMR and 13C NMR techniques. The sequence distributions could be obtained from the six methine triads observed in the 500-MHz 1H NMR spectra of the copolymers: the three methylene dyads and the three carbonyl triads observed in 125.6-MHz 13C NMR spectra of the copolymers. The reaction activity order of different tacticity 306 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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hydroxyl in PVA was found to be rr 4 mr 4 mm by investigating VOH-centered methine tacticity triads. The vinyl levulinate content (VLC), the number-average sequence length, dyad–triad relation and triad–triad relation (R) were calculated from methine triads, methylene dyads and carbonyl triads in 1H NMR and 13C NMR spectra successfully, and they were in good agreement with each other. The consistency of the dyad–triad and triad–triad relations shows that head to head or tail to tail fragments are hardly present in VOH-VLA copolymer.386 The local structure of sodium ions in poly(ethylene-ran-methacrylic acid) ionomer neutralized by sodium hydroxide has been investigated using 23Na MAS and multiple-quantummagic-angle-spinning (MQMAS) NMR techniques at a high magnetic field. Isotropic chemical shifts and quadrupolar coupling products of three kinds of nonequivalent 23Na ions, i.e., isolated, hydrated, and aggregated 23Na ions were estimated from peak positions in 23Na MQMAS spectra. The MQMAS technique at high magnetic fields is expected to be a powerful tool to investigate the local structure in amorphous systems containing quadrupole nuclei.387 Nearest-neighbor chain packing in a homogeneous blend of carbonate 13C-labeled bisphenol A polycarbonate and CF3-labeled bisphenol A polycarbonate has been characterized using a shifted-pulse version of magic-angle spinning 13C {19F} rotational-echo double-resonance (REDOR) NMR. Complementary NMR experiments have also been performed on a polycarbonate homopolymer containing the same 13C and 19F labels. In the blend, the 13C observed spin was at high concentration, and the 19F dephasing or probe spin was at low concentration. In this situation, an analysis in terms of a distribution of isolated heteronuclear pairs of spins is valid. A comparison of the results for the blend and homopolymer defines the NMR conditions under which higher concentrations of probe labels can be used and a simple analysis of the REDOR results is still valid. The nearest neighbors of a CF3 on one chain generally include a carbonate group on an adjacent chain. A direct interpretation of the REDOR total dephasing for the polycarbonate blend indicates that at least 75% of carbonate-carbon 13C F3 nearest neighbors are separated by a narrow distribution of distances 4.7 0.3 angstrom. In addition, analysis of the variations in REDOR spinning-sideband dephasing shows that most of the 13C F3 dipolar vectors have a preferred orientation relative to the polycarbonate main-chain axis. This combination of distance and orientational constraints is interpreted in terms of local order in the packing of the carbonate group of one polycarbonate chain relative to the isopropylidene moiety in a neighboring chain.388 Dehydration during temperatureinduced phase separation in D2O solutions of poly(vinyl methyl ether) (PVME), poly(N-isopropylmethacrylamide) (PIPMAm) and poly(N-isopropylacrylamide) (PIPAAm) was followed from time dependences of NMR spin–spin relaxation times T2 of HDO. Both the time characterizing the exclusion of the water from mesoglobules (manifested by the increase in T2 values) and the induction period which precedes the increase in T2 values, increased in the order PVME o PIPMAm o PIPAAm. For D2O solutions of PIPMAm/PVME (or PIPMAm/PIPAAm) mixtures a direct connection between the state of the mesoglobules (hydrated or dehydrated) formed by the component with lower LCST (PVME, PIPAAm) and the temperatures of the phase transition of the PIPMAm component was established by NMR spectroscopy.389 Graft copolymers of poly(2-vinylpyridine), P2VP, grafted to a backbone of poly(N-iso-Pr acrylamide), PNIPAM, are investigated concerning their thermosensitive behavior in aqueous solution. 1H NMR monitors the coil-to-globule transition by quantifyingthe fraction of mobile segments in the liquid state. Field gradient NMR diffusion studies reveal a decrease of the hydrodynamic radius with temperature as the LCST is approached. The LCST and the width of the transition of PNIPAM are increasing with grafting density and decreasing upon salt addn., which is attributed to electrostatic forces. The grafted segments become partially immobilized only for low grafting density. For high grafting density a fraction of the backbone segments remains mobile even above the LCST. 2H spin relaxation rates of the hydration water indicate the presence of water molecules with very slow Nucl. Magn. Reson., 2008, 37, 293–326 | 307 This journal is

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dynamics in the transition regime, whereas above and below the transition only fast water dynamics is found.390 The 1H NMR spectrum of poly(ethylenimine) (PEI) has been assigned using two-dimensional NMR correlation with the previously established assignment of the 13C spectrum. The oxidative thermal and UV degradation of PEI has been studied using mass loss measurements, and NMR and Fourier transform IR spectroscopy. Analysis of the spectra of the degradation products shows that the degradation process may readily be monitored, particularly by 13C NMR. The major products are formamide and other amide groups which may be understood in terms of chain scission and dehydration reactions of hydroperoxides.391 The hydrogen bond interaction of poly(4-vinylphenol) (PVF), ligated by a 20 mol/mol excess of pyridine-d5 (PD) in tetrahydrofuran-d8, with poly(4-vinylpyridine) (PVP) was studied using liquid and solid-state NMR and quantum mechanical calculations. Because of its cooperative interactions, PVP substitutes PD in its hydrogen bond with PVF, thus forming a PVF–PVP complex, which gradually precipitates from solution. On the basis of the 1H/13C NMR spin-diffusion experiments and density functional theory quantum calculations, the complex is shown to have the fairly regular structure of a polymer sheet with intermittent H-bond links between PVF and PVP chains. The cooperativity of PVP interaction with PVF was studied by measuring the dependence of the binding degree a of PVP on its polymerization degree (Pn, being 10, 17, 30, 36, 48, 65, and 84) at various PVP/ PVF molar ratios. The value of a was established indirectly by measuring the fraction of liberated PD using its 2H quadrupolar relaxation and pulsed fieldgradient spin-echo measurement of self-diffusion. The cooperativity is of a higher order and two-dimensional, i.e., dependent on both the polymerization degree of PVP and its ratio to PVF. A mathematical model of such two-dimensional cooperativity based chiefly on a proximity effect is suggested.392 The changes in the dynamic structure during temperature-induced phase transition in D2O/ethanol solutions of poly(vinyl methyl ether) (PVME) were studied using NMR methods. The effect of polymer concentration and ethanol (EtOH) content in D2O/EtOH mixtures on the appearance and extent of the phase separation was determined. Measurements of 1H and 13C spin–spin and spin–lattice relaxations showed the presence of two kinds of EtOH molecules: besides the free EtOH expelled from the PVME mesoglobules there are also EtOH molecules bound in PVME mesoglobules. The existence of two different types of EtOH molecules at temperatures above the phase transition was in solutions with polymer concentration 20 wt% manifested by two well-resolved NMR signals (corresponding to free and bound EtOH) in 13C and 1 H NMR spectra. With time the originally bound EtOH is slowly released from globular-like structures. From the point of view of polymer-solvent interactions in the phase-separated PVME solutions both EtOH and water (HDO) molecules show a similar behavior so indicating that the decisive factor in this behavior is a polar character of these molecules and hydrogen bonding.393 Three-dimensional HCACX and HCACX-HH-TOCSY NMR experiments (J. Magn. Reson., 2004, 168, 352) at 750 MHz have been used to investigate the resonance assignments and monomer sequence distributions of C-centered triads and pentads in poly(ethylene-co-buthyl acrylate-co-13C-carbon monoxide), poly(EBC) terpolymer prepared from 13C-labeled carbon monoxide. These experiments provide spectra with correlations among mutually coupled atoms with dCO plotted along the f1 dimension and dCA and dH of adjoining groups plotted along the f2 and f3 dimensions, respectively. The correlation among signals in three planes in a 3D NMR spectrum facilitates selective detection of the resonances from the structure fragments near the 13C labeled ketone carbonyl groups. Moreover, these experiments provide enormous spectral resolution, permitting the identification of numerous unresolved signals that are overlapped in 2D 1H–13C HMBC NMR spectrum. The correlation of resonances involving three different nuclei (dH, dCA, and dCO) provides unambiguous at. connectivity information in the polymer backbone that facilitates analysis of comonomer composition, stereo-sequence distribution and branching structures. 308 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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These experiments provide additional proof of the methods adopted to perform chemical shift assignments from 2D HMBC NMR experiments.394 Studying the dynamics of the polymer-plasticizer system poly(methyl methacrylate) (PMMA)/trim-cresyl phosphate (TCP), it is found that pronounced dynamic heterogeneities for the additive TCP with one- and two-dimensional 31P NMR spectroscopy, whereas the dispersion of the dynamics of the polymer PMMA, studied simultaneously with 2 H NMR, remains essentially unchanged upon addition of the plasticizer TCP, despite a large decrease in the correlation time. TCP molecules reorient isotropically even in a rigid polymer matrix at temperatures well below the glass transition of the plasticized PMMA. Taking advantage of the very large time window accessible with the stimulated echo technique for the 31P nucleus, it is shown that the orientational correlation functions of TCP change from Kohlrausch decays for pure TCP to quasilogarithmic decays in the mixture, which resemble those from recent simulations with a bead-and-spring model. Two-dimensional spectra for TCP show that the dynamic heterogeneities of the plasticizer are transient in nature.395 Some possibilities of NMR spectroscopy (mainly spin–spin relaxation) in investigations of hydration and other polymer-solvent interactions during the temperature-induced phase separation in aqueous polymer solutions were reported. A certain portion of water molecules bound in phase-separated mesoglobules was revealed. The residence time of the bound HDO for poly(vinyl methyl ether) (PVME)/D2O solution (c = 6 wt%) is 1.2 ms. With time a slow release of originally bound water from the respective mesoglobules was observed. For highly concentrated PVME/D2O solutions (c = 20–60 wt%), the residence time of bound HDO c 2.7 ms and fractions of bound water unchanged even for 70 h were found. A similar behavior as described above for water (HDO) was also found for EtOH molecules in PVME/D2O/EtOH solutions.396 Poly(vinyl butyral) (PVB) with different wt% water was studied gravimetrically as well as with 1H MAS NMR. The composition of PVB samples changes during MAS NMR because of the centrifugal force. As MAS time progresses, initially free water was removed fast but bound water also was gradually depleted. More water was diminished at faster spinning speeds, longer spinning time, higher temperatures, and higher initial water contents. As water in PVB was reduced, the chemical shifts and line widths of different types of water and also those of PVB changed. The results demonstrate that 1H MAS NMR carried out at 10 kHz in less than about 5 min is a convenient and sensitive technique to measure: (a) the content variations of different types of water in polymers, (b) the degree of the interaction of water and polymer, and (c) the mol. dynamics of the polymer. This study can be extended to different soft polymers with other small molecules than water in them.397 Hybrid Nylon 6/silica composites have been studied. The effect of silica ratio on miscibility was evaluated by nuclear relaxation measurements using low-field NMR. The silica ratio was found to influence its distribution in the polymer matrix. To better investigate the miscibility and interaction between both blend components the proton T1 and T2 relaxation times have been used. The NMR results showed that, with up to 20% of silica, there is compatibility due to a weak intermolecular interaction. The relaxation data indicated that the direct measurements of proton T1 and T2, using low-field NMR can be a powerful resource to evaluate polymer Ny6/Si composite systems.398 Low-field 1H NMR was used to characterize the components of polymer gels formulated with partly hydrolyzed polyacrylamide (HPAm) and Cr(III) acetate. Changes in the NMR relaxation times were used to characterize samples of polymer, cross-linker, polymer solutions, and cross-linker solutions in bulk and in porous media. The results obtained indicated that changes of HPAm concentration do not have a significant effect on the relaxation times,while changes in Cr(III) acetate concentration do. Therefore, the concentration of cross-linker is the most critical variable in the process of characterizing HPAm/Cr(III) acetate polymer gels using low-field 1H NMR.399 Deuteron T1 and T2 was studied as a function of hydration in homopolyglycine (PG) and homopolyproline (PP). Water deuteron relaxation rates in PG conform to a Nucl. Magn. Reson., 2008, 37, 293–326 | 309 This journal is

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hydration model involving two types of primary hydration sites where water is directly bonded to the polymer. Once these sites are filled, additional water only bonds to water molecules at the primary sites and in so doing affect their dynamics. PP exhibits an anomalous T1 and T2 hydration dependence which has been interpreted in terms of a cooperative water molecule-PP molecule helical conformational rearrangement which occurs once a certain hydration level is reached. The proposal of a water-PP structure is tested using molecule dynamics simulations.400 Oxidatively degraded polypropylene (PP) samples, with selective 13C labeling of the three carbon sites on the PP chain (tertiary, secondary, and methyl carbons), were analyzed with a suite of one- and two-dimensional solid-state 13C NMR (NMR) experiments that were used to assign several 13C resonances attributed to oxidationinduced functional groups. These NMR techniques, several of which were recently developed, included dipolar dephasing for MAS speeds Z 10 kHz, chemical shift anisotropy (CSA) filtering, SUPER NMR to separate quasi-static CSA patterns, and 1H–13C heteronuclear correlation (HETCOR). In the course of the study, NMR experiments which utilize the 13C CSA for resonance identification can be sensitive to sample temperature as a result of molecular motion-induced averaging of the CSA. These experiments have allowed hemiketal groups to be identified for the first time in oxidized PP. Possible mechanisms for the formation of hemiketals and other functional groups were discussed.401 A melt-state 13C NMR analysis of highly stereoregular polyolefins (isotactic polypropylene and isotactic poly(3-methyl-1butene))including minor end-group and regiodefect structures at very high temperatures above 300 1C have been carried out. The optimized resolutions under MAS and 1 H DD allow us to characterize stereodefect, regiodefect, and end-group structures, although the spectral resolution of melt-state NMR is still less than that of solution-state NMR. Nevertheless, a large sensitivity enhancement allows us to investigate the RD dependences of signal intensities dominated by T1H, T1C, and NOE behaviors. Consequently, it was possible to evaluate the components of structural defects and Mn at relatively short recycle delays of 0.5–2 s, thereby enabling the determination of Mn, regiodefect concentration, and stereoregularity even for insoluble polymers.402 Solution polymerization was carried out using AIBN as initiator at 60 1C and varying the molar in feed ratio to get different composition of 9-ethyl-3-hydroxymethylcarbazolyl acrylate-comethacrylonitrile (C/N). The molecular weight was determined using GPC. DSC was used to determine the Tg. 13C{1H}, DEPT-45, 90 and 135 NMR techniques were used to distinguish the a-methyl, methine, backbone methylene and quaternary carbon resonance signals of C/N copolymers. Correlation of 1D (1H, 13 C{1H}, DEPT) and 2D (HSQC, TOCSY, HMBC) NMR data were used to completely assign various overlapping and broad signals of C/N copolymers. Heteronuclear multi bond correlation (HMBC) studies were used to completely assign various nitrile resonances. The reactivity ratios calculated by Kelen-Tudos (KT) method were found to be rC = 0.31 0.03 and rN = 0.80 0.02 whereas those calculated from RREVM method were found to be rC = 0.35 and rN = 0.83, respectively.403 Carbon-13 high-resolution solid-state NMR techniques have been invaluable in elucidating the structure of regenerated cellulosic materials. Studies of a range of fibers have shown systematic changes in chemical shifts, which can be related to the influences of physical processing or chemical modification. A constrained curve fitting method has been applied, where the C4 spectral envelope is represented as the sum of contributions from polymer in ordered, partially-ordered and disordered environments, associatedd with differing conformational arrangements of the cellulose hydroxymethyl and glycocidic bonds. The empirical gamma-gauche effect seems likely to provide the best rationalization for the relationship between C4 shifts and conformational order, taking into account the increased range of bond angles in disordered environments. The quantification of proportions of polymer units within different conformational groupings will provide new insights into the development of supramolecular texture. This will allow 310 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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better appreciation of the relationships between fiber processing and ultimate fiber performance.404 Copolymers of 2-hydroxy ethyl methacrylate and methyl acrylate (H/M) of different compositions were synthesized by free radical bulk polymerization using azobisisobutyronitrile (AIBN) as an initiator under nitrogen atmosphere. The copolymers compositions were calculated from 1 H NMR spectra. The reactivity ratios for H/M copolymers obtained from a linear Kelen-Tudos method (KT) and nonlinear error-in-variables method (EVM) are rH = 3.31 0.08, rM = 0.23 0.00 and rH = 3.32, rM = 0.23, respectively. The complete spectral assignment of methine, methylene, methyl and carbonyl carbon regions in terms of compositional and configurational sequences of H/M copolymers was done with the help of 13C{1H} NMR, DEPT, two-dimensional HSQC along with TOCSY. Further, the assignments of carbonyl region were made with the help of HMBC spectrum.405 Multinuclear solid-state NMR was used to characterize the molecular structures in nylon 6-montmorillonite nanocomposites in comparison with the two pure components. Both the polymer and the clay were studied. 27Al two-dimensional multiple quantum magic angle spinning (MQMAS) measurements reveal the existence of an addnl. four-coordinated aluminum site in the nanocomposites compared to in the pure clay. This site is most probably induced by interactions of the polymer chains with the silicate surface. A highly mobile component is observed only in the 1H NMR spectra of all nanocomposite samples, whose relative content increases with increasing clay content and which is generated during the extrusion process. High-resolution 1H and 13C NMR spectra of these mobile molecules are recorded and assigned to be a tertiary amine that is formed during the melt extrusion process as a result of the loss of one methyl group of the organic modifier dimethyl di(hydrogenated tallow) ammonium ion. As a result of the presence of paramagnetic Fe3+ inside the clay, the proton T1 of the polymer is strongly influenced. This effect can be used to get information on the degree of clay exfoliation. At higher clay contents on average just two platelets are stuck together. With this, the distance between clay platelets is calculated and correlated with the analysis of TEM measurements. 15N CP/MAS spectra show an increase of the fraction of the c-crystalline phase at the cost of the a-crystalline phase upon increasing clay content.406 A comprehensive structural characterization of cross-linked insoluble poly(amidoamine) (PAA) networks was performed by high-resolution MAS NMR spectroscopy. Model samples with 20%, 40% and 80% crosslinking degrees were prepared and the best conditions to obtain high-resolution spectra in the gel phase determined. Whereas the samples with 20% and 40% crosslinking degrees could be exhaustively resolved and described, the sample with 80% crosslinking degree could not be characterized by this technique owing to insufficient mobility of the polymer segments. Even with this limitation, the method developed in this study can be reasonably considered as a general one, which enables exhaustive characterization of cross-linked PAA networks of biomedical interest.407 A new analysis method based on the 2D HSQC NMR sequence is presented, which can be applied for quantative structural determination of complicated polymers. The influence of T1 and T2 relaxations, off-resonance effects, coupling constants and homonuclear couplings are discussed. It was found that the T2 values measured on polymeric samples with the conventional HSQC-CPMG sequence could not be used to correct the errors caused by T2 relaxations during the polarization transfer delay. A unique way of selecting the proper internal standard reference signal(s) is therefore proposed to eliminate the major errors caused by T2 relaxations, resonance offsets, coupling constant deviations and homonuclear couplings. Two polymer samples, a cellulose triacetate and an acetylated lignin, were used to illustrate the principles. The methodological developed in this work is robust to instrument miss-setting and it can find widespread applications in areas where a quantitative analysis of structurally complicated polymers is necessary.408 Nucl. Magn. Reson., 2008, 37, 293–326 | 311 This journal is

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6. Polymer blend and dynamics of the synthetic macromolecules Hyperpolarized (HP) 129Xe NMR spectroscopy has been applied to high-impact porous polymers and copolymers obtained by the latest generation supported Ziegler-Natta catalysts. Hyperpolarized xenon gas rapidly flows into the open cavities and then penetrates the amorphous phases of polypropylene (PP) and ethylene-propylene copolymer (EPR) millimeter particles. Variable temperature HP 129Xe NMR demonstrated that xenon uptake is largely modulated by the motional state of the phases and is considerably reduced if glass transition is approached because the polymeric matrix becomes impermeable to the gas phase. This is an alternative method to detect the occurrence of the glass transition even in polymeric complex systems. The competitive absorption of xenon in PP and EPR microphases shows the morphology of the particles and the phase architecture. The intermixing of the phases at micrometer level was established on the basis of the xenon diffusion rates. 2D 129Xe EXSY experiments disclose the freshly polarized xenon exchange pathways from the free gas to the EPR phase and, later on, between the polymeric phases.409 Polymer blends of sulfonated poly(ether ether ketone) (SPEEK) and poly(ether sulfone) (PES) in N-methyl-2-pyrrolidinone (NMP) were prepared by solution casting. The investigation on water uptake, methanol uptake, permeability and proton conductivity has been conducted. The spin–lattice relaxation time in the rotating frame (TH1r) of PES/SPEEK blend was obtained from the results of CP/MAS solid state 13C NMR. SPEEK blended with PES resulted in increasing TH1r, indicating the mol. motion of polymer chain was reduced. The glass transition temperature of the PES/SPEEK blend membranes were predicted by the Kwei equation. PES plays an important role in the decreasing water uptake, methanol uptake and methanol permeability while enhancing the thermal stability of the blend membrane, which shows the feasibility for direct methanol fuel cell.410 The miscibility of CA/P(VP-co-MMA) blends was examined as a function of DS of CA and the VP fraction in the copolymer composition, in an extension of the previous studies on cellulose ester blends using P(VP-co-VAc) as a counter component. It was observed by DSC thermal analysis that when CA of DS r 2.5 and P(VP-co-MMA) of VP 4 30 mol-% were two blending components, most of the binary polymer systems were miscible, whereas the other combinations of DS and VP values led to an immiscible series of blends, a possible exception being the miscible pair of DS = 2.70 and VP = 100 mol-%. Results of FT-IR and solid-state 13 C CP/MAS NMR spectra measurements suggested the miscibility to be driven by the hydrogen-bonding interaction between the residual hydroxyls of CA and the carbonyls of VP units in P(VP-co-MMA), as in the case of CA/P(VP-co-VAc) blends where the range of miscible pairing of acetyl DS and VP fraction was rather wide. From evaluations of proton spin–lattice relaxation times in the NMR study, it was confirmed that the homogeneity of the miscible blends of CA/P(VP-co-MMA) was substantially on a scale within a few nanometers. To interpret the difference in the DS- and copolymer composition-dependence of the miscibility behavior between three blend systems, CA/P(VP-co-MMA), CA/P(VP-co-VAc), and CB/P(VP-coVAc), Krigbaum-Wall intermol. interaction parameters were estd. by solution viscometry for different polymer pairs pertinent to those blends. In particular, discussion took into consideration the effectiveness of an intramol. repulsive action between the two units (VP and VAc, or VP and MMA) constituting the vinyl copolymers.411 The segmental order and dynamics of polymer network chains in a filled, trimodal silicone foam network have been studied by static 1H multiple quantum (MQ) NMR methods to gain insight into the structure property relationships. The foam materials were synthesized with two different types of cross-links, with functionalities, j, of 4 and near 60. The network chains were composed of distributions of high, low, and medium molecular weight chains. Crosslinking was accomplished by standard acid-catalyzed reactions. MQ NMR methods have detected domains with residual dipolar couplings (hOdi) of near 4 and 1 krad/s 312 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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assigned to (a) the shorter polymer chains and chains near the multifunctional (j = 60) crosslinking sites and to (b) the longer polymer chains far from these sites. Three structural variables were systematically varied and the mechanical properties via compression and distributions of residual dipolar couplings measured in order to gain insight into the network structural motifs that contribute significantly to the composite properties. The partitioning and average values of the residual dipolar couplings for the two domains were observed to be dependent on formulation variables and provided increased insight into the network structure of these materials which are unavailable from swelling and spin-echo methods. The results of this study suggest that the domains with high cross-link density contribute significantly to the high strain modulus, while the low cross-link density domains do not. This is in agreement with theories and exptl. studies on silicone bimodal networks over the last 20 years. In situ MQ-NMR of swollen samples suggests that the networks deform heterogeneously and nonaffinely. The heterogeneity of the deformation process was observed to depend on the amt. of the high functionality crosslinking site PMHS. The NMR experiments shown here provide increased ability to characterize multimodal networks of typical engineering silicone foam materials and to gain significant insight into structure-property relationships.412 Molecular motion in ultradispersed polytetrafluroethylene obtained by special gasphase technology has been studied experimental and theoretical based on a temperature dependence of the second moment of 19F NMR spectra and the time of spin–lattice relaxation. The results of observations are interpreted as the consequence of reorientation motion of CF2 groups around the axis of macromolecules at low temperature and of translational motion of macromolecules in the high temperature region. Qualitative differences from the molecular motion in industrial polytetrafluoroethylene (teflon-4) were detected and parameters of dynamic processes determined.413 Segmental dynamic heterogeneity of short-chain grafted poly(dimethylsiloxane) (PDMS) on pyrogenic silica was studied using 1H NMR spin-diffusion. A double-quantum dipolar filter was employed for selection of the interface (rigid) region. One-dimensional spin-diffusion equations were solved numerically for a space distribution of spin diffusivity D(x) of the mobile PDMS chains. The degree of heterogeneity can be quantified by the parameters of Gaussian and exponential diffusivity distribution functions which yield similar diffusivities. The rigid and mobile domain sizes and spin diffusivities were correlated with the PDMS chain length, the temperature, and 1H residual dipolar couplings414. Proton solid-state NMR T2 relaxation analysis is used to study model oil-extended ethylenepropylene-diene rubber (EPDM) and thermoplastic vulcanizates (TPV) composed of polypropylene (PP), EPDM and oil. It is shown that the method allows selective characterization of crystalline and amorphous phases of PP, cross-linked EPDM, and oil in TPVs. The network density in the rubbery (EPDM) phase is determined in a wide range of the TPV compositions, as well as in the oil-extended EPDM vulcanizates containing different amount of oil. The entanglement density decreases with increasing oil content in oil-extended EPDM. This decrease can be described using a scaling approach. Molecular mobility of oil molecules decreases with increasing EPDM network density and is significantly lower than that of pure oil due to physical interactions with the host matrix. It is shown that the network density in the rubbery phase of TPV is composed of chemical cross-links, physical junctions at the EPDM/PP interface, and temporary and trapped chain entanglements. The density of chemical cross-links increases with the amount of cross-linker per weight unit of EPDM. The density of the physical junctions increases with increasing PP content. Crystallinity of PP in TPV is hardly affected by the TPV composition. A small fraction of oil molecules plasticizes the amorphous phase of PP and the plasticization effect is proportional to an oil:PP mass ratio in the TPV composition. Two NMR methods for improving the selectivity of the T2 relaxation analysis to different phases of TPV are evaluated. The methods are based on the inversion-recovery experiment and double-quantum (DQ) filtering of the decay of Nucl. Magn. Reson., 2008, 37, 293–326 | 313 This journal is

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the transverse magnetization relaxation. The DQ filtered T2 relaxation expt. improves the selectivity of the method and could open new possibilities for characterization of the network heterogeneity in rubbery materials. Some relationships between the TPV composition, network density, and mechanical properties are shortly discussed.415 13C NMR in solution and molecular dynamics simulations were used to discuss the respective roles of intramolecular constraints and intermolecular contributions in poly(di-n-alkyl itaconate)s (PDAI) with various side chain lengths. These polymers exhibit the unusual phenomenon of two distinct glass transitions when the alkyl sidechains contain at least six carbon atoms. Nuclear Overhauser enhancement and spin–lattice relaxation time measurements in solution for PDAI’s with different side-chain lengths clearly indicated the existence of a competition between internal plasticization and organization of the alkyl parts of the side chains. This organization decreases the flexibility of the long side chains and slows down the internal mobility of the main chain and carbonyl groups. Molecular modeling of the relative organization of two polymer chains demonstrates the strong tendency of the long alkyl parts to order and form discrete regions, which can be related to the existence of the second low-temperature glass transition in PDAI’s with long side groups.416 Solid-state NMR spectroscopy, relaxation measurements, and DSC were used to elucidate the structure and molecular dynamics in poly(ethylene-co-vinyl acetate) (EVA). Besides immobile orthorhombic and monoclinic crystalline phases, the third mobile crystalline phase (possibly the phase) of a considerable amount (36% of total crystalline phases) appears in EVA, which forms during roomtemperature aging as a result of secondary crystallization and melts at temperature somewhat higher than room temperature. Such a mobile crystalline phase has welldefined chemical shift and different molecular mobility from the orthorhombic phase. The mobile crystalline phase is characterized by rapid relaxation of the longitudinal magnetization, which is caused by conventional spin–lattice relaxation, while the slow relaxation of the longitudinal magnetization occurring in the orthorhombic phase is originated from the chain diffusion. The amorphous phase also contains two components: an interfacial amorphous phase and a melt-like amorphous phase.417 Variable-temperature high-resolution solid-state 13C NMR experiments were performed on poly(di-n-alkylitaconate)s in bulk. Temperaturedependent line broadenings resulting from either motional modulation of the 13 C–1H dipolar coupling or motional modulation of the chemical shift anisotropy were observed for each carbon atom of the polymer main chain and side chains. Similarly, independent determinations of the 13C–1H dipolar couplings and 13C chemical shift anisotropies demonstrated the existence of local motions in solid poly(di-n-alkylitaconate)s. All of these measurements led to a direct identification of the moving units that are involved in the various relaxations, which were previously investigated by using dielectric relaxation experiments.418 An improved proton NMR method for the real time measurement of the hard/soft ratio or the crystallinity, and the mobile-fraction dynamics, in phase-separated or semicrystalline polymers is presented. It avoids some difficulties associated with earlier approaches and can be applied on high- as well as inexpensive low-field instrumentation. A pulsed mixed magic-sandwich echo is shown to provide near-quantitative refocusing of the rigid contribution to the initial part of the free induction decay. This essentially removes the need to account for signal loss during the receiver dead time, and the method should thus be useful for a variety of applications where the magnetization distribution over differently mobile fractions is to be determined. The overall decay of the mobile signal of a semicrystalline polymer was found to exhibit significant field dependence, such that the apparent transverse relaxation function of the amorphous part is in a real-time expt. best characterized by a subsequent CarrPurcell-Meiboom-Gill pulse train. It is demonstrated to be mainly influenced by mobility, while instrumental effects play a minor role. The mobility of the amorphous fraction depends not only on the overall crystallinity, but also on the crystallization conditions, thus on the nanometer-scale morphology.419 29Si CP/ 314 | Nucl. Magn. Reson., 2008, 37, 293–326 This journal is

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MAS and 13C CP/MAS measurements were carried out for epoxy-silica hybrids treated at 200 1C and 300 1C. For each sample, the 29Si spin–lattice relaxation time was evaluated and compared with the corresponding values for reference samples prepared under the same conditions but without epoxy compound. This work clearly shows the sensitivity of the 29Si T1 to the morphology of composite materials. The mechanism of thermal decomposition is proposed on the basis of 13C CP/MAS experiments and analysis of changes of the 29Si T1 relaxation time.420 On the basis of solid-state NMR characterization of dynamics in two model salts, it can be drawn the analogy to the fuel cell membrane candidate, phosphoric aciddoped poly(benzimidazole), and conclude that phosphate anion dynamics contribute to long-range proton transport, whereas the mobility of the polymer itself is not a contributing factor. This is contrasted with emerging membrane candidates, which rely on fully covalently bonded acid donors and acceptors, and target high-temperature PEM fuel cell operation in the absence of liquid electrolyte. The hydrogenbonding structures of benzimidazolium phosphate and benzimidazolium methanephosphonate are established using X-ray diffraction paired with solid-state 1H DQF NMR. By comparing the dynamics of the phosphate and methanephosphonate anions with the dynamics of imidazolium and benzimidazolium cations, the relative importance of these processes in proton transport is determined. The imidazolium cation is known to undergo two-site ring reorientation on the millisecond time scale. In contrast, it is shown here that the benzimidazolium rings are immobile in analogous salts, on a time scale extending into the tens of seconds. It is demonstrated that the time scale of tetrahedral reorientation of the phosphate anions is comparably fast (50 ms). Moreover, the 31P CODEX NMR data clearly indicate a four-site jump process. In contrast, the methanephosphonate undergoes a three-site jump on a slower time scale (75 ms). A mechanism for a zigzag pathway of proton transport through the phosphonate salt crystallites is developed based on the 31P CODEX and 1 H variable-temperature MAS NMR data.421 The chain dynamics of short-chain perfluoropolyether melts confined in Vycor nanoporous media has been characterized by field cycling NMR relaxometry and the dipolar correlation effect. The slowdown of motions under confinement, leading to larger residual dipolar couplings, has been probed by looking at the quotient of stimulated and primary echoes. Using field cycling relaxometry, it has been shown that there is strong evidence of reptation-like motion, even for such short-chain polymers as shown by the frequency and molecular weight dependences of the spin–lattice relaxation time.422

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382 P. Hazendonk, C. Denus, A. Iuga, P. Cahoon, B. Nilsson and D. Iuga, Journal of Inorganic and Organometallic Polymers and Materials, 2006, 16, 343–357. 383 C. Regano, R. Marin, A. Alla, J. I. Iribarren, A. M. De Ilarduya and S. Munoz-Guerra, Journal of Polymer Science, Part B: Polymer Physics, 2006, 45, 116–125. 384 A. S. Brar and S. Gandhi, Journal of Applied Polymer Science, 2006, 102, 5595–5606. 385 H. Kaehlig and B. X. Mayer-Helm, Journal of Chromatography, A, 2006, 1131, 235–241. 386 Y. Wang, H. Ono, A. Ikeda, N. Hori, A. Takemura, T. Yamada and T. Tsukatani, Polymer, 2006, 7, 7827–7834. 387 Y. Yamamoto, M. Murakami, R. Ikeda, K. Deguchi, M. Tansho and T. Shimizu, Chemistry Letters, 2006, 35, 1058–1059. 388 D. Stueber, A. K. Mehta, Z. Chen, K. L. Wooley and J. Schaefer, Journal of Polymer Science, Part B: Polymer Physics, 2006, 44, 2760–2775. 389 L. Starovoytova and J. Spevacek, Polymer, 2006, 47, 7329–7334. 390 M. Rusu, S. Wohlrab, D. Kuckling, H. Moehwald and M. Schoenhoff, Macromolecules, 2006, 39, 7358–7363. 391 S. A. Idris, O. A. Mkhatresh and F. Heatley, Polymer International, 2006, 55, 1040–1048. 392 J. Kriz, J. Dybal and J. Brus, Journal of Physical Chemistry B, 2006, 110, 18338–18346. 393 L. Hanykova, J. Labuta and J. Spevacek, Polymer, 2006, 47, 6107–6116. 394 A. Al-Amri, S. K. Sahoo, M. Monwar, E. F. McCord and P. L. Rinaldi, Macromolecules, 2006, 39, 5768–5776. 395 D. Bingemann, N. Wirth, J. Gmeiner and E. A. Roessler, Macromolecules, 2007, 40, 5379–5388. 396 J. Spevacek and L. Hanykova, Macromolecular Symposia, 2007, 251, 72–80. 397 S. Y. Jeong and O. H. Han, Bulletin of the Korean Chemical Society, 2007, 28, 662–666. 398 M. Preto, M. I. B. Tavares and E. P. da Silva, Polymer Testing, 2007, 26, 501–504. 399 S. M. Vargas-Vasquez, L. B. Romero-Zeron and B. MacMillan, International Journal of Polymer Analysis and Characterization, 2007, 12, 115–129. 400 H. Peemoeller, J. A. Stanley, M. B. MacMillan, W. P. Weglarz, J. C. Bennett, J. M. Corbett, M. Hawton and R. Holly, Biopolymers, 2007, 86, 11–22. 401 D. M. Mowery, R. L. Clough and R. A. Assink, Macromolecules, 2007, 40, 3615–3623. 402 W. Hu, H. Hagihara and T. Miyoshi, Macromolecules, 2007, 4, 3505–3509. 403 A. S. Brar and S. Gandhi, Journal of Molecular Structure, 2007, 832, 26–37. 404 R. N. Ibbett, D. Domvoglou and M. Fasching, Polymer, 2007, 48, 1287–1296. 405 A. S. Brar, S. Hooda and A. K. Goyal, Journal of Molecular Structure, 2007, 828, 25–37. 406 M. Bertmer, M. Wang, M. Krueger, B. Bluemich, V. M. Litvinov and M. van Es, Chemistry of Materials, 2007, 19, 1089–1097. 407 R. Annunziata, J. Franchini, E. Ranucci and P. Ferruti, Magnetic Resonance in Chemistry, 2007, 45, 51–58. 408 L. Zhang and G. Gellerstedt, Magnetic Resonance in Chemistry, 2007, 45, 37–45. 409 R. Simonutti, S. Bracco, A. Comotti, M. Mauri and P. Sozzani, Chemistry of Materials, 2006, 18, 4651–4657. 410 H.-L. Wu, C.-C. M. Ma, F.-Y. Liu, C.-Y. Chen, S.-J. Lee and C.-L. Chiang, European Polymer Journal, 2006, 42, 1688–1695. 411 T. Ohno and Y. Nishio, Macromolecular Chemistry and Physics, 2007, 208, 622–634. 412 E. Gjersing, S. Chinn, J. R. Giuliani, J. Herberg, R. S. Maxwell, E. Eastwood, D. Bowen and T. Stephens, Macromolecules, 2007, 40, 4953–4962. 413 V. M. Buznik, A. I. Livshits, M. Ol’shevskii, A. R. Semenov and N. A. Sergeev, Journal of Structural Chemistry, 2006, 47, 668–673. 414 M. Bertmer, D. E. Demco, M. Wang, C. Melian, R. I. Marcean-Chelcea, R. Fechete, M. Baias and B. Bluemich, Chemical Physics Letters, 2006, 431, 404–409. 415 V. M. Litvinov, Macromolecules, 2006, 39, 8727–8741. 416 A.-C. Genix and F. Laupretre, Journal of Non-Crystalline Solids, 2006, 352, 5035–5041. 417 L. Wang, P. Fang, C. Ye and J. Feng, Journal of Polymer Science, Part B: Polymer Physics, 2006, 44, 2864–2879. 418 A.-C. Genix and F. Laupretre, Macromolecules, 2006, 39, 7313–7323. 419 A. Maus, C. Hertlein and K. Saalwaechter, Macromolecular Chemistry and Physics, 2006, 207, 1150–1158. 420 M. J. Potrzebowski, W. Ciesielski, K. Ganicz, J. Gluszek, B. Szczygiel, B. Kucharczyk and J. Masalski, Polish Journal of Chemistry, 2006, 80, 1185–1194. 421 J. W. Traer, J. F. Britten and G. R. Goward, Journal of Physical Chemistry B, 2007, 111, 5602–5609. 422 R. Kausik, N. Fatkullin, N. Huesing and R. Kimmich, Magnetic Resonance Imaging, 2007, 25, 489–492.


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NMR in living systems M. J. W. Prior DOI: 10.1039/b617234m

1

General applications and methodologies

1.1 Spectral editing An evaluation has been carried out on the use of proton-observed carbon-edited (POCE) NMR spectroscopy (MRS) for the detection of strongly coupled secondorder spin systems. The results showed that the multiplet signal for strongly coupled second-order spin systems at a specific proton chemical shift in POCE spectra does not necessarily directly reflect 13C enrichment of the carbon attached to that proton. The effect was demonstrated theoretically with density matrix calculations and simulations, and experimentally with measured POCE spectra of [3-13C]glutamate.1 A new double quantum filter for glutathione editing has been introduced. The new method has two major advantages compared to the conventional double quantum coherence filter: it eliminates the need for calibration scans for optimizing the signal yield, and it removes the influence of water saturation pulses on the quantification of the glutathione peak. Using point resolved spectroscopy (PRESS), the glutathione concentrations in the left and right parietal lobes of five healthy volunteers were determined to be 0.91 0.16 mM and 0.89 0.16 mM, respectively, in agreement with previous studies.2 Ultra-short echo-time (TE) stimulated echo acquisition mode (STEAM) spectroscopy and frequency selected refocused PRESS (MEGA-PRESS) edited spectroscopy have been used to measure ascorbate in the developing rat brain. Reliable quantification of ascorbate by LC-Model analysis of stimulated echo acquisition mode STEAM spectra was performed at 9.4 T. Ascorbate concentrations quantified from the STEAM spectra were in good agreement with concentrations calculated from MEGA-PRESS edited spectra. Ascorbate concentrations measured using STEAM decreased with increasing postnatal rat age in agreement with published values.3 A pulse sequence has been designed for the simultaneous detection of ascorbate and glutathione in the human brain at 4 T. Double editing with (DEW) MEGA-PRESS at 4 T detected resolved resonances from ascorbate and glutathione in the occipital lobe of four human subjects. The ascorbate and glutathione concentrations measured using LCModel analysis of DEW MEGAPRESS spectra were 0.8 0.1 and 1.0 0.1 mmol g 1, respectively. Apart from the effects of J-modulation at a common echo time (TE), double editing did not compromise sensitivity. To determine the extent to which the metabolised forms of ascorbate and glutathione contribute to DEW MEGA-PRESS spectra in vivo, chemical shifts and coupling constants for dehydroascorbate and oxidized glutathione were measured at physiologic pH and temperature. Dehydroascorbate did not contribute to the resonance for ascorbate at 3.73 ppm. However, oxidized glutathione does contribute to the glutathione resonance (3.0 ppm), though this contribution would be negligible under physiologic conditions.4 A new single-voxel proton MRS spectrally-selective refocusing method for measuring Glu and Gln in the human brain has been reported. The technique uses triple-resonance selective 180 degrees RF pulses with a bandwidth of 12 Hz implemented within the PRESS sequence for selective detection of Glu or Gln; the singlet from creatine plus phosphocreatine (tCr) was also acquired with this method for use as a reference during phase correction. 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, The Brain and Body Centre, University of Nottingham, Nottingham, UK NG7 2RD


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referenced to a tCr concentration of 8 mM.5 A single-voxel 1H NMR J-difference editing method for discriminating between the 1.31 ppm resonances of lactate (Lac) and threonine (Thr) in human brain in vivo at 3 T has been developed. One doubleband and two triple-band Gaussian 180 degrees RF pulses, with bandwidths of 15 Hz, are employed within an adiabatic-refocused double-echo localization sequence to simultaneously acquire signals from Lac, Thr and tCr. The Lac and Thr signals, extracted from three sub-spectra, were used to calculated the concentrations of Lac and Thr in the human occipital cortex; these were 0.47 0.07 and 0.56 0.06 mM, respectively, with reference to [tCr] of 8 mM.6 A technique has been proposed that is designed to remove signals that contribute unwanted modulation patterns in localised spectra of lactate. The method uses ‘‘inner volume saturation’’, which makes use of high bandwidth spatial pulses to remove the signal corresponding to the regions of the localized volume that contribute unwanted modulation patterns. The method was described theoretically and demonstrated experimentally at 3 Tesla in a phantom and a patient with acute stroke.7 A method for the detection of lactate in the presence of lipid signals has been proposed. The method was developed in phantoms and then used to measure lactate in the brains of rats following middle cerebral artery occlusion. The technique relies on the difference between the transverse relaxation rate of lipid compared to that of lactate. A long TE was used in a 1H STEAM sequence to detect lactate, without interference from lipid signals, in the rat brain.8 1.2 Data reproducibility, acquisition and processing The precision of single-voxel PRESS data has been characterized from measurements in the anterior cingulate and hippocampus of a healthy subject. Data acquisition was replicated 10 times after voxel repositioning and readjusting higher order shims. Measurements showed that the scan-to-scan precision was better in anterior cingulate than in hippocampus, with an average coefficient of variance of 9.2% for N-acetylaspartate-containing compounds (NAA), choline-containing compounds (Cho) and tCr in anterior cingulate; there was an average coefficient of variance of 13.9% for these compounds in the hippocampus. Variability measurements made by the same method in 24 healthy subjects and in 29 schizophrenia patients showed that there is substantial biological variability in metabolite levels, even in healthy subjects. The authors suggest that more than 200 subjects would be needed to detect a 5% difference in NAA between patients and controls.9 A new CSI data acquisition strategy and reconstruction algorithm (natural linewidth CSI) has been presented that eliminates effects of magnetic field inhomogeneity-induced inter-voxel signal leakage and intra-voxel phase dispersion on acquired data. The approach uses information from 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 compartments10 A simple modification of the Hadamard RF pulse synthesis, that exploits its unique ability to encode non-contiguous slices, has been proposed. Computer simulation, in vitro and in vivo experiments were used to confirm the theoretical derivation of voxel bleed reduction from similar to 17% to below 5% per Hadamard-encoded direction11 A new post-acquisition processing method has been proposed that selectively removes unwanted lipid signals from 1H magnetic resonance spectra used for the measurement of intramyocellular lipid (IMCL). The method is based on the spectral localization by imaging technique. The effectiveness of this lipid measurement method has been demonstrated by computer simulation and in vivo experiments in the human calf.12 A processing environment has been described that integrates and automates processing and analysis functions for image reconstruction of proton metabolite distributions in the normal human brain. The capabilities of the method include normalization of metabolite signal intensities and transformation into a 328 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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common spatial reference frame, thereby allowing the formation of a database of human metabolite values measured by MRS as a function of acquisition, spatial and subject parameters.13 A magnetic resonance spectroscopic imaging (MRSI) method has been developed that uses an online-optimized acquisition of k-space has been developed to reduce acquisition time without sacrificing spatial resolution. The method uses a scout image to generate an optimized set of phase encodings to reduce the acquisition time of the MRSI sequence. Reconstruction and processing software was also developed in-house to process and reconstruct MRSI using the projections onto convex sets method. Data was collected from phantoms and in vivo with an approximately 80% reduction in acquisition time.14 The use of a radial basis function neural network for fast quantification of phase corrected spectra has been explored. The method was tested on simulated and normal human brain data acquired at 3 T. The ratios of NAA/tCr, Cho/tCr, Glx/tCr, and myo-inositol/tCr (mI/tCr) in normal subjects were compared with a line fitting technique, jMRUIAMARES analysis and published values. The average NAA/tCr, Cho/tCr, (Glu + Gln)/tCr (Glx/tCr) and mI/tCr ratios in normal controls were found to be 1.58 0.13, 0.9 0.08, 0.7 0.17 and 0.42 0.07, respectively. The corresponding ratios using line fitting and jMRUI-AMARES methods were 1.6 0.11, 0.95 0.08, 0.78 0.18, 0.49 0.1 and 1.61 0.15, 0.78 0.07, 0.61 0.18, 0.42 0.13, respectively. The results agreed with those published. The computational time for the radial basis function neural network method was 15 s.15 A revised model, describing the relationship between glial and neuronal energy metabolism has been proposed, which takes into account recent results from tracer studies to produce a more comprehensive description.16

1.3 Quantification and hardware A review of methods for the determination of absolute metabolite concentrations in 1 H MRS single-voxel spectra and chemical shift images obtained using a clinical system has been produced.17 A methodological development for quantitative short-echo-time in vivo 1H NMR spectroscopy (1H MRS) without water suppression has been described that integrates experimental and software approaches. Alterations to the phase cycling, pulse sequence timings and gradients parameters were used eliminate frequency modulation sidebands and first-order phase errors. The dominant water signal was modelled and extracted by the matrix pencil method and was used as an internal reference for absolute metabolite quantification. Spectral fitting was performed by combining the baseline characterization by a wavelet transform-based technique and time-domain parametric spectral analysis using full prior knowledge of the metabolite spectra obtained from simulations. The performance of the methodology was evaluated by Monte Carlo studies, phantom measurements and in vivo measurements on rat brains. More than 10 metabolites were quantified from spectra measured at TE = 20 ms on a 4.7 T-system.18 The use of tissue water as a concentration standard in 1H MRSI studies on the brain has been presented; potential errors that may arise with the method were also examined. Different image segmentation approaches that are commonly used to account for partial volume effects (SIPM2, FSL’s FAST, and Kmeans) were tested and lead to different estimates of metabolite levels. A multispectral segmentation approach using FAST yielded the lowest inter-subject variability in the estimates of grey matter metabolites. In this analysis, the mean levels of NAA, Cho and tCr in grey matter were 17.16 1.19, 3.27 0.47 and 13.98 1.20 mM, respectively. Mean levels in white matter were 14.26 1.38, 2.65 0.25 and 7.10 0.67 mM, respectively.19 A novel construction protocol for sample-specific passive shims has been presented. These are comprised of diamagnetic (bismuth) and paramagnetic (zirconium) materials. A prototype shim was constructed and shown to significantly improve the Nucl. Magn. Reson., 2008, 37, 327–356 | 329 This journal is

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field homogeneity in the mouse brain at 9.4 T. Further field-homogenization capabilities were simulated through alteration of the shim construction.20

2

Cells

2.1 Mammalian Metabolite profiling of 1H MRS spectra has been used to investigate the metabolic changes associated with deletion of the gene for the transcriptional co-activator p300 in the human colon carcinoma cell line HCT116. Multivariate statistical methods were used to distinguish between metabolite patterns in extracts of cells. In the absence of serum, wild-type cells showed slower growth and a marked decrease in phosphocholine concentration, which was not observed in otherwise isogenic cell lines lacking p300. In the presence of serum, several metabolites were identified as being significantly different between the two cell types. Localized in vivo 1H MRS measurements on the tumours formed following s.c. implantation of these cells into mice showed an increase in the intensity of the peak from Cho in the tumours lacking p300.21 The NMR-visible mobile lipid signals of C6 glioma cells have been monitored in cell pellets by 1H MRS. Mobile lipid signals increase from log phase (4 days of culture) to post-confluence (7 days of culture). This was paralleled by the percentage of cells containing epifluorescence detectable Nile Red stained cytosolic oil droplets. The arrest of proliferation of C6 cells induced by deprivation growth factors deprivation induced an even higher accumulation of cytosolic droplets and an increase of the mobile lipid signal. When neutral lipid content was quantified by thin-layer chromatography on total lipid extracts of C6 cells, no statistically significant change could be detected in major neutral lipid containing species, except for diacyl glycerol, which decreased in post-confluent, 7-day cells.22 The use of the fluorinated lysine derivative Boc-Lys-(Tfa)-OH as an indicator of histone deacetylase activity has been investigated using 19F MRS. Furthermore, 31P MRS was also used to monitor phosphorous metabolites in PC3 cells treated with the histone deacetylase inhibitor p-fluoro-suberoylanilicle hydroxamic acid. When PC3 cells treated with p-fluoro-suberoylanilicle hydroxamic acid up to 10 mmol dm 3, histone deacetylase activity dropped, reaching 53% of control values at 10 mmol dm 3. In parallel, a steady increase in intracellular Boc-Lys-(Tfa)-OH from 14 to 32 fmol cell 1 was observed. Boc-Lys-(Tfa)-OH levels negatively correlated with histone deacetylase activity. 31P MRS detected an increase in phosphocholine from 7 to 16 fmol cell 1 following treatment, which negatively correlated with histone deacetylase activity.23 Biomarkers of the inhibition of phosphoinositide 3kinase signalling in human breast cancer cells have been detected using 31P MRS. Changes in phosphocholine and glycerophosphocholine levels were detectable in the spectra of intact MDA-MB-231 cells following exposure to LY294002. Furthermore, MDA-MB-231, MCF-7, and Hs578T cells were treated with LY294002 and metabolite changes were monitored in spectra of cell extracts. LY294002 treatment was associated with a significant decrease in phosphocholine levels and a significant increase in glycerophosphocholine levels, whereas the content of glycerophosphoethanolamine, when detectable, did not change significantly.24 Water exchange across the plasma membrane of erythrocytes has been studied with high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. Erythrocytes were dispersed and immobilized within a matrix made of cross-linked albumin and a single exchange-averaged peak for water was detected in 1H HR-MAS NMR spectra. Line-shape analysis, according to a two-site exchange model, was used to investigate transmembrane exchange kinetics and yielded a residence lifetime of about 10 ms (at 37 1C) for a water molecule within the intracellular compartment. The results were in agreement with the generally accepted value of 9.6–14.8 ms.25 330 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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2.2 Bacteria Studies using HR-MAS NMR for investigations of intact bacteria, with reference to technical consideration and current limitations in have been reviewed.26 High resolution MAS NMR has been used to follow the activation of ethionamide directly within living mycobacterial cells. The results indicated that the intracellular metabolism of ethionamide depends on the presence of the monooxygenase EthA. However, 2-ethyl-4-hydroxymethylpyridine, a previously identified metabolite of ethionamide, was produced in substantial amounts by the ethionamide-treated mycobacteria but it was present exclusively outside of the bacteria. In contrast, a still unidentified ethionamide metabolite (ETH*) was the only ethionamide derivative detected within the bacterial cell. Furthermore, ETH* appears to be unable to cross the bacterial envelope and consequently accumulates within the cytoplasm of the ethionamide-treated mycobacteria.27

3

Plants

The influence of hypoxia and anoxia on cytoplasmic pH (pHcyt), vacuolar pH (pHvac), glucose-6-phosphate and nucleoside triphosphate (NTP) contents in rice (Oryza sativa L.) root tips, compared with those in wheat (Triticum aestivum L.) root tips has been investigated with 31P MRS. Both cereals responded to hypoxia by rapid cytoplasmic acidification (from pH 7.6–7.7 to 7.1), which was followed by slow partial recovery (0.3 units after 6 h). Anoxia led to a dramatic drop in pHcyt of both species (from pH 7.6–7.7 to less than 7.0) but partial recovery took place in rice only. In wheat, the acidification continued to pH 6.8 after 6 h of exposure. In both plants, NTP content followed the dynamics of pHcyt. The amount of glucose-6-phosphate increased in rice under anoxia and hypoxia. In wheat, glucose-6-phosphate was not detectable under anoxia but increased under hypoxia.28

4

Tissues

4.1 Brain The turnover kinetics of [4-13C]glutamate has been measured using in vivo 1H 13Cedited MRS at 11.7 T in an investigation into changes in the tricarboxylic acid (TCA) cycle flux rate in the primary somatosensory cortex of a-chloralose anesthetized rats during electrical forepaw stimulation. The peak for [4-13C]glutamate at 2.35 ppm was spectrally resolved from overlapping resonances of [4-13C]glutamine at 2.46 ppm and [2-13C]g-aminobutyric acid at 2.28 ppm. The results showed a significantly increased TCA cycle flux rate in focally activated primary somatosensory cortex during forepaw stimulation, corresponding to approximately 51 27% increase in cerebral oxygen consumption rate.29 A 13C MRS method based on INEPT polarisation transfer has been used to detect dynamic 13C isotopomer turnover from intravenously infused [U–13C]glucose in a 211 mm3 voxel located in the adult rat brain. The sequence used a combination of outer volume suppression, image selected in vivo spectroscopy (ISIS), and a single-shot three-dimensional localization scheme built into the INEPT pulse sequence to detect isotopomer patterns of glutamate C4 at 34.00 ppm and glutamine C4 at 31.38 ppm. These peaks were dominated first by a doublet originated from labelling at C4 and C5, but not at C3, and then by a quartet originating from labelling at C3, C4 and C5. A lag in the transition of glutamine C4 from dominance by the doublet to dominance by the quartet was observed when compared to the transition of glutamate C4.30 The kinetics of glial Gln transport into the extracellular fluid, and the mechanism of transport of glutamine from the extracellular fluid (GlnECF) into the neuron, has been studied in the mildly hyperammonemic rat brain by MRS and microdialysis to monitor intra- and extracellular glutamine, respectively. The minimum rate of glial Gln efflux, determined from the rate of the increase of GlnECF during perfusion of Nucl. Magn. Reson., 2008, 37, 327–356 | 331 This journal is

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alpha-(methylamino)isobutyrate was 2.88 0.22 mmol g 1 h 1 at a steady-state brain Gln concentration of 8.5 0.8 mmol g 1.31 The incorporation of 13C label from [13C]glucose into amino acids in the rat brain has been monitored using localized 13C MRS without the application of 1H decoupling at 9.4 Tesla. The spectra were analysed using LCModel quantification with prior knowledge of onebond and multiple-bond J(CH) coupling constants. This analysis resulted in an uncertainty in the measurement of metabolites concentrations of 35% to 91% higher compared to that decoupled spectra depending on the carbon resonance of interest.32 The pseudo first-order rate constant for the flux of pyruvate to lactate in the rat brain has been measured in vivo using 13C MRS. An infusion of [2-13C]glucose was used to allow labelling of pyruvate C2 at 207.9 ppm. During systemic administration of bicuculline to increase lactate levels, the pseudo first-order rate constant for the flux of pyruvate to lactate was determined to be 0.08 0.01 s 1 in halothaneanesthetized adult rat brain. In 9 L and C6 rat glioma models, the 13C saturation transfer effect of the lactate dehydrogenase reaction was also detected in vivo.33 1 H MRS has been used to measure the uptake and clearance of ethanol in the rat brain and to estimate the effects of acute alcohol on brain metabolites. The observed time course of alcohol concentration in the brain followed a consistent pattern characterized by a rapid absorption, an intermediate distribution and a slower clearance that approached a linear decay. The intercept of the linear clearance term, extrapolated back to the time of injection, correlated well with the administered dose per unit of lean body mass. Estimates of alcohol concentration from 1H MRS were compared with blood alcohol levels from blood samples. Serial proton spectroscopy measurements provided an in vivo method for quantifying brain alcohol uptake and elimination kinetics in real time.34 The rise in cortical g-aminobutyric acid (GABA), and the time taken to reach steady-state levels, have been measured using localized 1 H MRS in anesthetized rats following treatment with vigabatrin. Rates of GABA synthesis were estimated from the accumulation of [2-13C]GABA for the period of constant GABA levels following a 20 min infusion of either [1,6-13C2] glucose or [2-13C]acetate. Increased GABA concentrations did not appear to cause inhibition of glutamate decarboxylase or reduced synthesis from [1,6-13C2]glucose. Fractional changes in steady-state GABA levels and GABA transaminase activities 5–6 h after vigabatrin treatment were approximately equal.35 31P and 1H MRS have been used to monitor changes in brain metabolites following intravenous administration of cytidine diphosphocholine (CDPCholine). Twelve healthy rats were treated with CDPCholine in three doses of 1 g kg 1. There was a statistically significant increase of the Cho/tCr ratio after first CDPCholine injection.36 The effects of chronic hypoglycaemia on brain glucose and glycogen have been measured in the rat brain using localized 13C MRS. Hypoglycaemia was maintained for 12 to 14 days by implantation of insulin pellets. Following an infusion of [1-13C]glucose, concentrations of glucose and glycogen were measured in vivo and in extracts. Brain glucose was significantly increased by around 48% in chronic hypoglycaemic rats compared to controls. There was a minor increase in brain glycogen content measured in vivo and in extracts.37 The use of ultra-short echo time (TE = 2 ms) MRSI to detect intracranial mobile lipids in the rat brain has been developed. High-performance outer volume suppression and pre-localization were demonstrated in phantoms and by the total absence of signals arising from extra-cranial lipids in MRSI spectra from control rats. The sequence performance was tested on BDIX rats implanted with a glioma. Fast-relaxing lipid signals were spatially varied within a glioma during herpes simplex virus thymidine kinase-mediated gene therapy.38 The technique of ultra-short TE MRSI has also been used for the identification and analysis of mobile cholesterol compounds in the same experimental glioma model. The cholesterol compounds comprised up to 17 mol% of MRS visible total lipids.39 A diffusion-weighted stimulated echo acquisition mode sequence has been implemented to measure the apparent diffusion coefficient of glutamate in the monkey brain. Echo time and mixing time were adjusted too maximise the signal from 332 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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glutamate. The data was obtained from a 5.8 cm3 voxel, made of gray and white matter, in macaque monkey brain. The effect of post-processing on the estimated apparent diffusion coefficient was carefully taken into account; individual scan phasing and macromolecule subtraction corrected for B25% and B15% of biases, respectively, in the apparent diffusion coefficient of glutamate. The apparent diffusion coefficients for Glu, NAA, tCr, Cho and mI were 0.21 0.03 mm2 ms 1, 0.15 0.04 mm2 ms 1, 0.12 0.03 mm2 ms 1, 0.11 0.05 mm2 ms 1 and 0.18 0.04 mm2 ms 1, respectively.40 The effect of isoflurane dose on the apparent diffusion coefficient of 5 metabolites in the monkey brain has been evaluated using diffusion tensor spectroscopy. All of the detected intracellular metabolites exhibited a significant increase in their apparent diffusion coefficient when the isoflurane dose varied from 1% to 2%. The changes were: 13% 8% for mI, 14% 13% for NAA, 20% 18% for Glu, 27% 7% for tCr and 53% 17% for Cho. Detailed analysis of changes in the apparent diffusion coefficient experienced by the five different metabolites suggested a facilitated metabolite exchange between subcellular structures at high isoflurane dose.41 Measurements of T1 and T2 relaxation times for water, cellular metabolites and macromolecules have been made in the rat brain at 4.0, 9.4 and 11.7 Tesla. Water relaxation showed a highly significant increase in T1 and a decrease in T2 with increasing field strength in nine brain structures. Similar but less pronounced effects were observed for all metabolites whilst macromolecules displayed field-independent T2 relaxation and a strong increase of T1 with field strength.42 1H NMR spectra have been obtained from wild-type mouse brains at post natal days 5, 10, 15 and 21. Developmental changes of metabolite concentrations were measured in the thalamus, the olfactory bulb and the cerebellum. The voxel size varied from 2 to 8 mm3 according to the size of the brain structure analysed. The absolute concentrations of the tCr, taurine, Cho, NAA and Glx. Variations observed during brain development were in accordance with those previously reported in mice using ex vivo MRS studies.43 Magnetic resonance imaging (MRI), 31P and 1H MRS have been used to characterize the cerebral morphologic and metabolic endophenotypes of C57BL/6J, FVB/N and 129/SvJ mice. Great variability in the volume of ventricles, cerebellum and hippocampus was observed between these strains. In addition, distinct 1H MRS metabolic profiles were obtained from each strain, showing particular variability in NAA and Cho levels. Furthermore, significant differences in high-energy phosphates and phospholipids were detected.44 Changes in relaxation times, lipid accumulation, and elemental distributions in the brain of rats subjected to 15 min of middle cerebral artery occlusion have been assessed using magnetic resonance imaging, 1H MRS and synchrotron radiation X-ray fluorescence. The results showed that a delayed (2 weeks after ischemia) increase in T1-weighted image intensity in the ischemic striatum is associated with significant increases in manganese, calcium and iron, but without evident accumulation of NMR-visible lipids or hydroxyapatite precipitation. It was also found that 15 min of middle cerebral artery occlusion results in an acutely reduced NAA/tCr ratio in the ipsilateral striatum, which recovers to the control level at 2 weeks after ischemia45 The effects of chronic constant hypoxia and chronic intermittent hypoxia on the rat brain have been assessed with 1H MRS measurements of NAA/tCr. Mice exposed to intermittent hypoxia for 4 weeks demonstrated a significant decrease in the NAA/tCr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 weeks of normoxia. However, mice exposed to 4 weeks of constant hypoxia did not demonstrate any differences in the NAA/tCr ratio compared to controls46 The effects of stem cells on the outcome of transient middle cerebral artery occlusion in the rat have been investigated using MRS and MRI and histology. Human mesenchymal stem cells (SH2+, SH3+, CD34( ), and CD45( )) immortalized with a human-telomerase gene (hTERT-MSCs) and transfected with eGFP or LacZ were introduced into rats 12 h after induction of transient middle cerebral artery occlusion (MCAO). Intravenous delivery of hTERT-MSCs reduced Nucl. Magn. Reson., 2008, 37, 327–356 | 333 This journal is

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lesion volume. The magnitude of the reduction and functional improvement was positively correlated with the number of cells injected. The reduction of lesion size was assessed in vivo with T2-weighted MRI and MRS measurements of lactate and NAA. These measurements correlated with subsequent histological examination of the brain47 The neurochemical profile of the striatum in the R6/2 mouse model of Huntington’s disease has been measured at different stages of pathogenesis using in vivo 1H MRS at 9.4 T. Between 8 and 12 weeks, R6/2 mice exhibited distinct changes in a set of 17 quantifiable metabolites compared with littermate controls. Concentrations of tCr, glycerophosphorylcholine, Glu and glutathione increased and NAA decreased at 8 weeks. By 12 weeks, concentrations of phosphocreatine (PCr), taurine, ascorbate, Glu, and mI increased and phosphorylethanolamine decreased.48 The activity of creatine kinase (CK) and the function of mitochondrial respiratory chain in a rat model of Huntington’s disease has been investigated. Dynamic 31P MRS was used for determination of the pseudo-first order rate constant of the forward creatine kinase reaction and steady-state 31P MRS was used to detect the levels of phosphorous metabolites and intracellular Mg2+. Polarographic assessment of respiratory chain function was carried out in isolated mitochondria, whilst the concentration of CoQ(10) and alpha-tocopherol were measured using high performance liquid chromatography. A significant elevation of pseudo-first order rate constant was found in brains of 3-nitropropionic acid-treated rats. Furthermore, the function of respiratory chain in the presence of succinate was severely diminished. The tissue content of CoQ(10) was decreased in 3-nitropropionic acid-treated rats. Administration of CoQ(10) plus vitamin E prevented the increase of pseudo-first order rate constant and the decrease of CoQ(10) content in brain tissue, but were ineffective to prevent the decline of respiratory chain function.49 The effects of pharmacological manipulation of the endocannabinoid system during adolescence have been investigated in rats following early maternal deprivation. Wistar male rats, maternally deprived for 24 hours on postnatal day 9, were administered the fatty-acid amide hydrolase inhibitor URB597 (0, 0.1 or 0.5 mg kg 1 day 1) for six days during adolescence and tested in the intolerance-to-delay task. Deprived adolescent rats showed a trend for higher impulsivity levels and an increased locomotor response to novelty when compared to controls. The low dose of URB597 effectively decreased impulsive behaviour specifically in deprived subjects. Long-term metabolic brain changes, induced by drug treatment during adolescence, were detected by 1H MRS in deprived animals. However, significant changes were only found within the hippocampus; the level of NAA and tCr were increased following a low dose URB597, whereas Glu and Glx decreased following the higher dose.50 The role of the 65-kDa isoform of glutamate decarboxylase (GAD(65)) in activity-dependent GABA synthesis invoked by seizures has been investigated in anesthetized rats. GABA synthesis was measured following acute GABA-transaminase inhibition by gabaculine using spatially localized 1H MRS before and after bicuculline-induced seizures. Experiments were conducted with animals pre-treated with vigabatrin 24 h earlier in order to reduce the 67-kDa isoform of glutamate decarboxylase (GAD(67)) and also with non-treated controls. GAD isoform content was quantified by immunoblotting. GABA was higher in vigabatrin-treated rats compared to non-treated controls. In vigabatrin-treated 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 vigabatrin-treated rats. GAD(67) could account for at least half of basal GABA synthesis but only 20% of the twofold increase observed in vigabatrin-treated rats during seizures. Measurements by 31 P MRS showed that seizure-induced activation of GAD(65) in control cortex occurs concomitantly with a 2.3-fold increase in inorganic phosphate, known to be a potent activator of apoGAD(65) in vitro.51 The impact of chronic insulin-deficient diabetes mellitus on mitochondrial respiratory chain and creatine kinase function 334 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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has been investigated in the brains of diabetic, middle-aged rats. Furthermore, the effects of long-term administration of coenzyme Q10, or the combination of omega-3 polyunsaturated fatty acids and coenzyme Q10, on these functions were examined. Diabetes mellitus was induced in 11-month old male Wistar rats by streptozotocin; coenzyme Q10 or omega-3 polyunsaturated fatty acids and coenzyme Q10 were administered i.p. daily for 3 months. The pseudo first-order rate constant of the forward creatine kinase reaction, determined in vivo by phosphorus 31P MRS saturation transfer, was increased. Respiration and ATP production in brain mitochondria, monitored using Clark-type oxygen electrode, showed a decreased glutamate-supported rate of mitochondrial ATP production. Administration of omega-3 polyunsaturated fatty acids and coenzyme Q10 prevented the decrease of respiratory chain function. Coenzyme Q10 alone did not improve the parameters of ATP production despite its increased concentration in brain mitochondria. Both administrations prevented the increase of creatine kinase system activity in the brain of diabetic rats.52 The relationships between aging, hippocampus and memory have been investigated using a combination of behavioural, non-invasive MRI and MRS, and post-mortem neuroanatomical measures. Age related changes have been investigated in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344 Brown Norway hybrid rats. Aging was associated with functional deficits in hippocampus-dependent memory tasks, accompanied by structural alterations observed in MRI measurements of hippocampal volume and post-mortem analysis of neuronal density and neurogenesis in the dentate gyrus. However, levels of NAA were preserved.53 4.2 Eye The effects of increased intraocular pressure on retinal ganglion cell damage, nerve fibre layer thickness and vitreous lactate concentrations have been investigated in a rabbit model of ocular hypertension. 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. In group II, 6 rabbits received an equal volume injection of vehicle only. The contralateral eye served as a control in both groups. Intraocular pressure was measured for two pretreatment days and then on post-treatment days 1, 3, 5, 7, 9, 16, 23, 30, and 37. 1H MRS was used to measure changes in vitreous lactate concentrations, post-mortem histochemical analysis at the light microscope level was used to quantify changes in the retinal nerve fibre layer thickness and in the numbers of retinal ganglion cell. Baseline intraocular pressure in Group I control and treated eyes were 12.0 1.9 and 12.5 1.3 mmHg, respectively. Between days 5 and 9 post-treatment, the intraocular pressure in Group I treated eyes rose to 23.9 4.2 mmHg. Vitreous lactate levels in Group I treated eyes increased by 100%, from pre-treatment values. Levels in control eyes remained unchanged. Group II control and treated eyes showed no significant changes in either intraocular pressure or lactate. Group I treated eyes had a reduced nerve fibre layer thickness at the temporal medullary ray. A smaller reduction was found in the nasal medullary ray areas. Retinal ganglion cell numbers also were decreased in the treated eyes, most likely due to apoptosis.54 4.3 Tissues heart The use of 31P and 1H MRS in the study of metabolic changes that occur in heart failure in patients and experimental animal studies has been reviewed.55 A study has been carried out into the possible cardioprotective effects of low concentrations of carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone (FCCP), a mitochondrial protonophore. The drug was used to bypass the mitochondrial ATP sensitive potassium channel (K-ATP) channel and partially uncouple the Nucl. Magn. Reson., 2008, 37, 327–356 | 335 This journal is

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mitochondria to establish whether this activates protective pathways within the rat heart analogous to K-ATP channel openers or preconditioning. Isolated, Langendorff-perfused rat hearts were pre-treated with FCCP (30–300 nM) in the presence or absence of glibenclamide (1 mM), 5-hydroxydecanoate (5-HD: 100 mM), N-acetyl cysteine (4 mM), or N-2-mercaptopropionyl glycine (1 mM) and then subjected to 25 min global zero-flow ischaemia. The metabolic consequences of FCCP perfusion were studied using 31P MRS, and reactive oxygen species (ROS) production was measured using DCF fluorescence in isolated rat ventricular myocytes. FCCP exerted a dose-dependent cardioprotective effect, with 100 nM FCCP being the optimal concentration. This effect could not be blocked by glibenclamide or 5-HD, but was completely attenuated by N-acetyl cysteine and N-2-mercaptopropionyl glycine. Perfusion with FCCP (100 nM) did not deplete bulk ATP during the pretreatment period but significantly depleted phosphocreatine. In ventricular myocytes, FCCP caused an antioxidant-sensitive increase in ROS production but diazoxide was without effect.56 The effects of combined blockade of the Na+ channel and Na+/H+ exchanger on ionic homeostasis has been investigated in the perfused rat heart. High energy phosphates and pH, and Na+i were measured using 31 P and 23Na MRS, respectively. Eniporide (3 mM) and/or lidocaine (200 mM) were administered 5 min prior to 40 min of global ischemia and 40 min of drug free reperfusion. Lidocaine reduced the rise in Na+i during the first 10 min of ischemia, followed by a rise in Na+ levels with a rate similar to the one found in untreated hearts. Eniporide reduced the influx of Na+ during the entire ischemic period. Administration of both drugs resulted in a summation of the effects found in the lidocaine and eniporide groups. Contractile recovery and infarct size were significantly improved in hearts treated with both drugs, although this was not significantly different from the recovery in hearts treated with either drug.57 The effects of an intravenous infusion of adenosine plus lidocaine (AL) on myocardial high-energy phosphates and pH in the left ventricle during ischemia-reperfusion have been investigated using 31P MRS. The AL solution was administered 5 min before and during 30 min coronary artery ligation. Two control rats died from ventricular fibrillation, but no deaths were recorded in AL-treated rats. There was no significant difference in the heart rate, mean arterial pressure, and rate-pressure product between the control and AL treated rats during ischemia and reperfusion. Furthermore, there was no significant difference in the level of ATP throughout the experiment in controls that survived and AL-treated rats. In contrast, PCr was significantly reduced in controls compared with AL-treated rats during ischemia and reperfusion. Changes in intramyocardial pH between each group were not significantly different during ischemia and fell by about 1 pH unit to 6.6. During reperfusion, pH in AL-treated rats recovered to baseline in 5 min but returned to only around pH 7.1 in controls.58 The effects of knockout of the K+ ion-selective subunit of the K-ATP cardiac sarcolemmal channel have been investigated in the Langendorff-perfused mouse heart. 87RB and 31P MRS were used to measure K+ fluxes and high energy phosphates, respectively. A comparison with control C57BL6 hearts demonstrated that the Kir6.2 knockout resulted in a lack of stimulation of the unidirectional potassium efflux from the hearts when K-ATP channels were activated metabolically by 2,4-dintrophenol. Furthermore, the knockout hearts had lower ATP levels that became more pronounced when the hearts were subjected to stress. A significantly higher reduction of cytochrome c oxidase in response to 2,4dintrophenol was detected using optical spectroscopy in knockout hearts, which also had a blunted response to isoproterenol stimulation.59 The relationship between insulin resistance and ischemic damage has been investigated in the chronically infarcted Wistar rat heart. Left ventricular ejection fractions in vivo were 40% lower in rats 10 weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated [2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and 336 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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with fasting plasma free fatty acids concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and 31P MRS detected 35% lower PCr in infarcted hearts. During 32-min ischemia, ATP was hydrolysed by 12% in control hearts and by 40% in infarcted hearts. Recovery of left ventricular developed pressure was 42% lower and PCr recovery was 55% lower in infarcted hearts during reperfusion compared to that in controls.60 31 P MRS has been used to study a new heart preparation consisting of left ventricular slices superfused with extracellular medium. The ratio of PCr/ATP in the slices was close to 2.1 and the intracellular pH and [Mg2+]i were comparable with those found under condition of retrograde perfusion. A significant increase in [Mg2+]i was detected when extracellular Na+ was removed.61 Pulsed field gradient MRS has been used to measure the endogenous myoglobin translational diffusion coefficient in the perfused rat myocardium. At 22 1C, the diffusion coefficient was 4.24 10 7 cm2 s 1.62 Furthermore, the temperature-dependent diffusion of myoglobin in perfused rat myocardium has also been measured. Myoglobin had an averaged translational diffusion coefficient of 4.24 8.37 10 7 cm2 s 1 from 22 1C to 40 1C and showed no orientation preference over a root mean-square displacement of 2.5–3.5 mm. The temperature-dependent diffusion of myoglobin agreed with the value predicted by rotational diffusion measurements.63 4.4 Tissue muscle The distribution of IMCL within the rat tibialis anterior muscle has been investigated using single-voxel 1H MRS in vivo and compared with the muscle fibre distribution in the tibialis anterior muscle determined from immunohistological assays. Levels of IMCL in the tibialis anterior muscle 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 emerged in a pattern similar to the distribution of the predominantly oxidative muscle fibre types. There was no significant change the typical fibre type-dependent pattern of IMCL content when rats were fed on a high fat diet for 7 days or starved for 15 h before examination.64 A perfused preparation for evaluation of metabolism in pig intercostal muscle has been investigated with 31P MRS. Preserved vessels and nerves to an intercostal segment, including two adjacent ribs, allowed for tissue perfusion and electrical stimulation with measurement of contraction force and oxygen consumption. When the preparation was perfused at rest with Krebs-Ringer buffer, it maintained physiological levels of PCr, inorganic phosphate (Pi) ATP and pH at a stable oxygen consumption of 0.51 0.01 mmol min 1 g 1 for more than 2 hours. Tonic stimulation of the nerve caused a reduction in anaerobic energy consumption, PCr and pH. During stimulation, force increased to 0.040 N g 1 (range, 0.031–0.103 N g 1) and it gradually decreased by about 70% during the subsequent 5 min of stimulation. The calculated free ADP concentration increased from 7.4 2.1 nmol g 1 at rest to 28 12 nmol g 1 by the end of the stimulation. Anaerobic ATP turnover was zero at rest, 6.1 2 mmol min 1 g 1 during the first minute of stimulation and 3.5 0.5 mmol min 1 g 1 during the two last minutes, corresponding to the drop in force. The level of PCr and pH recovered after the contraction with half-time values of around 7 min. When the preparation was left unperfused, anaerobic ATP turnover averaged 0.40 0.15 mmol min 1 g 1 for the first 10 minutes.65 4.5 Tissue tumour Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells have been examined by 1H and 31P MRS before and after treatment with MN58b (an inhibitor of choline kinase) in cultures and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P o 0.05) was observed in vitro in both cell lines after Nucl. Magn. Reson., 2008, 37, 327–356 | 337 This journal is

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MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDAMB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58h treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels and choline kinase activities following MN58b treatment. Phosphomonoesters also decreased significantly (P o 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. Examination of tumour extracts showed a significant decrease in phosphocholine (P r 0.05).66 The response of radiation-induced fibrosarcoma 1 tumours treated with the vascular-disrupting agent ZD6126 has been assessed by in vivo and ex vivo 1H MRS methods. Tumours treated with 200 mg/kg ZD6126 showed a significant reduction in total Cho, in vivo, 24 hours after treatment, whereas control tumours showed a significant increase in Cho. High-resolution MASS NMR and 1H MRS of metabolite extracts revealed a significant reduction in phosphocholine and glycerophosphocholine in biopsies of ZD6126-treated tumours. The diffusion of water in tumour tissue and measurements of lactate levels in vivo showed no significant changes in response to ZD6126. Spin–spin relaxation times of water and metabolites also remained unchanged.67 The effects of carbogen breathing on tumour blood plasma volume, pH, and energy status, and on the uptake and metabolism of 5-fluorouracil (5FU) has been investigated in two colon tumour models (C38 and C26a), which differ in their vascular structure and hypoxic status. 31P MRS was used to assess tumour pH and energy status whilst 19F MRS was used to follow 5FU uptake and metabolism. The results showed that carbogen breathing significantly decreased extracellular pH, increased tumour blood plasma volume and increased 5FU uptake in tumours. These effects were most significant in the C38 tumour line, which has the largest relative vascular area. In the C26a tumour line, carbogen breathing increased tumour growth delay by 5FU. Carbogen breathing also enhanced systemic toxicity by 5FU.68 The use of hexamethyldisiloxane as a probe for investigating dynamic changes in tissue oxygen tension (pO(2)) has been evaluated. Hexamethyldisiloxane has a single proton resonance and the spin–lattice relaxation rate exhibits a linear dependence on the partial pressure of oxygen (PO2). Hexamethyldisiloxane was administered into healthy rat thigh muscle and tumours. Local PO2 was determined from the T2 relaxation rate measured using pulse-burst saturation recovery 1H MRS. Water and fat signals were effectively suppressed by frequency-selective excitation of the hexamethyldisiloxane resonance. When the rats breathed air, the mean baseline PO2 in thigh muscle was 35 11 torr, with a typical stability of 3 torr over 20 min. A significant increase in PO2 to 100–200 torr was achieved by altering the inhaled gas to oxygen. In tumours, altering the inspired gas also produced significant, though generally smaller, changes.69

4.6 Tissue reproductive Localized in vivo 1H MRS using the STEAM sequence with a short TE has been used to measure metabolites in rat testes. However, large lipid signals dominated the chemical shift range of 0.89–2.78 ppm, which prevented the observation of other metabolite signals in this region. To suppress these lipid signals, an inversion recovery sequence with a short inversion time was combined with STEAM; the optimal inversion time was typically 320 ms. This combination allowed the detection of Cho, tCr, Glu and Gly in normal testes. In addition to these metabolites, a lactate signal was observed in ischemic testes.70

5

Clinical

The potentials, techniques and challenges of MRS at 3.0 T in the clinic have been reviewed.71 A review has been produced of spatial localisation in MRS techniques 338 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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covering their various advantages and disadvantages, and the implications for clinical applications.72 5.1 Brain 1

H MRS findings in current research on bipolar disorder have been reviewed. Levels of NAA, Cho, mI, Glx and tCr in 22 studies involving 328 adult bipolar and 349 control subjects were analysed.73 A review of the current literature containing studies using 1H MRS to investigate major depressive disorder has been produced. Levels of NAA, Cho, ml, Glx, and tCr were examined and separate meta-analyses comparing adult and paediatric major depressive disorder patients with healthy controls were performed.74 A review of the application of MRI and MRS techniques to hepatic encephalopathy has been produced.75 The transverse relaxation time of Glu in human brain at 3.0 T has been measured using a spectrally selective refocusing sequence. An 81.4-ms-long dual-band Gaussian 180 degrees RF pulse, designed for refocusing at 2.35 and 3.03 ppm, was employed within the PRESS sequence to generate a Glu C4 1H-multiplet and a tCr singlet. Six echo times between 128 and 380 ms were selected from numerical analysis of the filtering performance for effective detection of the Glu signal with minimal contamination from Gin, NAA, and glutathione. Apparent T2 values of Glu and tCr were estimated to be 201 18 and 164 12 ms for the medial prefrontal cortex and 198 22 and 169 15 ms for the left frontal cortex, respectively. The concentration of Glu and tCr were also estimated using data obtained from two voxels; these were 10.37 1.06 and 8.87 0.56 mM for gray matter, and 5.06 0.57 and 5.16 0.45 mM for white matter, respectively.76 The concentration of Glu in the hippocampus has been measuredusing 1H MRS at 3 T during an auditory target detection paradigm. Furthermore, electroencephalography was used to monitor theta activity in the brains of the subjects during the same task. A relationship between hippocampal Glu and frontal theta activity during stimulus processing was found. The frontal theta oscillations were also related to response speed.77 The anaplerotic contribution, via glial pyruvate carboxylase, to the glutamine pool in human brain has been investigated using 13C MRS. Incorporation of 13C-label into glutamate and glutamine in the occipital-parietal region of awake humans was measured during an infusion of [1-13C]glucose. These results were compared to labelling from [2-13C]glucose, which labels the C2 and C3 positions of glutamine and glutamate exclusively via pyruvate carboxylase. Compared to [1-13C]glucose, the labelling incorporated in Glu and Gln from [2-13C]glucose was much lower. Metabolic modelling of the labelling data indicated that pyruvate carboxylase accounts for 6 4% of the rate of glutamine synthesis, or 0.02 mmol g 1 min 1.78 In vivo localized 13C MRS has been used to measure glycogen content and turnover in the human brain. Nine healthy volunteers received intravenous infusions of [1-13C]glucose for durations ranging from 6 to 50 h. Brain glycogen labelling and washout were measured in the occipital lobe for up to 84 h. Upon fitting a model of glycogen metabolism to the time courses of newly synthesized glycogen, human brain glycogen content was estimated at similar to 3.5 mmol g 1 and the turnover of bulk brain glycogen occurred at a rate of 0.16 mmol g 1 h 1. Twenty minutes of visual stimulation did not result in detectable glycogen utilization in the visual cortex.79 A 32 s block design visual stimulation paradigm has been employed with 1H MRS to investigate changes in temperature and metabolism in the human primary visual cortex induced by activation. A marginally significant increase in the local temperature of the visual cortex was found (0.1 1C, P = 0.09). The total pools of Glu, Gln, ml, NAA, Cho and lactate were not significantly affected by activation.80 The sensitivity of 1H MRS to changes in brain metabolite concentrations during functional experiments has been investigated in humans at 7 T. Stability and reproducibility of the measurements were evaluated from LCModel analysis of the time series of spectra measured during a visual stimulation paradigm and by Nucl. Magn. Reson., 2008, 37, 327–356 | 339 This journal is

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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 of 0.2 mmol g 1. In addition, the influence of a small line-narrowing effect due to the blood oxygenation leveldependent changes in T2* on the estimated concentrations was simulated. Quantification of metabolites was, in general, not affected beyond 1% by line-width changes within 0.5 Hz.81 Furthermore, the concentrations of 17 metabolites have been measured in the human visual cortex during two paradigms of visual stimulation lasting 5.3 and 10.6 min. Significant concentration changes of approximately 0.2 mmol g 1 were observed for lactate, glutamate and aspartate. The concentration of glucose had a tendency to decrease during activation periods.82 The effects of a 40 hour period of sleep deprivation on the brain metabolites in eight healthy women has been investigated with 1H MRS. The ratios of NAA, tCr and Cho to H2O were determined from the occipital cortex during baseline conditions and during photic stimulation. In sleep deprived subjects, NAA/H2O decreased by 7% and Cho/H2O decreased by 12%. Photic stimulation had no effect on the measured metabolites in the alert state, but in the sleep-deprived state, the level of Cho/H2O increased during neuronal activation.83 1 H MRS has been used to assess NAA, Cho and tCr levels in the hippocampus of first-episode patients with bipolar disorder. Twelve patients meeting DSM-IV criteria for bipolar disorder and 12 healthy controls were studied. Analysis showed that patients had a significant bilateral reduction of NAA/tCr and of NAA/Cho. No significant correlation was found between hippocampus volume and ratios of metabolites. Analysis revealed significant correlation between NAA values for both sides of the hippocampus and the assessment of mania, but not for any of the other clinical variables (age, age at onset, and duration of illness).84 The effects of olanzapine on prefrontal metabolite levels have been investigated with 1H MRS in nineteen adolescents admitted for their first hospitalization for bipolar disorder, type I, manic or mixed. These were compared to 10 demographically matched healthy subjects. Medial and left and right lateral ventral prefrontal NAA, Cho, tCr, myoinositol, and Glx were measured at baseline, prior to receiving medication, and on days 7 and 28 of treatment. Although there was no overall increase in NAA in manic adolescents following 28 days of treatment with olanzapine, patients treated successfully with olanzapine (N = 11, 58%) exhibited a greater increase in medial ventral prefrontal NAA compared with those not successfully treated (N = 8, 42%, p = 0.006). Specifically, NAA levels decreased in non-remitters and increased in remitters. Furthermore, manic adolescents treated with olanzapine had an increase from baseline to day 7 in medial and right lateral ventral prefrontal Cho; baseline medial ventral prefrontal Cho was greater in olanzapine remitters than in nonremitters.85 1H MRS has been used to study drug-free patients with bipolar disorder, patients undergoing valproate treatment, patients administered valproate plus quetiapine and healthy controls. Measurements of NAA, Cho and tCr in hippocampal regions were obtained. The drug-free patients had significantly lower NAA/ tCr and NAA/Cho ratios compared with the valproate group, the valproate plus quetiapine group and the healthy controls. The lower NAA/tCr and NAA/Cho ratios remained statistically significant even after co-varying for age or whole brain volume compared with the valproate group, the valproate plus quetiapine group and healthy controls. A significant difference was found between the valproate plus quetiapine group and the valproate group only with regard to NAA/Cho.86 Changes in mI in response to treatment with lithium have been measured with 1H MRS in 28 adolescents with bipolar disorder, current episode depressed. Concentrations of mI in the medial prefrontal cortex and the left and right lateral prefrontal white matter were measured at baseline, day 7, and day 42 of treatment. Significant main effects of time were observed for mI concentrations in the medial prefrontal cortex and right lateral prefrontal white matter. Baseline concentrations of mI were not significantly 340 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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different from day 7 or day 42 concentrations. However, mI concentrations on day 42 were significantly higher than those on day 7 in the medial prefrontal cortex and right lateral prefrontal white matter.87 Nineteen antipsychotic-naive schizophrenics, of whom 11 had developmental reflexes, have been examined using 2D 31P MRS. The results were compared with results from 26 age-sex-matched healthy subjects without developmental reflexes. The mean age-at-onset of psychosis was significantly lower in patients with developmental reflexes. The mean ratio of PCr/ATP in bilateral basal ganglia was lower in patients than healthy subjects and lowest in patients with developmental reflexes.88 The use of frontal and temporal spectroscopy measures for prediction of outcome in patients with first-episode psychoses has been assessed. 1H MRS was used to measure the ratio of NAA/tCr and Cho/tCr in the left prefrontal cortex and left mediotemporal lobe of 46 patients with first-episode psychosis. These data were used to predict outcome at 18 months after admission, as assessed by a systematic medical record audit. Regression models were used that included age at imaging and duration of untreated psychosis to predict outcome scores on the Global Assessment of Functioning Scale, Clinical Global Impression scales, and Social and Occupational Functional Assessment Scale, as well as the number of admissions during the treatment period. The only spectroscopic predictor of outcome was the NAA/tCr ratio in the prefrontal cortex. Low scores on this variable were related to poorer outcome on all measures. In addition, the frontal NAA/tCr ratio explained 17% to 30% of the variance in outcome.89 MRSI has been used to compare 45 children (aged 3- to 4 years) with autism spectrum disorder, 12 age-matched children with delayed development and 10 agematched children with typical development. Children with autism spectrum disorder demonstrated decreased gray matter concentrations of Cho, tCr, NAA and mI compared with children with typical development. Gray matter Cho transverse relaxation was also prolonged for the autism spectrum disorder sample compared with the typical development group. The children with autism spectrum disorder demonstrated significantly decreased levels of Cho and mI, and trend-level NAA in gray matter compared with the delayed development group. Children with autism spectrum disorder and children with delayed development showed a similar decreases in NAA and mI in white matter.90 An investigation of changes in metabolite concentration in patients with generalized anxiety disorder has reanalysed data obtained using 1H MRS chemical shift imaging. A sample of 15 patients with generalized anxiety disorder (6 with early trauma and 15 healthy age- and sexmatched volunteers) were reanalyzed for metabolite alterations in the centrum semiovale. Self-reported worry was scored using the Penn State Worry Questionnaire and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence. Patients without early trauma exhibited bilaterally decreased concentrations of Cho and tCr in centrum semiovale in comparison to healthy volunteers, whereas patients with early trauma were indistinguishable from controls. In patients with generalized anxiety disorder, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted Cho concentrations in the left and right centrum semiovale, independent of age, sex, group assignment and Penn State Worry Questionnaire scores.91 The level of GABA in the occipital cortex of 9 women with postpartum major depression, 14 postpartum healthy controls, and ten healthy follicular phase females has been measured with 1H MRS at 2.1 Tesla. Cortical GABA and plasma allopregnanolone concentrations were reduced in both groups of postpartum women, regardless of postpartum major depression diagnosis, compared to healthy follicular phase women. There was no correlation between cortical GABA concentrations and oestradiol, progesterone, allopregnanolone or pregnenolone.92 A retrospective evaluation of MRI, 1H MRS, apparent diffusion coefficient, T1, and T2 measurements for prediction of late neurologic outcome has been carried out on data from term neonates exposed to severe perinatal asphyxia. Thirty term neonates (12 boys, 18 girls; age range, 2–12 days) with severe hypoxic-ischemic Nucl. Magn. Reson., 2008, 37, 327–356 | 341 This journal is

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encephalopathy were examined during the first 12 days of life. Quantitative 1H MRS, T1, and T2 data were acquired on one 10-mm slab positioned at the level of the basal ganglia. The neonates were assigned to one of two groups according to their late (412-month follow-up) neurologic outcome: those with an unfavourable outcome (i.e. death or severe disability) and those with a favourable outcome. The unfavourable (n = 16) and favourable (n = 14) outcome groups were similar in terms of clinical data (i.e., Apgar scores, visceral hypoxic injuries), visualization of brain oedema in magnetic resonance images, and T1 and T2 relaxation times. Late unfavourable neurologic outcome was associated with a mixed pattern of cortical and basal ganglia signal intensity abnormalities in magnetic resonance images. However, in the basal ganglia, NAA concentrations lower than 4 mmol dm 3 indicated an unfavourable individual prognosis with 94% sensitivity and 93% specificity. Significantly reduced apparent diffusion coefficients were also noted in the unfavourable outcome group, but only during the first 6 days of life.93 Seventeen term infants with neonatal encephalopathy and 10 healthy controls have been studied using 1H MRS at 1 and 2 days after birth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/ fatal), according to neurodevelopmental assessments at 1 year. The peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), tCr, NAA and Cho from a voxel centred on the thalami were analyzed according to outcome group. The ratios of Lac/NAA, Lac/Cho, and Lac/tCr increased and NAA/tCr and NAA/Cho decreased in the severe/fatal group compared with the controls. The T2 of Lac, NAA, and tCr increased. Furthermore, the concentration of Lac increased and the concentrations of Cho, tCr and NAA decreased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased concentrations of NAA, Cho, and tCr were observed in the infants with normal/mild outcome. An increased Lac/NAA and Lac/Cho and decreased NAA/tCr and NAA/Cho peak-area ratios were observed in the normal/mild compared to the severe/fatal group. Furthermore, there was reduced concentration of NAA and increased Lac T2 in the infants with the worse outcome.94 1H MRS has been used to investigate 12 children meeting the criteria of isolated developmental delay and 11 healthy controls. Children with abnormal MRI findings were excluded. A single 8 cm3 voxel was placed in the white matter of the left centrum semiovale. Concentrations of NAA, Cho, tCr and mI, and ratios of NAA, Cho, and mI to tCr were measured. In children with isolated developmental delay, a significant decrease in the ratios of NAA/tCr, NAA/Cho, and NAA/mI was observed compared to controls. The mean NAA/tCr ratio in isolated developmental delay children was 1.92 compared to 2.09 and in controls; no significant differences were seen in the remaining ratios.95 Brain metabolites have been measured in adolescent subjects born with very low birth weight, born small for gestational age and controls. 1H MRS at 1.5 T was used to acquire spectra from volumes localized in the left frontal lobe, containing mainly white matter, of 54 subjects. Peak areas of NAA, Cho and tCr were determined, and the peak area ratio of NAA/tCr, Cho/tCr or NAA/Cho was calculated. Probabilistic neural network analysis was performed utilizing the chemical shift region containing resonances from NAA, Cho and tCr as inputs. No significant difference in the peak area ratios could be found using the Kruskal-Wallis test. By application of probabilistic neural network, a correct classification of 52 of the 54 adolescents with a sensitivity and specificity exceeding 93% for all groups was achieved.96 An assessment of the potential value of 1H MRS measurements in the brain stem to evaluate the functionality of the consciousness areas has been carried out in patients with traumatic brain injury. Single voxel 1H MRS in the brain stem and morphological MRI of the whole brain were performed at day 17.5 6.4. Disability Rating Scale and Glasgow Outcome Scale (GOS) were evaluated at 18 months posttrauma. MRS appeared to be a reliable tool in the exploration of brainstem metabolism in traumatic brain injury. Three different spectra were observed (normal, 342 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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cholinergic reaction, or neuronal damage) allowing an evaluation of functional damage. Spectral changes were not correlated with anatomical MRI lesions. In two vegetative patients with normal morphological MRI, MRS detected severe functional damage of the brainstem (NAA/tCr o1.50) that was described as ‘‘invisible brain stem damage.’’ When a principal component analysis of combined MRI and MRS data was carried out a clear-cut separation between GOS 1-2, GOS 3, and GOS 4-5 patients was found with no overlap between groups.97 Two-dimensional MRSI has been used to acquire data through the level of the corpus callosum from 42 adults with severe traumatic brain injury 7 4 days after injury. Measurements were repeated in 31 patients six to 12 months later. Initial mean NAA ratios were lower and Cho/tCr ratios were higher in all traumatic brain injury patients compared to controls when data from all voxels were combined. Ratios from the corpus callosum region were affected most and predicted long-term outcome with 83% accuracy. When repeated at 6 to 12 months after injury, pooled mean NAA/tCr remained lower and Cho/tCr remained higher in patients with poor outcomes.98 Magnetic resonance spectroscopy has been used to investigate the biochemical basis of the reduction in fractional anisotropy and increase in mean diffusivity that occurs in cerebral small vessel disease. Twenty-five patients with lacunar stroke and radiological leukoaraiosis were examined using chemical shift imaging and diffusion tensor imaging. A region of interest was positioned in the white matter of the centrum semiovale and diffusion tensor imaging parameters were obtained from the same region. Univariate analysis revealed a positive correlation between NAA/tCr and fractional anisotropy (r = 0.52, p = 0.008) and a negative correlation with mean diffusivity (r = 0.51, p = 0.009). Results remained little changed after controlling for mean percentage lesion and mean percentage white matter per voxel.99 A MRSI technique has been developed to measure regional brain temperatures in human subjects. The technique was validated in a homogeneous phantom and in four healthy volunteers. Simulations and calculations were used to determine the theoretical measurement precision as approximately 0.3 1C for individual 1 cm3 voxels. In healthy volunteers, repeated measurements from individual voxels had all S.D. = 1.2 1C. Forty patients with acute ischemic stroke were imaged within 26 h (mean 10 h) of onset. Temperatures were highest in the region that appeared abnormal (i.e. ischemic) on diffusion-weighted imaging compared with a normalappearing brain. The mean temperature difference between the lesion area and the normal brain was 0.17 1C.100 Fourteen patients with Alzheimer disease and 22 cognitively normal elderly have been studied using structural magnetic resonance imaging and magnetic resonance spectroscopic imaging in frontal and parietal lobe gray matter and white matter. Alzheimer disease patients had increased mI and mI/tCr ratios primarily in parietal lobe grey matter whereas frontal lobe grey matter and white matter were spared. In the frontal lobe, Alzheimer disease patients had decreased NAA and NAA/tCr ratios. However, increased mI or mI/tCr ratios did not correlate with decreased NAA or NAA/tCr ratios.101 In an investigation of frontotemporal dementia, 1H MRS has been used to measure the ratio of NAA/tCr and mI/tCr in the temporal, parietal, and anterior cingulate cortices; structural MRI and neuropsychometry were also performed. Five patients with the established semantic dementia form of frontotemporal dementia, two patients with the frontal form of frontotemporal dementia and 13 age matched controls were analysed. Patients with frontotemporal dementia had reduced NAA/tCr in frontal and temporal lobes, but not parietal lobes. The two patients with the frontal form of frontotemporal dementia had increased ml/tCr in their cingulate cortices.102 Short TE 1H NMR spectra from the right hippocampus of 8 patients with probable Alzheimer’s disease, 14 healthy elderly adults and 14 healthy young adults have been obtained before and after glucose loading. Patients with Alzheimer’s disease exhibited significantly elevated hippocampal glucose concentrations after glucose ingestion relative to baseline levels when compared to control subjects.103 The effects of rivastigmine on metabolite Nucl. Magn. Reson., 2008, 37, 327–356 | 343 This journal is

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levels in the brain of patients with Alzheimer’s disease have been investigated in 24 patients with mild or moderate Alzheimer’s disease. Furthermore, a correlation between changes in metabolite levels and clinical outcome was assessed. A comparison group of ten untreated patients with Alzheimer’s disease with similar cognitive impairment to the treatment group were also enrolled. Patients were treated with rivastigmine at a target dosage of 12 mg day 1 for 4 months. Each patient underwent assessment using the Mini-Mental State Examination (Spanish version), the Blessed Dementia Rating Scale, the Clinical Dementia Rating scale, the Interview for Deterioration in Daily living activities in Dementia, the Alzheimer’s Disease Assessment Scale cognitive and non-cognitive subscales. Single-voxel MRS in the frontal, parietal and occipital cortices of the brain was used to assess levels of NAA, Cho and mI and the ratios of these metabolites to tCr. All assessments were performed at baseline and after 4 months of treatment with rivastigmine, and at baseline and I month later in the comparison group. Globally, although there was some mean improvement, no significant changes in the cognitive and non-cognitive scale scores between baseline and post-treatment assessments were seen in patients who received rivastigmine. A significant increase in the NAA/tCr ratio in the frontal cortex and in the mI/tCr ratio in the occipital cortex was seen in rivastigmine-treated patients. No other significant changes in the metabolite levels or their ratios to tCr were seen in these patients. After correction for multiple comparisons, the significant effects disappeared. Only in the frontal cortex did the changes in metabolite ratios correlate with changes on the clinical scales. In the comparison group, no significant differences between the metabolite levels or the ratios of metabolites to tCr were observed between the two scans.104 1H MRS has been used to observe possible changes in brain metabolites in subjects with amnesic subtype of mild cognitive impairment at risk of conversion towards Alzheimer’s disease. Twenty-five subjects and 29 normal elderly underwent a comprehensive clinical assessment and bilateral measurements of NAA, Cho, mI and tCr in the paratrigonal white matter. After 1 year, 5 subjects became demented. Their baseline levels of metabolites were compared with those evaluated in stable mild cognitive impairment and in controls. A significant difference was found in the NAA/tCr ratio in the left hemisphere between subjects with progressive mild cognitive impairment and those with stable mild cognitive impairment. Furthermore, a difference between progressive mild cognitive impairment and controls was also found.105 Quantitative 1H MRS has been used to investigate two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers. Magnetic resonance images and short TE spectra were acquired from the thalamus, caudate region and frontal white matter. One subject with familial Creutzfeldt-Jakob disease had generalised atrophy and showed increased levels of mI in the thalamus whilst another had decreased levels of NAA and diffuse signal abnormality in the frontal white matter. Metabolite levels and ratios were measured and compared to age-matched normal controls. Both asymptomatic gene carriers had normal magnetic resonance images, but increased frontal white matter mI and the one had increased mI in the caudate.106 Metabolite concentrations and ratios have been measured with quantitative, short TE 1H NMR spectroscopy in three patients with definite or probable variant Creutzfeldt-Jakob disease and in eight normal agematched controls. Data were obtained from the thalami, caudate nuclei and frontal white matter. Abnormal signals were apparent in T2-weighted magnetic resonance imaging of the pulvinar region in all patients with variant Creutzfeldt-Jakob disease. The pulvinar region also showed increased mI and decreased NAA. Two patients also showed increased mI (one had decreased NAA) in normal-appearing caudate nuclei.107 1H MRS has been used to analyse of the occipital and temporoparietal cortical regions, as well as the subcortical frontal white matter, of patients with myotonic dystrophy type 2 (DM2, n = 15) and type 1 (DM1, n = 14). Relative to healthy subjects, the concentration of NAA was significantly reduced in all tested brain regions in both disease groups. A concomitant depletion of tCr and Cho levels, 344 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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particularly in the frontal white matter was also observed in the DM1 patients. A discriminant analysis based on 1H MRS data distinguished between the DM2, DM1, and control groups with an overall accuracy of 88%.108 Regional metabolite levels have been measured by 1H MRSI in 8 patients with ataxia-telangiectasia and compared to 8 age-matched controls. Spectroscopic images of NAA, Cho and tCr were obtained in various regions of interest, including the cerebellum, brainstem, and basal ganglia. Ataxia-telangiectasia patients had a decrease of all metabolites in the cerebellar vermis (NAA, p o 0.01; tCr and Cho, p o 0.05) and a trend for decreased metabolites within the cerebellar hemispheres. No abnormalities were detected in the basal ganglia.109 Short-echo (5 ms) STEAM at 4 T and analysis with LCModel have been used to measure the neurochemical profile of the unilateral substantia nigra in ten patients with mild to moderate Parkinson’s disease and 11 age matched controls. The substantia nigra had a fourfold higher GABA/Glu ratio compared to the cortex, in agreement with established neurochemistry. The presence of elevated GABA levels in substantia nigra was validated from data obtained with spectral editing. No significant differences were observed between patients and controls, though trends in Glu, NAA, GSH and Cho were seen.110 The changes in NAA, tCr, Cho, mI and Glx concentrations in normal-appearing white matter and in cortical gray matter have been measured in subjects with clinically early relapsingremitting multiple sclerosis. Twenty subjects and ten healthy controls were examined yearly for two years. Using the LCModel, NAA, tCr, Cho, mI and Glx concentrations were estimated both in normal-appearing white matter and cortical gray matter. At baseline, the concentration of NAA was significantly reduced in the normal-appearing white matter and in the cortical gray matter of the multiple sclerosis patients. The concentrations of NAA in normal-appearing white matter tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in patients, or relatively between patients and healthy control subjects.111 1H MRS has been used to determine the NAA/tCr, NAA/Cho, Ins/ tCr and NAA/mI ratios in the motor cortex of seventeen patients with amyotrophic lateral sclerosis and 15 healthy control subjects. The results were assessed for their value as a biomarker of the degree of cerebral involvement in amyotrophic lateral sclerosis. The greatest abnormality in patients was a 22% decrease in NAA/mI (71% sensitivity and 93% specificity, P = 0.001), whilst mI/tCr was increased 18% (88% sensitivity and 53% specificity, P = 0.04), NAA/tCr was decreased 10% (88% sensitivity and 47% specificity, P = 0.04) and NAA/Cho was decreased 14% (53% sensitivity and 87% specificity, P = 0.047). Correlation of the amyotrophic lateral sclerosis Functional Rating Scale with NAA/mI approached statistical significance (R = 0.43, P = 0.07).112 The neuronal response of patients with amyotrophic lateral sclerosis to 1 day of riluzole treatment has been assessed using 1H NMR spectroscopic imaging in motor and non-motor regions of the brain. In 10 patients, the NAA/tCr ratio increased in the precentral gyrus and supplementary motor area, but not in the post-central gyrus or parietal lobe.113 The effects of a low dose of ecstasy on the brain, in ecstasy-naive volunteers, have been investigated using a combination of NMR techniques and self-report questionnaires on psychopathology. Outcomes of 1H MRS, diffusion tensor imaging, perfusion-weighted imaging and questionnaires on depression, impulsivity, and sensation seeking were compared in 30 subjects in two sessions before and after first ecstasy use. The interval between baseline and follow-up was on average 8.1 6.5 months and time between last ecstasy use and follow-up was 7.7 4.4 weeks. No significant changes were observed in metabolite concentrations of NAA, Cho, ml and tCr, nor in the ratios of NAA, Cho and ml relative to tCr. However, a 0.9% increase in fractional anisotropy in frontoparietal white matter, a 3.4% decrease in apparent diffusion in the thalamus, and a sustained decrease in relative regional cerebral blood volume in the thalamus, dorsolateral frontal cortex and superior parietal cortex were observed. However, only the decrease in the relative regional cerebral blood volume in the dorsolateral frontal cortex was significant after Nucl. Magn. Reson., 2008, 37, 327–356 | 345 This journal is

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correction for multiple comparisons.114 The effects of tobacco smoking on cortical GABA levels in ethanol-dependent patients with mild to moderate withdrawal severity has been investigated with 1H MRS. The levels of NAA, Glx and GABA were measured in the occipital cortex of 12 ethanol-dependent men at approximately 1 week and 1 month of medication-free sobriety; eight healthy men were studied once as control subjects. The tissue composition of the MRS volume was determined. Adjusting for less white matter in patients, GABA differed insignificantly between ethanol-dependent patients (smokers plus non-smokers) and healthy subjects. In early sobriety, non-smoking ethanol-dependent men had more GABA than did smoking patients, but by 1 month, GABA decreased in non-smokers without changing in smokers. Smoking was associated with increased Glx in ethanoldependent men and healthy subjects.115 The effects of acute oral topiramate on Glu and Gln levels in the anterior cingulate cortex and occipital lobe have been investigated with 1H MRS at 4 T. Spectra were acquired from healthy men at baseline, and 2 h and 6 h after ingesting 50 or 100 mg of topiramate. Serum topiramate levels were obtained from blood samples acquired prior to each scan. A 100-mg dose of topiramate significantly increased glutamine levels in the anterior cingulate cortex within 2 h of ingestion and in the occipital lobe within 6 h of ingestion. There were no measured significant effects of topiramate on glutamate levels in the anterior cingulate cortex or occipital lobe.116 The effects of extensive use of mobile phones on brain metabolites detectable by 1H MRS has been studied in twenty-one extensive mobile phone users (average use = 5.5 2.2 years at 2.4 1.1 hours per day) and 15 control subjects. Data were recorded in the most exposed right temporal and pontobulbar areas as well as in the contralateral left temporal area. The ratios of NAA/tCr, Cho/tCr and mI/tCr were measured. No statistically significant changes in any of the ratios were found between mobile phone users and control subjects, or between the exposed and contralateral temporal areas.117 5.2 Heart Myocardial and epicardial fat, left ventricular function, and metabolic risk factors in nine men (five lean, four moderately obese) has been assessed using 1H MRS to measure myocardial fat percent in the septum, MRI to determine left ventricular parameters and epicardial fat. Waist-to-hip ratio and liver enzymes (alanine transaminase) were used as surrogate markers of visceral and liver fat contents. Myocardial fat was 2.1 0.5 vs. 0.8 0.1% and epicardial fat was 120 33 vs. 55 12 g in obese compared and lean subjects, respectively. Individuals with abovemedian alanine transaminase values had a 4-fold elevation in myocardial fat. Myocardial fat was correlated with free fatty acid levels, epicardial fat and waistto-hip ratio, and it showed a tendency to associate positively with left ventricular work. Epicardial fat was positively associated with peripheral vascular resistance and negatively associated with the cardiac index. Free fatty acid levels were significantly correlated with left ventricular mass and forward work.118 5.3 Liver Fat-selective MRI and 1H MRS have been applied to the assessment of hepatic lipids in healthy subjects. Hepatic lipids were analyzed in ventral and dorsal regions of interest in magnetic resonance images from ninety subjects (23–63 years old). The results were compared with those obtained by localized 1H MRS. Fat-selective images showed smooth and homogeneous distribution of hepatic lipids over the entire cross section of the liver, however, there was a marked interindividual variability in the amount. A lipid signal fraction between 0.5% and 39.3% was revealed by MRS. The fat content in the region of interest in images correlated well with the spectroscopic results (r Z 0.95).119 The absolute quantitation of a monofluorinated compound, and of its metabolites in the heart and liver of healthy 346 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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subjects, has been determined by 19F MRS at 4 T. Twenty-three healthy adult subjects were enrolled in the study. Surface coil localized 19F spectra were recorded 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, and washout measurements were made only on subjects in which in vivo fluorine signal was observed. The average in situ concentration was estimated to be 58 22 mM. In the liver of three of five subjects dosed at 270 mg day 1, signals from fluorine-containing tecastemizole-related moieties were observed at day 8.120 5.4 Muscle The concentration of glycogen in the vastus lateralis of 6 male cyclists have been measured using MRS. Two hours after breakfast (7.0 kcal kg 1; 0.3 g kg 1 protein, 1.2 g kg 1 carbohydrate, 0.1 g kg 1 fat), cyclists performed a 60-min time trial. Immediately, 1 h, and 2 h post-exercise, participants ingested 4.8 kcal kg 1 in the form of 0.8 g kg 1 carbohydrate with 0.4 g kg 1 protein (C + P group), 4.8 kcal kg 1 in the form of 1.2 g kg 1 carbohydrate (LCHO group) or no energy (PLB group). Four hours post-exercise, the C + P and LCHO groups ingested a solid meal identical to breakfast, whereas the PLB group received 21 kcal kg 1 (1 g kg 1 protein, 3.6 g kg 1 carbohydrate, 0.3 g kg 1 fat); the energy intake during 6 h of recovery was identical among treatments. After 6 h of recovery, measurement and cycling protocols were repeated. Muscle glycogen utilization in the first bout of exercise was 18% greater relative to that in the second bout of exercise and there were no differences between groups. During 6 h of recovery, muscle glycogen resynthesis was greater in the C + P group versus the LCHO or PLB groups. Cycling performance was similar (P = 0.282) among treatments during the first and second bouts of exercise.121 A peak at 2.13 ppm in 1H NMR spectra of post-exercise skeletal muscle, previously attributed to the acetyl groups of acetylcarnitine, has been investigated. Ten healthy males (31 4 yr) cycled continuously for 45 minutes with intensity alternating between 50% (3 min) and 110% (2 min) of ventilatory threshold. Spectra were acquired from the vastus lateralis before and for 60 minutes following exercise. The peak at 2.13 ppm was not quantifiable at rest in any subject, however, it was present in all subjects following intense exercise.122 The effects of short-term starvation versus short-term low-carbohydrate/high-fat diet on intramyocellular triglyceride accumulation and insulin resistance has been investigated in physically fit men. 1H MRS was used to measure IMCL whilst insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test. Subjects followed a water-only starvation or a very low-CHO/high-fat diet lasting 67 hours. Results were compared with those measured after a mixed carbohydrate diet lasting 67 hours and dietary interventions were administered by cross-over design. The level of IMCL, insulin resistance and glucose intolerance was not different between wateronly starvation and very low-CHO/high-fat diet treatments; intramyocellular triglyceride content and insulin sensitivity were negatively correlated.123 Muscle PCr recovery time constant and contractile ATP cost have been estimated from a gated 31P MRS protocol which does not require intense, repetitive exercise. Subjects performed maximum voluntary isometric ankle dorsiflexion contractions of 2 s duration at 30 s intervals for 8 min for total 15 contractions. Single-shot 31P spectra were acquired from the anterior compartment muscle. Spectra were retrospectively sorted, yielding 10 spectra, each with 10 signal averages, gated to times before and after contraction. There was no significant decrease in muscle pH, allowing the calculation of contractile ATP cost directly from the percentage change in PCr during contraction cycles. PCr fell by 8.86 0.82%, corresponding to an ATP cost of 1.69 0.16 mM s 1, assuming an 8.2 mM ATP concentration. The time constant for PCr recovery was calculated to be 41.8 4.2 s. In the same subjects, the monoexponential PCr recovery time constant after more intense, repetitive isometric Nucl. Magn. Reson., 2008, 37, 327–356 | 347 This journal is

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ankle dorsiflexion exercise (30 s at 0.5 Hz, 50% duty cycle) was 36.2 3.5 s. In contrast to the gated protocol, muscle pH decreased from 7.01 0.01 to 6.78 0.04 during recovery after the repetitive protocol.124 31P MRS data from the human forearm flexor muscle have been analyzed using a model of mitochondrial oxidative phosphorylation. Model-based predictions of cytoplasmic concentrations of ATP, ADP, and Pi matched data obtained from 20 healthy volunteers. Additional data from patients with a defect of complex I of the respiratory chain and a patient with a deficiency in mitochondrial adenine nucleotide translocase were also predicted by the model after making the appropriate adjustments to the activities of the affected proteins associates with the defects.125 The effect of cholesterol-lowering drugs on skeletal muscle phosphorus metabolites has been measured with 31P MRS. Resting 31 P metabolites of the anterior compartment muscles were measured in subjects who were taking statins and in a control group. The levels of muscle phosphodiesters were 57% greater in the statin group than the control group.126 The myotoxic effects of statins (cholesterol-lowering drugs) have been investigated in eleven patients with increased creatine kinase levels and myalgias after statin treatment and compared to patients treated for hypercholesterolaemia with statins who were otherwise unaffected. Evaluation was carried out using in vitro contracture tests, histology, and 31P MRS. In vitro contracture test results were abnormal in 7 of the 9 patients with myalgia compared to control subjects, indicating an impaired calcium homeostasis. 31 P MRS showed no anomaly at rest and the recovery of PCr during the postexercise recovery period was normal in patients with myalgia. However, the kinetics of the recovery of pH was significantly slowed for those patients with increased creatine kinase levels and myalgias after statin treatment.127 Fourteen normal subjects and 20 patients with mild-to-moderate symptomatic peripheral arterial disease have been investigated with 31P MRS. Subjects exercised one leg to exhaustion while supine in a 1.5-T magnetic resonance scanner using a custom-built plantar flexion device. Surface coil-localized acquisition in the mid-calf was used to collect 25 signal averages at a repetition time of 550 ms. Median exercise time was 195.0 s in normal subjects and 162.5 s in peripheral arterial disease patients. The median recovery time constant of PCr was 34.7 s in normal subjects and 91.0 s in peripheral arterial disease patients.128 5.5 Diabetes and metabolic studies The possible role of muscle mitochondrial function in reduced whole body maximal oxygen uptake that is observed in individuals with low insulin sensitivity has been investigated. Thirty seven Caucasian-American and twenty two African-American premenopausal women (age: 33.6 6.3 yr) were assessed for insulin sensitivity with an intravenous glucose tolerance test, for body composition by dual-energy X-ray absorptiometry, and for visceral adipose tissue with computed tomography. Mitochondrial function, assessed from the time constant of ADP, was measured during a 90-s unilateral isometric contraction using 31P MRS. Between-race comparisons indicated that muscle oxidative capacity was lower among African-Americans vs. Caucasian-Americans (ADP time constant: 25.6 9.8 vs. 21.4 9.9 s). A multiple linear regression model for the dependent variable of insulin sensitivity, containing visceral adipose tissue, race, and the time constant for ADP, suggested that muscle mitochondrial function contributed to the racial difference in insulin sensitivity.129 The prevalence of insulin resistance and differences in intracellular lipid distribution among healthy, young, lean individuals of different ethnic groups has been investigated. An oral glucose tolerance test was administered and IMCL and hepatic triglyceride contents were measured using 1H MRS in 482 young, lean, healthy, sedentary, non-smoking Eastern Asians (n = 49), Asian-Indians (n = 59), Blacks (n = 48), Caucasians (n = 292) and Hispanics (n = 34). The prevalence of insulin resistance, defined as the lower quartile of insulin sensitivity index, was approximate to 2- to 3-fold higher in the Asian-Indians compared with all other ethnic groups. 348 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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This increased prevalence of insulin resistance was associated with an approximate to 2-fold increase in hepatic triglycerides and plasma IL-6 concentrations compared with Caucasian men.130 The relationships among total body fat, visceral adipose tissue, fat cell size, ectopic fat deposition in liver, IMCL and insulin sensitivity index has been investigated in healthy overweight, glucose-tolerant subjects. Furthermore, the effects of calorie restriction by diet alone or in conjunction with exercise on these variables were assessed. Forty-eight overweight Volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction, 12.5% calorie restriction +12.5% energy expenditure through structured exercise, 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (low-calorie diet). At baseline, fat cell size was related to visceral adipose tissue and intrahepatic lipid (P o 0.05) but not to IMCL. Fat cell size was also the strongest determinant of insulin sensitivity index (P o 0.01). Weight loss at month 6 was 1 1% (control, mean-SE), 10 1% (calorie restriction), 10 1% (energy expenditure through structured exercise), and 14 1% (low-calorie diet). Visceral adipose tissue, fat cell size, percent body fat, and intrahepatic lipid were reduced in the three intervention groups (P o 0.01), but IMCL was unchanged. Insulin sensitivity index was increased at month 6 (P = 0.05) in the energy expenditure through structured exercise (37 18%) and low-calorie diet (70 34%) groups (P o 0.05) and tended to increase in the calorie restriction group (40 20%, P = 0.08). The improvements in insulin sensitivity index were related to loss in weight, fat mass, and visceral adipose tissue, but not intrahepatic lipid, IMCL or fat cell size.131 A comparison has been made of the measurement of skeletal muscle lipid by computerised tomography and the measurement made using MRS. Mean muscle attenuation in soleus and tibialis anterior muscles measured by computerised tomography were compared to the levels of IMCL and extramyocellular lipids (EMCL) measured by MRS in volunteers. Mean muscle attenuation of soleus was significantly associated with IMCL (r = 0.64) and EMCL, which by multiple regression analysis was explained mostly by IMCL (p o 0.001) rather than EMCL (beta = 0.010, p = 0.94). Muscle triglyceride was lower in tibialis anterior than in soleus muscles and mean muscle attenuation of tibialis anterior was significantly correlated with EMCL (r = 0.40) but not IMCL (r = 0.16). Mean muscle attenuation of midthighs was correlated with mean muscle attenuation in soleus (r = 0.40, p = 0.07) and whole calf (r = 0.62, p o 0.05). Mean muscle attenuation and IMCL were highly reliable in soleus (coefficient of variation = o2% and 6.7%, respectively) and less reliable in tibialis anterior (4% and 10%, respectively).132 5.6 Tumour The use of in vivo MRI, in vivo MRS, and ex vivo MRS of biopsy samples for preoperative diagnosis and provision of prognostic information on tumours has been reviewed.133 A review of the current status of magnetic resonance imaging and spectroscopy in the management of breast cancer has been produced.134 A multi-institutional study of the standardization and reproducibility of localized 31 P magnetic resonance spectra in cancer patients has been performed. The cancers tested were non-Hodgkin’s lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best spectral quality was achieved with the non-Hodgkin’s lymphomas. Spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional data.135 An internal reference method has been used for the absolute quantification of Cho in malignant breast tumours. Measurements in vitro in four phantoms of known choline chloride concentration were used to examine the accuracy of absolute quantification. The technique was applied to 45 patients with biopsy-confirmed breast cancer. Cho levels ranged from 0.76 to 21.20 Nucl. Magn. Reson., 2008, 37, 327–356 | 349 This journal is

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mmol kg 1 in 34 spectra of 32 patients with malignant breast lesions.136 1H NMR spectra have been recorded before and after the completion of chemotherapy in 33 locally advanced breast cancer patients with infiltrating ductal carcinoma. In addition, spectra from normal breast tissues of 28 healthy volunteers were recorded. Malignant breast tissues showed elevated ratio of water/fat compared to normal breast tissues of controls. Statistically significant higher pretherapy water/fat ratio (P o 0.01) was observed in patients compared to controls. In patients who received neoadjuvant chemotherapy resulting in the reduction of the primary tumour size, the water/fat ratio showed a decrease that was statistically significant (P o 0.01). Analysis of the magnetic resonance data further indicates that the water/fat ratio had no correlation with the menstrual status of the patients. A comparison of pretherapy water/fat ratio with pretherapy tumour volume showed a correlation (P = 0.05), while the post-therapy ratio showed no such correlation with the post-therapy tumour volume.137 The possible relationship between MRSI measurements of Cho and vascular parameters measured by dynamic contrast enhanced magnetic resonance imaging in breast cancer has been investigated in fourteen patients with histologically proven invasive breast cancer. MRSI was performed with 64 voxels of 1.0 1.0 1.2 cm3. Cho signal-to-noise ratio was measured from each voxel showing an identifiable Cho peak. The kinetics of dynamic contrast enhancement were measured from each voxel and analyzed with a 2-compartmental model to obtain pharmacokinetic parameters. All parameters showed a wide variation within each lesion, and there were no consistent correlations between regional Cho and dynamic contrast enhancement parameters within the lesion of each individual patient. When Cho and dynamic contrast enhancement parameters were obtained for each patient by averaging over all Cho-positive voxels, there was a significant linear correlation between Cho with percent enhancement at 2 min after injection.138 Single-voxel 1H MRS data have been collected from patients with suspicious or biopsy-proved malignant breast lesions measuring 1 cm or larger in magnetic resonance images. 1H MRS findings were defined as positive if the signal-to-noise ratio of the Cho resonance peak was greater than or equal to 2 and as negative in all other cases. 1H MRS findings were then compared with histological findings. A total of 56 patients (age range, 20–77 years) with 57 lesions were imaged; the median lesion size in magnetic resonance images was 2.3 cm (range, 1–15 cm) and 31 (54%) of 57 lesions were malignant. A Cho peak was present in 34 of 57 lesions (including all cancers) and in three of 26 benign lesions, giving magnetic resonance spectroscopy a sensitivity of 100% and a specificity of 88%.139 The potential diagnostic role of in vivo 1H MRS measurements of lipid methylene to methyl signal ratio in differentiation of recurrent brain tumour from radiation injury has been investigated. Two patients were monitored before and two years after radiation therapy. One patient had documented recurrence and the other was without recurrence. A comparative group was examined and consisted of 20 patients with glial tumour recurrence diagnosed 2 years after the radiotherapy. In the case of tumour recurrence, an increase of the lipid CH2/CH3 value was observed. In the patient with no tumour recurrence, the CH2/CH3 ratio had a negative correlation with time after irradiation in the brain areas distant from the tumour. The trend to an increase in the CH2/CH3 ratio after radiotherapy in the tumour bed and within the non-involved areas lessened the value of the ratio as a marker of tumour recurrence.140 The clinical value of MRI in combination with MRS has been assessed in 35 patients with single brain tumours and final histopathological verification. The investigation used Gd-enhanced T1-weighted imaging, T2-weighted imaging and 1H MRS to measure the concentration of NAA, tCr, Cho and mI. When enhancement of T1-weighted images was measured with a contrast to noise ratio of greater than 35.86, malignancy was predicted at 82.6% sensitivity and 91.7% specificity. In NMR spectra, a Cho/tCr ratio higher than 1.56 predicted malignancy at 88.9% sensitivity and 91.7% specificity. A combination of these two parameters, with the presence of lactate in the spectrum, increased the predictive power 350 | Nucl. Magn. Reson., 2008, 37, 327–356 This journal is

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significantly. However, the techniques were unable to accurately distinguish metastases from high-grade gliomas.141 The use of MRI and 1H MRS for the pre-surgical management of patients with brain tumours has been used to examine 121 patients with tumours of various histological subtypes confirmed by surgical biopsy. Univariate statistical analysis of metabolic ratios demonstrated significant differences in between-group comparisons, but failed to provide sufficiently robust classification of individual cases. However, a multivariate statistical approach correctly classified the tumours using linear discriminant analysis of combined MRI and MRS data. After initial separation of contrast-enhancing and non-contrast-enhancing lesions, 91% of the former and 87% of the latter were correctly classified. This diagnostic strategy was tested on a further 43 patients and gave over 90% correct classification.142 1 H magnetic resonance spectroscopic imaging and diffusion-weighted imaging have been used to examine men with increased prostate-specific antigen levels. Thirteen patients with prostate-specific antigen levels 420 ng cm3 blood (Group I) and 20 patients with prostate-specific antigen levels of 4–20 ng cm 3 blood (Group II) were investigated using endorectal coil at 1.5 T prior to transrectal ultrasoundguided biopsy. Seven controls subject were also examined. The ratio of citrate/ (Cho + tCr) and the apparent diffusion coefficient were calculated for identical voxels. In patients, voxels that showed lower metabolite ratio had a reduced apparent diffusion coefficient and voxels with increased metabolite ratio had a higher apparent diffusion coefficient. Metabolite ratios were used to predict areas of malignancy if the ratio was o1.4 and if the apparent diffusion coefficient value was o1.17 10 3 mm2 s 1. Patients in Group I had lower metabolite ratios and an apparent diffusion coefficient compared to controls and Group II. All Group I were predicted to be positive for malignancy from magnetic resonance data, while 12 of 13 were positive on transrectal ultrasound-guided sextant biopsy. In Group II, certain voxels of the peripheral zone that showed reduced metabolite ratio also showed lower apparent diffusion coefficient. A positive correlation was observed between metabolite ratio and apparent diffusion coefficient. Magnetic resonance parameters predicted areas of malignancy in 15 of 20 patients; however, only six were positive on biopsy.143 5.7 Bone marrow Bone marrow composition has been measured by 1H MRS in a sample volume placed in the epiphysis of the intact femoral heads of patients with unilateral osteonecrosis of the hip and age-matched controls. The linewidth of lipid and water differed significantly between groups. The lipid/water ratio had border-line significance for the assessment of risk of development of avascular necrosis. The three variables differed significantly between groups when multivariate regression was analyzed and age or sex had no significant effect on the three dependent variables.144

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Oriented molecules K. V. Ramanathan,a Uday R. Prabhua and C. L. Khetrapalb DOI: 10.1039/b617223g

1. Introduction The report on the oriented molecules is published in alternate volumes of this series and the present one covers the available literature during the biennial period ending May 2007. Earlier literature on the subject is available from the previous volumes of this series. Historically the use of NMR spectroscopy of oriented molecules for structural studies started about four decades ago, with the study of small and symmetrical molecules. Since then this field has continued to progress with enormous applications in different areas. In between there was a decline in interest in this field for a while. However with several new developments taking place in recent years, applications of NMR spectroscopy of oriented molecules for structural studies has once again become an area of great interest. During the current period, the developments in various areas have in general followed the trend that was pointed out in the previous report.1 Thus study of weakly ordered biological macromolecules continues to be of great interest with the literature covering a range of topics such as developments of new orienting media, novel experimental techniques and pulse schemes, new and improved procedures for structure calculation using residual dipolar couplings (RDCs) and other anisotropic parameters and applications to proteins, peptides and nucleic acids. An important new development during this period is the greater interest in the study of membrane proteins. As membranes and model membranes exhibit liquid crystalline phases, they are conveniently oriented either by the magnetic field or by mechanical means. Application of solid state NMR methodologies to such systems provides partially averaged anisotropic parameters which are a rich source of structural information. Another notable area which has promise for the future is the development of techniques for weak ordering of small organic molecules. More reports on molecules that exhibit conformational freedom have also been published. The network of the strongly coupled spin systems, provided by the liquid crystalline environment, is being exploited for quantum information processing. But the number of published papers in this area has declined in comparison to that for the previous reporting period. Hence these papers have been included under the heading of General Studies, instead of the special section devoted to them in previous reports. Interesting applications in unusual areas such as observation of dipolar couplings in the spectra of human leg muscles originating from nematic like order have been reported. Similar developments in other areas have continued and hold promise of increased future activities. The classification of the topics is essentially the same as that followed in earlier volumes and the available literature is presented under the following headings: Reviews, Theory and General Studies; New Techniques; Dynamic NMR Studies; Chiral, Smectic, Lyotropic, and Polymeric Systems; Relaxation Studies; Orientational Order in liquid crystals; Membranes and Molecules Oriented therein; Structure and Orientation of Small Molecules; Weak Ordering and Biomolecular Studies.

2. Reviews, theory and general studies A book in three volumes on Modern Magnetic Resonance has appeared.2 It contains several articles of relevance to the topic of this report. They have been highlighted at a b

Indian Institute of Science, Bangalore 560 012, India Centre for Biomedical Magnetic Resonance, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Lucknow 226 014, India


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the appropriate places. Residual dipolar couplings (RDCs) are being increasingly used in the study of small organic molecules as parameters for the determination of structure and configuration. An overview of the use of RDCs for rigid organic compounds is available.3 Some practical considerations concerning alignment media have also been described. The problems associated with very large residual dipolar couplings have been pointed out and the means to reduce them for strychnine in substituted polyglutamate liquid crystals described. The use of RDCs for the assignment of diastereotopic protons and for the determination of the relative configuration in rigid compounds has also been described. Some drawbacks of the technique have been highlighted. The application of partial alignment of organic molecules for structure determination and the use of residual dipolar couplings for the determination of stereochemistry of small molecules like drugs or drug-like molecules has been presented.4 The partial alignment of molecules in organic solvents by the use of mechanically constrained polymer gels or modified liquid crystalline phases has been discussed.5 NMR in chiral and achiral smectic phases has been reviewed. Structure, orientational order and dynamics aspects have been dealt with.6 A review on studies of columnar liquid crystals by 13C NMR with particular emphasis on applications of recently developed NMR methods is available.7 The techniques, designed for spectral assignment, measurements of various anisotropic spin interactions, studies of molecular conformation and slow molecular dynamics have been described. A review of the recent studies of the molecular dynamics of the smectic liquid crystalline phases formed by rod-like molecules and of the new liquid crystalline mesophases formed by banana-shaped molecules has been reported.8 Deuterium NMR spectroscopy has been employed for such studies. An overview of techniques such as multiple quantum NMR and spectral subtraction methods has been presented.9 The theoretical background, the use of magic mixtures, the reorientation–vibration interaction, the use of model calculations based on size and shape of the various solutes and the use of computer simulations have been described. Applications to probe molecules such as hydrogen, methane, ethane, and butane and their isotopomers have been illustrated. Reviews of multiple-quantum NMR methodologies as well as studies of the structure, orientation, morphology and dynamics of polymers, biomolecules and ordered tissues are available.10 NMR methods of studying orientational order in the liquid crystalline and isotropic phases of mesogenic samples have been reviewed.11 It is explained how biaxial ordering can be characterized for rigid molecules and the conformation-dependent order parameters of flexible molecules obtained. A review of phase transitions of chain molecules containing mesogenic units via a nematic liquid crystalline phase monitored using 1H and 2H NMR as well as other spectroscopic techniques is available.12 Lattice spin models of polymer dispersed liquid crystals has been reviewed paying particular attention to the calculation of deuterium NMR spectra from the simulation data.13 The study of the molecular organization and thermodynamics of these systems by such simulations has been emphasized. Diffusion studies provide important insights into both lyotropic and thermotropic liquid crystalline systems. The experimental techniques, the theoretical description and computer simulations of diffusion as applied to oriented systems have been reviewed.14 Work on the phase diagram of liquid crystals made of mixtures of rods and spheres has been described.15 The massive flexibility of such molecules poses a severe problem for the prediction of their liquid crystalline behavior. Theoretical predictions have been tested by the use of quasi-spherical solutes such as tetraethyltin. The reasons for the failure of the experiments to conform to theory were studied and explained in terms of the orientational order, determined using deuterium NMR spectroscopy. The same approach was also employed to predict the variation of the transitional properties of liquid crystal dimers with the length of the spacer. Application of acoustically stimulated NMR relaxometry to the study of molecular dynamics in liquid crystalline materials has been discussed.16 Efforts to obtain unequivocal evidence for a biaxial nematic phase in low-molar-mass calamitic 358 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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thermotropic liquid crystals are continuing. In order to validate the claim of biaxiality for the mesogens based on the oxadiazole heterocycle and to establish the methodology used to test for biaxiality, experiments have been performed on the uniaxial nematic liquid crystal TBBA. Based on the results it has been concluded that the claim of biaxial order for oxadiazole mesogens is valid.17 Monte Carlo simulations of NMR spectral parameters for atomic xenon dissolved in a model thermotropic liquid crystal has been presented.18 The simulations have been shown to reproduce many of the characteristic experimental features of Xe NMR in thermotropic liquid crystals such as discontinuity in the value of the shielding and quadrupole coupling at the nematic-isotropic and smectic-A-nematic phase transitions, the behavior of the orientational order parameter, and decreasing shift in the smectic-A phase. A conformational distribution function for a molecule dissolved in an anisotropic condensed fluid medium has been proposed which combines an a priori model with the maximum entropy principle applied to treatment of liquid crystal-NMR data.19 A new computational method has been proposed for calculating 2H NMR lineshapes of H2O in microheterogeneous systems, such as lyotropic liquid crystals that exhibit curved lipid/water interfaces.20 Creation of two kinds order, namely, intrapair and interpair order in thermotropic liquid crystals has been considered and the experimental conditions and the preparation sequence for creating each kind of such order discussed.21 The applicability of the above spin thermodynamics has been tested in two typical thermotropic nematic samples. Solute–solvent interactions and chiral induction in liquid crystals has been studied with methyl-phenyl-sulfoxide, a flexible, chiral molecule which, dissolved in different nematics, produces cholesteric phases of opposite handedness.22 The study allowed insight to be obtained into the role of solvent in mediating the chirality transfer from molecule to phase. In order to understand the liquid crystal-like phase behavior and the dipolar coupling observable in the NMR spectrum of orientationally ordered fluids, thermodynamics of a simple model system has been considered.23 The behaviour of the isotropic-nematic phase transition has been explored as a function of magnetic field strength and the relative orientation between the nematic director and the external magnetic field studied. The model supports the hypothesis that dipolar couplings observed in the spectra of human leg muscle originate from nematic-like liquid crystal phases in relatively small metabolite molecules. A study of order and dynamics in tendon by NMR and MRI has been reported.24 Tendons are composed of a parallel arrangement of densely packed collagen fibrils that results in unique biomechanical properties of strength and flexibility. The study reviews several advanced magnetic resonance spectroscopy and imaging techniques that have been used to extract parameters such as the 1H–1H and 1H–2H dipolar interactions, the proton exchange rates between water and collagen and between water molecules, the distribution of fibril orientations and the anisotropy of diffusion. A study of molecular organization and surface induced ordering in cylindrical nanocavities has been made using liquid crystals and the analysis of order parameters obtained by NMR has been reported.25 NMR spectroscopy of oriented molecules has been exploited for quantum information processing. Projective quantum measurement and probabilities of outcome of such a measurement have been demonstrated using a cluster of six dipolarcoupled nuclear spins of benzene in a liquid crystal matrix.26 The experiment measures Sx when the system is in one of the eigen states of Sz. Further, it is shown that by employing the same idea, multiple-quantum coherences can be detected and therefore the mixing period in a 2-dimensional NMR experiment which converts multiple quantum coherences into observable single-quantum coherence, is not necessary. This is illustrated with examples of two finite clusters benzene oriented in a liquid crystal and the liquid crystal 4 0 -n-pentyl-4-cyanobiphenyl and also for solid adamantane with an infinite network of dipolar couplings. The use of quadrupolar nuclei with spin greater than 1/2 as a suitable candidate for quantum information processing has been considered.27 By utilizing a spin-7/2 system of 133Cs Nucl. Magn. Reson., 2008, 37, 357–388 | 359 This journal is

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nucleus oriented in a liquid crystalline matrix, implementation of the three-qubit quantum Deutsch-Jozsa algorithm has been demonstrated. Pseudopure ‘‘cat’’ state, a superposition of quantum states with all spins up and all spins down, has been experimentally demonstrated for a system of 12 dipolar-coupled nuclear spins of fully 13C-labeled benzene molecule oriented in liquid crystal matrix.28

3. New techniques While the spectra of oriented molecules are rich in information, the analysis of the spectra is complicated in the presence of homonuclear dipolar coupling. To alleviate this problem several strategies are being developed. They pertain to new experimental approaches, novel pulse sequences, new orienting strategies and efficient computational methods. The complexity of 1H NMR spectra of solutes in partially ordered solvents such as liquid crystals increases rapidly with the number of spins. To circumvent this problem, the application of a general automated genetic algorithm to solving highly complex spin systems with minimal operator intervention has been presented.29 The robustness of the method has been demonstrated for the nine-spin system p-bromo-biphenyl, a solute interconverting between two symmetry-related conformations. Numerical iterative analysis of the proton spectra of strongly coupled spins is difficult and time consuming. However such analysis is simplified if nearly accurate starting parameters are available. With this in view, a two dimensional experiment in which homonuclear dipolar decoupling is employed to obtain chemical shifts in the oriented phase has been proposed.30 Experiments on the molecule cis,cis-mucononitrile demonstrate that the chemical shifts obtained by this procedure are nearly the same as the chemical shifts derived by iterative analysis of the one dimensional spectrum of the molecule following standard procedure. The method has also been used to analyze the spectrum of 1-iodopropane. Several experiments that employ selective excitation as well as bilinear rotation decoupling sequence (BIRD) have been proposed for the purpose of visualization of enantiomers in chiral ordering solvents.31 The method allows extracting precise values of 1-bond carbon–proton residual dipolar couplings for each enantiomer from unresolved spectra. A technique to simplify overcrowded proton spectra in chiral liquid crystal solvents using rotation of the sample near the magic angle has been presented.32 Combined with homonuclear selective refocusing 2D NMR experiments the method provides a useful tool to visualize enantiomers and to estimate enantiomeric excesses. A method to separate subspectra of a homonuclear dipolar coupled spin system on the basis of the spin states of the coupled heteronuclei by multiple quantum-single quantum correlation experiments has been proposed.33 The method results in fewer transitions thereby simplifying the analysis of the complex spectrum. The methodology has been demonstrated on doubly 13C labeled acetonitrile and on an oriented six spin system. A new method for polarization transfer between heteronuclei for static oriented samples has been presented.34 The method employs an INEPT like sequence for the transfer of polarization through heteronuclear dipolar couplings during homonuclear dipolar decoupling under a BLEW12 pulse sequence. The method has been demonstrated on a nematic liquid crystal oriented in a magnetic field. Experiments on samples of chloroform and dichloromethane oriented in the liquid crystal matrix demonstrate that the technique can also be used for estimating heteronuclear dipolar couplings. 15N–1H and 13C–1H dipolar couplings of molecules in strongly orienting media have been determined using twodimensional inverse experiments.35 Unlike monitoring the satellite lines in the proton spectrum for the identification of transitions belonging to each spin system which is a formidable task, the method allows selective detection of spectra of each rare spin coupled to protons. A set of 1D NMR methods for accurate and precise measurement of proton–proton RDCs of small and medium size molecules which are typically characterized by the presence of overlapping and broad multiplets has been described.36 The technique is illustrated by the determination of the alignment 360 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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tensor of the reducing monosaccharide ring of cellobiose and the determination of the relative configuration of sodium cholate. Residual dipolar couplings between nuclei with known and fixed distance provide angular information which makes the accurate and sign-sensitive measurement of the couplings highly desirable. With this in view, an E.COSY based experiment has been proposed which allows the simultaneous measurement of precise values of heteronuclear and homonuclear couplings.37 The relative signs of the coupling constants could also be obtained from the experiment. Stretched gels made of cross-linked poly(acrylonitrile) swollen in dimethyl sulfoxide have been suggested as a freely scalable alignment media for the measurement of residual dipolar couplings.38 The method of production of the gel, characterization of the spectral lines of the alignment medium and methods for their suppression have been presented. Using the proposed medium, RDC measurements have been demonstrated on a number of typical molecules. Homo- and heteronuclear residual dipolar couplings have been obtained for the case of a-methylene-gbutyrolactone and used to show that the compound has a trans configuration.39 It is interesting to note that in this case NOE and 3J coupling data could not provide the relative configuration. The use of Variable Angle Spinning (VAS) for appropriately scaling the anisotropic interactions in order to obtain structural information has been illustrated for the case of strychnine oriented in the liquid crystalline phases.40 New heteronuclear dipolar decoupling sequences for oriented liquid-crystal samples have been proposed and their performance compared with standard sequences that are commonly used.41 A new separated local field NMR experiment designed for accurate measurements of heteronuclear dipolar couplings has been described.42 The pulse sequence employs windowless homonuclear decoupling combined with heteronuclear isotropic mixing to achieve polarization transfer between heteronuclear spins. The technique, demonstrated on a columnar liquid crystal, has been shown to be insensitive to frequency offset variations. Approaches that markedly reduce radiofrequency power requirement for separated local field experiments have been proposed.43,44 The experiments have been demonstrated on liquid crystal samples. By alternating the directions of the effective fields for 1H nuclei with unequal durations and amplitudes of r.f., significantly reduced power requirement and consequent reduction of sample heating was achieved. A detailed study of crosspolarization employing phase- and frequency-switched Lee-Goldburg decoupling under magic-angle spinning conditions has been carried out and the performance evaluated by the estimation of motionally averaged dipolar couplings of a liquid crystal sample.45 A pulse sequence for separated local field spectroscopy which provides narrow and more uniform linewidths over the entire spectrum has been proposed. Its utility for a two-dimensional HETCOR experiment has also been presented.46 It has been shown that natural polarization of 13C nuclei in the static magnetic field can be used advantageously for SLF experiments involving liquid crystals, instead of the polarization obtained from protons by cross-polarisation.47,48 A detailed theoretical analysis of the experiment and a comparison with the polarization inversion technique have been presented. A method of characterization of high resolution 1H-NMR spectra of liquid crystals through the variation of the proton decoupling frequency off-sets in 13C spectra has been proposed.49 Both the intramolecular 1H–1H dipolar interaction and the chemical shifts have been characterized. A new system for partial alignment of polar organic molecules has been proposed which consists of a 1:1 or a 2:1 mixture of water and DMSO with 3–13% n-alkylpentaethylene glycol as the surfactant.50 As examples, residual dipolar couplings for an amino acid and for an organic molecule have been obtained.

4. Dynamic NMR studies This section describes both dynamics studies at the molecular level and also cooperative bulk macroscopic responses to external perturbations such as electric and magnetic fields and sample rotation. A deuterium two-dimensional exchange Nucl. Magn. Reson., 2008, 37, 357–388 | 361 This journal is

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NMR technique has been combined with sample rotation in the magnetic field to obtain the translational self-diffusion constant along the helical pitch in the SmC* phase and to shed light on the structure of the helicoidal superlattice in the threelayer and the four-layer phases of the smectogen (s)-1-methylheptyl 4 0 -(4-n-decyloxybenzoyloxy) biphenyl-4-carboxylate.51 The results support the asymmetric Clock model as an appropriate description of the ferrielectric phases in this compound. Two-dimensional 129Xe exchange NMR measurements have been presented for xenon atoms dissolved in a thermotropic nematic liquid crystal, confined to a mesoporous controlled-pore glass.52 The exchange rate constants for xenon diffusing between the bulk sample and the sample confined inside the pores have obtained. The use of 2H–{1H} NMR spectroscopy in weakly ordering, chiral lyotropic liquid crystals, made of poly-g-benzyl-L-glutamate (PBLG) dissolved in chloroform or dichloromethane, has been demonstrated for investigating the intramolecular dynamic processes of four deuterated diaryl derivatives of 1-(4 0 -methylphenyl)naphthalene.53 When the rotation of the aryl groups about the sp2–sp2 bond is sufficiently slow relative to the NMR timescale, the method allows the spectral discrimination of enantiomeric atropisomers or enantiotopic directions in the prochiral derivatives. Conformational dynamics as well as coalescence phenomena in these compounds have been examined. The study allowed the activation parameters for the internal rotation processes to be calculated. Deuterium NMR in polypeptide chiral liquid crystals has been used to investigate the internal rotational isomerism phenomenon and the interconversion between conformers of 1-(2 0 ,6 0 dideutero-4 0 -methylphenyl)naphthalene has been studied.54 Director dynamics in liquid crystals subjected to magnetic and electric fields simultaneously have been reported. Detailed deuterium NMR measurements have been carried out on deuterated nematic liquid crystals 4-pentyl-4 0 -cyonobiphenyl (5CB) and 4-octyl-4 0 -cyanobiphenyl (8CB) subjected to magnetic and alternating electric fields.55 The angles between the magnetic and electric fields as well as the frequency of the electric field have been varied. Different director reorientation behaviours have been observed at different frequency regimes and at different geometries of the electric and magnetic fields. The results have been discussed and interpreted in terms of the torque-balance equation for a time dependent electric field. Use of 2H NMR spectroscopy for the study the field-induced director orientation in nematic liquid crystals has been presented and illustrated with specifically deuterated 5CB subject to the magnetic field of the spectrometer and an electric field applied at an angle to it.56 Analysis of the results are shown to provide the physical properties of the system. Director dynamics of perdeuterated of smectogens, where the director was aligned by an electric field has been studied.57,58 After the electric field is switched off, the director relaxes back to being parallel to the magnetic field. It was observed that the relaxation time in the smectic A phase is several orders of magnitude larger than that in the nematic phase. A distortion of the helicoidal structure of the ferroelectric phase of a partially deuterated smectogen, induced gradually by rotating the sample in the NMR magnet, has been studied by 2 H NMR and the critical field for unwinding the helix has been obtained.59 Self diffusion along the phase director in the nematic phase and parallel to and across the layer in the smectic A phase of 4,4 0 -dioctylazoxy benzene has been reported.60 2H NMR line-width and diffusion measurements have been reported for the liquid crystal 1-methyl heptyl 4 0 -(400 -n-decyloxy benzoyloxy) biphenyl-4-carboxylate and the peculiar behaviour occurring at the transition between the ferroelectric and the antiferroelectric phases explained.61,62 Orientation and dynamics studies of benzyl alcohol and benzyl alkyl ethers dissolved in nematic lyotropic liquid crystals by 2H NMR and molecular dynamics simulations have been reported.63 Deuterium quadrupole splittings and longitudinal relaxation times have been measured. 13C and 2H NMR studies have been carried out on the banana mesogen 1,3-phenylene-bis-4-[4(10-undecenyloxy)benzoyloxy]benzoate (Pbis11BB). The molecular structure and dynamics in the B2 and crystalline phases have been studied and the results point to 362 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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the slow dynamics in the B2 phase.64 Experimental evidence for the presence of slow dynamic behavior of banana-shaped liquid crystals namely 4-chloro 1,3-phenylene bis{4-4 0 -(11-undecenyloxy) benzoyloxy} benzoate, detected by means of deuterium NMR in its nematic phase has been reported and discussed in terms of overall and internal molecular motions.65,66 A detailed 2H NMR study of a discotic monomer has been reported in its columnar phase. Angular-dependent spectral patterns and signal intensities as well as spin-lattice relaxation rates have been measured for the study.67 The behavior of nematic liquid crystal Merck Phase 4 confined to controlled pore glass materials has been studied using 129Xe NMR spectroscopy of xenon gas dissolved in the liquid crystal.68 When pore diameter is small xenon experiences an isotropic environment inside the pore and when the size is larger than approximately 150 A˚, a nematic phase behaviour is observed and the molecules are oriented along pore axis. In the largest pores, the orientation of the molecules deviates from the pore axis direction to magnetic field direction, which implies that the size of the pores is close to magnetic coherence length. Further studies have also been carried out as a function of temperature. Polymorphism and molecular dynamics of the liquid crystal MBBA [N-(p-methoxybenzylidene)-p-n-butylaniline], confined in controlled pores of porous glasses have been investigated using 1H NMR spectroscopy.69 The transition temperatures determined from the analysis of NMR line-shapes and spinlattice relaxation times indicate that the depression of the phase-transition temperatures is linearly related to the inverse of the pore diameter.

5. Chiral, smectic, lyotropic and polymeric systems In general, studies reported on the nematic phases are much more than the ones on other phases. This section deals with studies on phases other than nematic phases. Since several molecules exhibit more than one phase, it is not possible to clearly demarcate the different studies reported and the division has been done based essentially on the main theme of the report. Chiral liquid crystal media are gaining importance for discrimination of enantiomers and such studies are also included in this section. Deuterium NMR investigations have been carried out in the chiral phases of liquid crystals and both theory and experiments have been utilized to study the distortion of the helix by the NMR magnetic field.70,71 Analysis and the assignment of absolute configuration of natural abundance deuterium spectra associated with (R)- and (S)-enantioisotopomers in a fatty acid aligned in a Chiral Liquid Crystal has been reported.72 Enantiodifferentiation of acyclic phosphonium salts in chiral liquid crystalline solutions has been achieved by the use 2H, 13C and 31P NMR.73 13C NMR spectroscopy has been applied to chiral triazole compounds dissolved in the PBLG liquid crystal and the enantiomeric excess has been determined.74 Chiral differentiation of planar-chiral arenechromium tricarbonyl complexes by 13C NMR spectroscopy has been reported and the results discussed.75 Deuterium NMR spectra of perdeuterated tris (diimine) ruthenium(II) complexes have been recorded in lyotropic liquid crystal phase formed by the chiral polypeptide, PBLG and cosolvents.76 It has been shown that the left- and right-rotation isomers of these octahedral metal complexes with D3 symmetry can be distinguished in this medium. 13 C NMR spectroscopy has been used to probe the orientational ordering in the smectic A phase of a chiral liquid crystal. From a quantitative analysis of the chemical shifts and dipolar splittings, the location of the long molecular axis of the core and its order parameters have been obtained.77 Study of structure and dynamics of chiral ferrielectric phases by deuteron NMR has been reported. Angular dependent spectral parameters in a magnetic field in the chiral smectic C phases of a smectogen 1-methylheptyl 4 0 -(4-n-decyloxybenzoyloxy)biphenyl-4-carboxylate have been obtained. The data provide direct evidence of a phase transition between two ferrielectric phases in this compound.78 2H NMR measurements have been carried out to determine the alignment of deuterated 4 0 -pentyl-4-cyanobiphenyl Nucl. Magn. Reson., 2008, 37, 357–388 | 363 This journal is

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deposited on a SiO2 film comprised of independent, helical structures. Comparing measured spectra with models, it was concluded that the liquid crystalline molecules exhibit chiral ordering dictated by the features of the template films.79 A 13C NMR study of orientational ordering in the chiral phase of partially deuterated smectic liquid crystals has been reported.80 The addition of 2 to 6 weight percent of a chiral dopant to a series of nematic copolymers has been shown to induce blue and cholesteric mesophases which have been characterised by deuterium NMR spectroscopy.81 Using NMR and optical microscopy, nematic lyomesophases with discotic and cylindrical micelles in complex multicomponent lyotropic systems based on alkyltrimethylammonium bromide detergents have been identified. Addition of chiral dopants to the mixture was also found to lead to the formation of cholesteric phases.82 The synthesis and mesomorphic properties of a series of novel dimesogenic compounds containing the cholesteryl ester unit and a phenyl benzoate group have been reported. The compounds are observed to exhibit a cholesteric liquid crystalline phase over a wide range of temperatures.83 Deuterium two-dimensional exchange NMR experiments have been used to study the chiral phases of a smectogen (s)-1methylheptyl 4 0 -(4-n-decyloxy-benzoyloxy)biphenyl-4-carboxylate with the aim of obtaining information about translational self-diffusion constant and the structure of the helicoidal superlattice.84 2 H NMR spectroscopy along with other techniques, has been applied on a selectively deuterated sample of 4-n-butyl-4 0 -acetyl-biphenyl to study the properties of alignment of the smectic mesophases within a magnetic field, as well as to characterize molecular dynamics.85 Stochastic molecular motions in the nematic, smectic-A, and solid phases of p,p 0 -di-n-heptylazoxybenzene have been investigated by quasielastic neutron scattering and 13C NMR.86 Molecular dynamics studies by 2 H NMR spectroscopy in the ferroelectric liquid crystal (-)-(S)-[4-(2-methyl butyloxy carbonyl) phenyl] 4-heptyl biphenyl carboxylate-d8 in its smectic phases have been reported.87 Molecular dynamics in the smectic A and C phases of a long-chain ferroelectric liquid crystal has been studied by 2H NMR as well as other techniques.88 The orientation and order parameter of a liquid crystalline side chain copolymer has been studied by 13C NMR which indicates that the the smectic Asmectic C* transition in the system is attributable predominantly to a change of the molecular tilt angle.89 Viscosity coefficients corresponding to the Smectic-C* phase have been calculated based on parameters obtained from 2H NMR studies on the ferroelectric smectogens 4-[4 0 -(1-methylheptyloxy)] biphenyl (10-undecenyloxy) benzoate and (S)-[4-(2-methylbutyl) phenyl] 4 0 -octylbiphenylcarboxylate. The calculations help in predicting the laminar flow regime in high shear flow for these liquid crystals.90 A novel 2-dimensional pulsed gradient spin-echo NMR method has been proposed to obtain a correlation of molecular diffusion coefficients and thereby useful structural information on the mesophases of lyotropic liquid crystals. Experiments carried out in the lamellar mesophase of a 4-component system containing both nonionic and ionic surfactants, H2O and decane revealed local anisotropic selfdiffusion of the H2O molecules and suggested a preferred orientation of the lamellae. Information about defects/domain size could also be obtained.91 Using pulsed field gradient NMR, the anisotropic diffusion of H2O molecules in the lamellar phase of lyotropic system composed of cetylpyridinium chloride/hexanol diluted in brine has been studied. This lead to the measurement of both the amplitude and fluctuation correlation time of lamellar undulations in the phase.92 The phase diagram and the structure of the nematic mesophase present in the tetradecyl-trimethylammonium bromide/sodium bromide/water ternary system has been determined by studying the quadrupolar splitting of the deuterated surfactant and from diffusion measurements.93 Diffusion correlation measurements by NMR have been used to study the degree of orientational order in the lamellar phase of Aerosol OT (bis(2-ethylhexyl) Na sulfosuccinate) and H2O over a range of surfactant concentrations.94 The


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magnetically aligned nematic and hexagonal liquid crystalline phases of aqueous cetyltrimethylammonium bromide have been characterized.95 New polymer nematic nanocomposites have been reported containing 1.43–4.64% of Ag nanoparticles.96 Deuterium NMR spectroscopic measurements indicate that on increasing the content of metallic nanoparticles, the orientational order parameter of the nematic phase of the nanocomposites increases. 13C NMR along with other techniques has been used to show the formation of a highly ordered mesophase in the case of a liquid crystalline polyetherester derived from 4 0 -hydroxy-1,1 0 biphenyl-4-carboxylic acid and the ether-diol 4-(3-hydroxy propoxy) butan-1-ol.97 Deuterium NMR experiments on different types of liquid crystalline side-chain polymers have been presented and different parameters that affect the formation of a biaxial nematic phase discussed.98 Deuterium NMR has also been used for a comparative study of planar motion in powder samples of monomeric and dimeric discotics as a function of temperature in their columnar phases.99 The planar motion in the dimer is found to be at least 30 times smaller than that of the monomer which indicates that an enhancement of charge and energy transport in the dimer is possible. Structural and orientational behaviour of the liquid crystal (S)-2-methylbutyl-[4 0 -(400 -heptyloxyphenyl) benzoyl-4-oxy-(S)-2-((S)-2 0 -benzoyl) propionyl] propionate exhibiting a number of phases have been studied by 2H NMR spectroscopy and other experimental techniques.100 The unusual exhibition of a biaxial nematic phase in nonlinear thermotropic mesogens derived from the 2,5-oxadiazole biphenol (ODBP) core has been investigated and the NMR spectra of labeled probe molecules dissolved in the biaxial nematic phases studied.101 Several chemical modifications of the ODBP mesogenic core are presented.

6. Relaxation studies Field-cycling NMR technique has been used to measure proton spin-lattice relaxation time dispersion under simultaneous sonication in the nematic phase of 5CB.102 The results have been interpreted as arising out of metastable ordered states subject to a memory effect induced by the combined action of an amplitude-modulated ultrasonication and a pulsed magnetic field. Molecular motion in the ferroelectric liquid crystal p-decyloxybenzylidene p 0 -amino 2-Me Bu cinnamate has been investigated in the smectic A and chiral smectic C phases by 13C-NMR.103 The T1 measurements indicate that the rotational motion about the long molecular axis becomes less hindered in the SmC* phase. Molecular reorientations and internal conformational transitions of an aligned chiral liquid crystal has been studied by 2H spin-lattice relaxation in its smectic A and smectic C* phase.104 Molecular rotation around the long axis in chiral smectic phases has been studied by following the temperature dependence of 13C T1 in the ferroelectric liquid crystals, (S)-4-(1methylhexyloxycarbonyl)phenyl 4 0 -octyloxybiphenyl-4-carboxylate and (S)-(+)-2methylbutyl 4-(4-decyloxybenzylideneamino)cinamate.105–107 The study reveals that the activation energy of the molecular rotation in the Smectic C* phase is lower than that in the Smectic A phase. A proton spin-lattice relaxation time dispersion study in smectic A phase of two poly-(amidoamine) liquid crystalline dendrimers has been reported and the results interpreted in terms of disorder induced by the dendritic core.108 In a similar study on a liquid crystal dendrimer exhibiting columnar rectangular and smectic-A phases, the results have been interpreted using relaxation mechanisms associated with collective motions and local molecular reorientations of the dendritic segments as well as the spatial constraints imposed by the dendritic architecture and by the supermolecular arrangement in the mesophases.109 The influence local motions and slow cooperative fluctuations have on the relaxation of the intrapair dipolar order in the nematic 5CB has been studied by the measurement of deuterium Zeeman and dipolar order relaxation times as a function of temperature and the relaxation mechanisms identified.110 Redfield spin-lattice relaxation theory has been used for calculating the relaxation times of the different dipolar Nucl. Magn. Reson., 2008, 37, 357–388 | 365 This journal is

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quasi-invariants in an eight-spin system provided by methyl deuterated paraazoxyanisole (PAA-d6) in the nematic phase and the results discussed in the context of the effect that slow and ultraslow molecular modes could have on the relaxation of the dipolar order.111 Deuterium and 14N spectral densities of motion for the decylammonium chloride/H2O system have been obtained in its lamellar phase and the results analysed to obtain information on the headgroup dynamics.112 Proton relaxation rates of nematic liquid crystals confined in nanoporous cavities have been measured over a broad frequency range. Experimental results have been interpreted in terms of surface-induced orientational order and diffusion between sites with different orientations of local directors.113,114

7. Orientational order in liquid crystals 13

C and 1H NMR studies of the columnar phases of 2,3,6,7,10,11-hexahexylthiotriphenylene have been reported wherein the order and dynamics of the mesophases have been investigated at the molecular level.115 The orientational order parameters and conformational behavior of five rodlike molecules viz., biphenyl, trans-stilbene, 1,3-diphenylbutadiene, 1,3,5-diphenylhexatriene, and 1,3,5,7-diphenyloctatetraene, dissolved in the thermotropic liquid crystal ZLI-1167, have been studied using 13C NMR measurements and computations of 13C chemical shift tensors. The study supports the common assumption of effective uniaxiality of these probes.116 A method based on the measurement of the Saupe ordering matrices of a collection of biaxial solute molecules dissolved in the nematic liquid crystal has been proposed to study the director distribution in a nematic liquid crystal confined in a slab geometry.117 The orientation of banana-shaped molecules in the magnetic field has been studied and a new hypothesis for the peculiar aggregation of these molecules has been proposed and discussed in the light of 2H NMR measurements on selectively 2H labeled mesogens and their sub-units.118,119 Orientational order properties of two fluorinated nematogens have been investigated by means of optical methods, dielectric spectroscopy, and 13C NMR and the obtained order parameters compared in terms of the anisotropies of the corresponding parameters.120 The Saupe ordering matrix of a banana-shaped mesogenic molecule as a solute in a common nematic calamitic solvent has been measured by 2H-NMR as a function of temperature and the study indicates a glassy behavior in the reorientational motion exhibited by the system.121 The utility of 13C chemical shift anisotropy tensors for obtaining ordering information in the case of achiral molecules which form the banana phase has been demonstrated.122 Synthesis and characterisation of new thiophene-containing mesogens are reported and their liquid crystalline properties and molecular order studied using natural abundance 1D and 2D 13C solid-state NMR techniques.123–125 Mesogens consisting of a terminal dimethylamino group, which can act as a charge-transfer donor, are of significant interest for their light emission and nonlinear optical properties. One such compound, 4-(dodecyloxy) benzoic acid 4-[((4-(dimethylamino) phenyl) imino) methyl] phenyl ester, has been studied by solid-state NMR. 1H and 13C chemical shifts and dipolar couplings have been obtained and the results discussed in terms of orientation and ordering in the molecule.126 Behavior of the orientational order parameter in composite structures formed by a nematic liquid crystal and fullerene has been studied by 1H-NMR and an increase in the order parameter reported which is a typical of nonmesogenic additives.127 13C NMR studies of chloroform/cryptophane-A and chloroform/biscryptophane inclusion complexes oriented in thermotropic liquid crystals have been reported and the alignment of these host–guest systems studied.128 Large 1H–13C dipolar splittings for the chloroform guests provided an indication of the significantly enhanced ordering for the trapped ligands in comparioson to the free ligands. From variable-temperature studies the sign and the magnitude of the order parameter for C–H bond of chloroform have been determined and the results interpreted to obtain an overall alignment of the complexes. 366 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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8. Membranes and molecules oriented therein This section deals with studies of membranes, model membranes and molecules oriented in them. The literature covered essentially pertains to samples which are in the liquid crystalline phase and are oriented by the magnetic field of the NMR magnet or by mechanical means. There is significant amount of literature which pertains to unoriented powder samples which are studied by techniques like magic angle spinning. This report does not cover these aspects. Studies which are in the nature of methodological development are summarized below and this is followed by various applications. Recent studies aimed at the determination of membrane protein structure and dynamics and their interactions with ligands have been summarized.129 A review on the commonly used model membrane systems for studying drug–membrane interactions using NMR with an emphasis on phospholipid bicelles is available.130 A method for assigning solid-state NMR spectra of membrane proteins aligned in phospholipid bicelles that makes use of isotropic chemical shift frequencies and assignments has been demonstrated.131 The resonance assignments are based on comparisons of 15N chemical shift differences in spectra obtained from samples with their bilayer normals aligned perpendicular and parallel to the direction of the applied magnetic field. 15N detection of mechanically aligned membrane proteins require large sample volumes that compensate for the low sensitivity of the observe nuclei, dilute samples and for the poor filling factor arising from the presence of alignment plates. This problem has been addressed and the design and construction of a large volume flat coil probe reported.132 Membrane proteins in the lipid bilayer are studied by orienting them in the static magnetic field of the NMR spectrometer. For this purpose, oriented phospholipid bilayer and hexagonal phases prepared on mica have been examined.133 The straightforward preparation and handling of extremely thin mica substrates with consistent surface properties were found to be advantageous. The ability to cast thin films of lipids have been tested with different lipid and solvent combinations and the degree of orientation tested by 31P NMR. A 2D solid-state NMR approach that can be used to measure the heteronuclear dipolar couplings between 1H, 13C, and 31P nuclei in bicelles without the need for isotopic enrichment has been presented and its utility for structure determination of membrane peptides and proteins discussed.134 Though many biological phospholipids contain at least one unsaturated alkyl chain, only a few studies of order parameters of unsaturated lipids have been reported because of the difficulty associated with isotopic labeling of a double bond. In order to alleviate this problem a solid-state NMR technique optimized for measuring 1H–13C dipolar couplings at natural abundance and order parameters in lipid membranes in the fluid phase has been suggested and its utility demonstrated by applying it to determine the order parameters of each acyl chain of 1,2-dioleoyl-sn-glycero-3-phosphocholine.135 Pulsed field gradient NMR has been utilized for the study of lateral diffusion in macroscopically aligned lipid bilayers and the results of the study on molecules like cholesterol in membranes have been presented.136–138 2H NMR spectra have been obtained of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine /ergosterol bilayers in the liquid crystalline phase as a function temperature and relative concentrations and analysed to show the presence of two types of liquid crystalline domains over a wide temperature range. The study also indicates a linear relation between membrane lysis tension and the first moment of NMR spectral line, suggesting that changes in acyl chain ordering affects the tensile properties of the membrane.139 15N and 2H NMR studies have been carried out on macroscopically oriented samples of the a helical peptide, pleurocidin in model membranes and the obtained data have been discussed in terms of a general mechanism for the antibiotic activity of the compound.140 Samples of selectively deuterated N-palmitoyl sphingomyelins have been macroscopically aligned and the structure and interaction with the lipid studied by 2H NMR from the measurement of C–D bond order parameters, derived from Nucl. Magn. Reson., 2008, 37, 357–388 | 367 This journal is

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the 2H quadrupolar splittings.141 The alignment of pyrene in a 1-palmitoyl-2oleoylphosphatidylcholine bilayer has been investigated by measuring 2H quadrupolar splittings of deuterated pyrene-d10 in an oriented lipid bilayer and combining with molecular dynamics simulations.142 2H NMR experiments on dipalmitoylphosphatidylcholine/ergosterol has been combined with calorimetric studies and the phase diagram of the system has been obtained.143 Mixtures of phosphatidylcholine lipid containing a biphenyl group in one of its acyl chains, with a short-chain C6 lipid has been shown to lead to bicelle formation and the flat bilayered disks formed have been observed to align with their normal parallel to the magnetic field as detected by 31P, 14N, 2H solid-state NMR.144 Changes in membrane topology introduced by the association of molecules with membranes have been analyzed utilizing the 1H–13C heteronuclear dipolar couplings of magnetically aligned bicelles. The transmembrane segment of the antimicrobial peptide, phospholamban and cholesterol were incorporated into the bicelles and the 1H–13C dipolar coupling profiles monitored to study the interaction mechanisms exist between the molecules and the membranes.145 Phosphorus and deuterium NMR have been used to determine the phase diagram of binary mixtures of 1,2-di-O-tetradecyl-sn-glycero3-phosphocholine (DIOMPC) and 1,2-di-O-hexyl-sn-glycero-3-phosphocholine (DIOHPC) ether-phospholipids and the conditions for which such systems are oriented by the magnetic determined.146 The interaction of ethanol in magnetically aligned bicelles with the phospholipids has been studied by measuring residual 1H–1H and 1H–13C dipolar couplings and residual 2H quadrupole splittings of isotope-labeled ethanol.147 Information such as orientation and motions of ethanol in the membrane-bound state and the fraction of phosphatidylcholine-bound ethanol have been obtained. The anisotropic NMR parameters measured for a membrane protein in weakly oriented micelles and in oriented lipid bilayers have been shown to provide independent and complementary high-resolution restraints for structure determination of the protein.148 For the membrane protein studied, a similar structure in lipid micelles and bilayers was observed, allowing the restraints from micelle and bilayer samples to be combined in a complementary fashion to enhance the structural information. Mixtures of dicaproyl- , dimyristoyl- and 1-tetradecanoyl-2-biphenylbutanoyl-phosphatidylcholine in water are shown to form bicelle membranes that are oriented by magnetic fields over a narrow compositional range but over a large temperature range with the plane of the membrane orienting perpendicular to the magnetic field. The use of these bicelles as a potential tool to study the orientation of hydrophobic helixes in membranes using wide line 15N-NMR has been presented.149 Residual dipolar couplings have been used for the analysis of transient binding between phosphatidylcholine bilayers and polyols.150 Solid-state NMR spectra of three membrane proteins uniformly aligned in lipid bilayers between glass slides have been studied and the tilt angles of the transmembrane helixes have been obtained from the resonance patterns in the 2D-SLF spectra.151 The use of a laboratory-frame SLF experiment for accurately measuring long range hetero-nuclear dipolar couplings in magnetically aligned bicelles has been proposed and the measurement of 13 C–31P and 1H–31P couplings for a phospholipid described. The approach was also utilized to probe the membrane interaction of an antidepressant molecule, desipramine, and its location in the membrane.152 A magic-angle spinning cross-polarization NMR experiment has been proposed to study changes in the segmental order in lipid bilayers in the liquid crystalline phase with hydration.153 Deuterium NMR has been used to investigate the phase diagram of a phospholipid/sterol membrane system and from the study the region where two liquid crystalline phases coexist has been located and characterized.154 Dipolar couplings within and between distant CF3-groups in a membrane-bound peptide have been proposed to be obtained using the CPMG approach and the method has been applied to distinguish and assign two epimers of the labeled gramicidin S peptide on the basis of their distinct 19F dipolar coupling patterns.155 Use of giant proteolipidic vesicles as intermediate for the 368 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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preparation of well oriented membrane protein-lipid bilayers has been proposed.156 Solid-state NMR studies of membrane proteins in magnetically oriented bicelle samples has been summarised.157 Studies on the following membrane oriented systems have been reported: Structural and dynamical properties of membrane-anchored electron-carrier protein, Cytochrome b5.158 Three-dimensional structure of the transmembrane domain of Vpu from HIV-1 in aligned phospholipid bicelles.159 Spectral studies and drugreceptor interactions of a G protein-coupled receptor.160 Reconstitution and alignment in the magnetic field of a b-barrel membrane protein, tOmpA, in bicelles.161 Effect of gramicidin A on the orientation of bicelles in the absence and presence of Eu3+.162 Rotational diffusion of membrane proteins in aligned phospholipid bilayers; example of the protein Vpu from HIV-1.163 Structural studies of nAChR M2 peptide.164 Backbone structure of the M2 trans-membrane domain of the Influenza A virus blocked with amantadine.165 Membrane topology of a sysnthetic 14-mer model amphipathic peptide.166 Structure, dynamics and topology of membrane polypeptides by oriented 2H solid-state NMR spectroscopy.167 Dynamics and topology study of Phospholamban, a membrane protein that regulates heart muscle contraction and relaxation.168 Structure and dynamics of membrane-associated ICP47, a viral inhibitor of the antigen-processing machinery.169 Molecular recognition and biological function at water-bilayer interfaces using piscidins, antimicrobial peptides from fish.170,171 Membrane-disrupting mechanism of antimicrobial peptides MSI-78 and MSI-594 derived from magainin 2 and melittin.172 Structural domains study of viral protein U (Vpu) of human immunodeficiency virus-1 (HIV-1) in oriented phospholipid bilayers.173 Equilibrium between different topologies of ion channel peptides in oriented lipid bilayers.174 Detergent-like properties of magainin antibiotic peptides studied by 31P NMR.175 Structure, topology, and tilt of cellsignaling peptides SA and SKP in membrane bilayers.176 Peptide-lipid interactions of the b-hairpin antimicrobial peptide tachyplesin and its linear derivatives.177 Orientation of a b-hairpin antimicrobial peptide retrocyclin-2 in lipid bilayers.178 NMR investigations of the Pf3 coat protein in oriented phospholipid bilayers.179 Structural and orientational constraints of bacteriorhodopsin in purple membranes.180

9. Structure and orientation of small molecules This section covers essentially studies on structure and conformation of small organic molecules and their interaction with the orienting media. The liquid crystalline media considered are mostly thermotropic nematics with a large order parameter. Studies of large biological molecules in weakly orienting media are considered under separate section. The strong ordering and the large dipolar couplings of molecules oriented in thermotropic nematics make the spectra strongly coupled, requiring different strategies for analysis of such spectra than those obtained with weak ordering. The development in this area is covered in the literature presented below. The question of the influence of the solvent liquid crystal on the structure of a dissolved solute molecule has been addressed by studying norbornadiene, a rigid bicyclic molecule with a C2v symmetry, in three different nematic phases.181 It was observed that (i) the order parameters obtained by the analyses of the 1H NMR spectra at different temperatures could be successfully reproduced by a model based on Monte Carlo simulations and (ii) the theoretically calculated geometry of the molecule was compatible with experimental data within 5% error. This leads to the conclusion that the structure of the solute is not significantly distorted by the solvents used in the experiment. Single quantum and multiple quantum coherence experiments involving 19F and 33S for sulfur hexafluoride dissolved in thermotropic Nucl. Magn. Reson., 2008, 37, 357–388 | 369 This journal is

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liquid crystals have been carried out and the results have been used to investigate the influence of the liquid crystal environment on the NMR parameters of SF6.182 Obtaining order parameters of oriented solutes from 13C NMR data requires a knowledge of the 13C shielding tensors. As this information is scarce, a high-level ab initio computation and inclusion of the solvent effect with an appropriate model has been proposed for the purpose and applied to available experimental data.183 NMR spectra of ortho-, meta- and para-dichlorobenzene have been obtained in the nematic and smectic A phases of the liquid crystals 8CB and 8OCB and in a binary mixture of liquid crystals 6OCB/8OCB which exhibits both high temperature nematic and low temperature reentrant nematic phases.184,185 The analysis of the spectra gave two independent order parameters from which the solute smectic potential has been obtained. Deuterium NMR experiments on dideuterium dissolved in four different nematic liquid crystal solvents have been carried out as a function of temperature. The results have been analyzed in terms of an average electric field gradient anisotropy experienced by deuterium.186 The concentration dependence of the liquid crystalline orientational order parameter has been studied from the NMR spectra of four solutes each recorded at different concentrations. Agreement at the 3% level between experiments for different solutes has been observed under certain conditions.187 The magnitude of the partially averaged dipolar couplings for a non-rigid molecule depends upon several factors such as the bond lengths and angles, the rotational potentials and the orientational order of the molecules. For the molecule 1-chloro-2-bromoethane the problems inherent in deriving the form of the rotational potential and the molecular geometry from the set of partially averaged couplings between the protons and between protons and 13C nuclei have been studied and the results obtained have been compared with the results from a density-functional theory.188 Quantum chemical calculations have been used to obtain the structure and the distribution of conformers of tetraethyl stannane which are then used to explain the finite 2H quadrupolar splittings of the compound oriented in a nematic liquid crystalline solvent.189 The study emphasizes that to understand the orientational order of a flexible molecule in a liquid crystalline phase, it is essential to consider the symmetry of individual conformers rather than that of the average structure. Orientation of molecules by high magnetic fields has been considered. High-resolution 1H NMR spectra of 1,2,3-trichloronaphthalene at different magnetic field strengths have been recorded and the spectra analyzed to obtain the J and the dipole–dipole coupling constants and the magnetic susceptibility tensor parameters of the molecule. Ab initio calculations on the same molecule are in good agreement with the experimental values.190 Eathane and its isotpomers have been considered as examples of molecules with large-amplitude torsional motion and studied in partially oriented in a nematic liquid crystal.191 The obtained dipolar couplings were corrected for harmonic vibrational effects and the contribution from the torsional motion. However an additional reorientation–vibration contribution needed to be taken into account before good agreement between observed and calculated dipolar couplings was obtained. A conformational study of 2,2 0 -bithiophene from the analysis of 1H NMR and 13C satellite spectra the compound dissolved in partially orienting mesophases has been reported.192 Comparison of the results with those of high-level theoretical calculations provides evidence of a strong flattening as well as the sharpening effect of the medium on the conformer population. Conformation and orientation of tetraalanine in the lyotropic liquid crystal cesium pentadecafluorooctanoate (CsPFO)/water has been studied from the 1 H NMR spectra of two isotopomers of tetraalanine.193 For the allowed conformer, determined on the basis of theoretical calculation, the molecule was oriented with the long molecular axis tilted with respect to the surface of the micelles formed by CsPFO. An analysis of 1H–1H residual dipolar couplings obtained for diphenylmethane, based on the APME (Additive Potential/Maximum Entropy) procedure has been described and the results compared with those of earlier analysis.194 Chemical shifts and residual dipolar couplings between protons in solutes have 370 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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been studied in a series of dilute liquid crystal solvents and they are found to be almost independent of the local environment. A linear relationship between residual dipolar coupling and liquid crystal concentration was also observed at relatively low concentrations.195 A genetic algorithm for the automatic assignment of the complicated NMR spectra of oriented molecules has been proposed and the applicability of the method demonstrated for the nine-spin system of p-bromo-biphenyl, a molecule that interconverts between two symmetry-related conformations.196 199Hg–13C spin– spin coupling tensor parameters in methylmercury halides have been determined by obtaining their NMR spectra in liquid crystal solvents.197 The values obtained matched with density functional calculations with solvent effects taken into account. The dipolar couplings with the inclusion of vibrational corrections can provide accurate bond distances. A study has been undertaken to obtain the vibrational corrections required for the above purpose experimentally and from quantummechanical computations and to study the reliability of the methods used on benzene for which a very accurate structure is available.198 The conformational equilibrium of 1,3-butadiene has been investigated as an example for obtaining the structure and conformational distribution of a flexible molecule in a fluid phase.199 The full set of DHH and DCH dipolar couplings were determined and analysed using multiple quantum refocused spectroscopy and a Monte Carlo numerical simulation. The experimental data was observed to be fully compatible with the presence of about 99% of s-trans conformer while with regards to the remaining 1%, it was not possible to discriminate between the planar s-cis and s-gauche forms, both of which produce a very good fit of the dipolar couplings. NMR spectra of 1,2-dibromo-1,1difluoroethane and 1-bromo-2-iodo-tetrafluoroethane dissolved in nematic liquid crystal solvents have been analyzed to obtain spectral parameters involving 1H, 19F, and 13C nuclei which were used to determine the structure, orientational order, and the conformational distribution generated by rotation about the C–C bond.200 A comparison of the results with those obtained from ab initio calculations and density functional methods indicated no definitive evidence for significant contributions from anisotropic contributions of the J coupling involving fluorine in the two compounds studied. The proton NMR spectrum of the doubly 13C labeled acetophenone has been reported and analyzed to yield a data set of 19 dipolar couplings from which it was possible to investigate the cooperative nature of the internal rotational motions in the compound.201 The proton NMR spectra of samples of 2thiophenecarboxaldehyde and its 13C labeled isotopomers dissolved in a nematic liquid crystal solvent have been obtained.202 These have been analyzed to yield the structure and the relative amounts of the cis and trans forms of the compound, which are the two minimum energy structures generated by rotation about the ringaldehyde bond. A combined use of deuterium NMR and computer simulations for conformational investigation of flexible molecules in nematic solutions has been suggested.203 As a test of the methodology, the temperature dependence of inter-ring angle of biphenyl in a nematic solution was studied and the results showed a very slight tendency of the inter-ring angle to inter-ring angle to increase with the temperature. The structure of acrolein and its conformations generated by rotation around the C–C bond in a liquid crystal phase have been reported.204

10. Weak ordering and biomolecular studies This is an area that continues to receive considerable attention and the literature covering this area has been divided into the following sub-sections: Reviews and General studies, Orienting Media, New Experimental Methodologies, New Pulse Schemes, Computational Methods, Structure, Conformation, Domain Orientation and Dynamics Studies on Proteins, Peptides and Nucleic Acids. Nucl. Magn. Reson., 2008, 37, 357–388 | 371 This journal is

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10.1 Reviews and general studies The reviews cover several aspects. These include development and applications of orienting media for such studies,205,206 measurement and use of RDCs207–209 and applications to protein210 and nucleic acid211,212 structure and dynamics studies. In addition new applications for residual dipolar couplings that extend the range of use of NMR in structural biology have been described.213 Approaches to achieve paramagnetic tagging of proteins and precise measurements of residual dipolar couplings have been presented.214 A review describing topics such as options for solute alignment, NMR strategies for detection of RDCs, use of RDCs in protein structure determination and for establishing domain orientation has been presented.215 Transient binding of ligand to an aligned target molecule has also been illustrated with RDC-based structure determination of a rhodopsin-bound transducin peptide. Study of protein–RNA complexes by NMR has been reviewed particularly in the context probing the structure and dynamics of large complexes.216 Current trends in the studies of membrane amphiphiles and membrane proteins using both fast tumbling bicelles and magnetically aligned bicelle media for have been reviewed.217 A review of NMR of oriented bilayer systems is available. Topics discussed include magnetically and mechanically oriented bilayer systems, orientation-dependence of the chemical shift and dipolar interactions, and structure determination of membrane peptides by these techniques.218 A set of sensitivity enhanced experiments for the accurate measurement of backbone residual dipolar couplings in proteins has been described.219 Also a novel application for the use of RDCs has been presented by which it is possible detect certain conformational sub-states that are characterized by re-orienting bond vectors. The basic alignment process of an ensemble of protein conformations and the contributions of each member of the ensemble to the residual dipolar coupling signals has been considered.220 It is concluded that molecular fluctuations can affect the alignment and as a result emphasis of certain conformations. The use of precisely determined RDCs for studying subtle effects of internal protein dynamics has been highlighted. The potential of RDCs to reveal motions taking place on a timescale slower than rotational diffusion and their sensitivity not only to amplitude but also to the direction of motion has been discussed.221 An NMR protocol is described that relies primarily on orientational constraints obtained from residual dipolar couplings and can produce a backbone structure of a protein without the need for extensive experiments on the side chains.222 Procedures for sample preparation, data acquisition, and data analysis have been described, along with examples of application to small target proteins. 19F-NMR analysis of oriented biomembranes has been dealt with.223 A thorough study of RDCs has been presented which leads to a dynamic interpretation of RDCs in ubiquitin and to the presence of new modes of slow motion in the protein.224

10.2 Orienting media The effect of the alignment media used for measuring residual dipolar couplings on the molecular structure of the solute has been studied by obtaining the structural parameters of acetonitrile in different aligning media.225 Only minor variations of the structural data were observed which are shown to be in good agreement with microwave data and theoretical predictions. For achieving partial alignment of membrane proteins, the use of lanthanide ions bound to the protein through a small thiol-linked metal chelator has been proposed.226 This method has been shown to provide multiple alignment orientations depending on the ion bound and to permit RDC measurement of multiple bond vectors. Two new chiral EDTA-based metal chelates for weak alignment of proteins in solution have been proposed and their use for the measurement of residual dipolar couplings and pseudocontact shifts demonstrated.227 The problem of achieving weak alignment of membrane proteins in the 372 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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magnetic field has been considered.228 As many of the existing media used to align water-soluble proteins are not compatible with the detergents required to solubilize membrane proteins, newer strategies are being suggested. In that direction, the design and construction of a detergent-resistant liquid crystal made of DNAnanotubes that can be used to induce weak alignment of membrane proteins has been reported and accurate measurement of backbone RDCs for a detergentreconstituted membrane protein is demonstrated. Peptide sequences that can tightly and selectively complex two Lanthanide ions called double Lanthanide-binding tags (DLBTs) have been designed and their utility as alignment-inducing agents to obtain residual dipolar couplings investigated.229 Proteins encapsulated within the aqueous core of reverse micelles have been shown to partially align in a magnetic field and provide sizable residual 15N–1H dipolar couplings that can be easily measured.230 The measurement of independent sets of NMR residual dipolar couplings in multiple alignment media has been considered.231 This was demonstrated for ubiquitin using just a single alignment medium composed of aligned bacteriophage Pf1 particles embedded in a strained polyacrylamide gel matrix. Molecular alignment could be modulated by varying the angle between the directors of ordering for the Pf1 and strained gel matrix, or by varying the ionic strength or concentration of the Pf1 particles. Magnetic alignment of phospholipid bilayers in the gel and La phases has been studied by 2H NMR as well as other techniques.232 10.3 New experimental methodologies Experimental methodologies in this area are aimed at obtaining new information, improving the accuracy of measurements and for increasing the speed of spectral analysis and structure determination. Nonuniform sampling and maximum entropy reconstruction has been applied for accelerated and accurate measurement of residual dipolar couplings.233 By this technique RDCs have been obtained that agree within an RMS of 0.67 Hz with those derived from uniformly sampled, Fourier transformed spectra. The possibility of encountering systematic errors when using this technique and ways to overcome them have been discussed. Separated local field NMR experiments on oriented samples rotating at the magic angle has been described.234 Details of samples used and the experimental details have been presented with the demonstration of the feasibility of the experiments on highly ordered polyethylene fibers and on ordered multi-layers of bacteriorhodopsin. Determination of the residue-specific 13C 0 carbon CSA tensor principal components and the tensor orientation have been reported for ubiquitin.235 Correlation between the tensor components and hydrogen bonding in the system has been observed. However no strong correlation between any of the CSA tensor components was observed with any single structural feature for a similar study of 15N CSA tensors.236 Using residual chemical shift anisotropies measured in a weakly aligned stem-loop RNA, the carbon chemical shift anisotropy tensors of nucleobase adenine C2, pyrimidine C5 and C6, and purine C8 carbons have been examined.237 It is concluded that the residual chemical shift anisotropies can be translated into useful long-range orientational constraints for RNA structure determination. In view of the highthroughput requirements of structural genomics activities, methodologies have been presented which are based primarily on residual dipolar couplings, that constrain the orientation of backbone fragments irrespective of the separation in space.238,239 A new software tool has also been described that exploits this approach. Bond vibrations, random angular fluctuations around bond vectors and conformational exchange all influence the magnitude of RDCs. The effect that angular fluctuations have upon the magnitude of RDCs has been quantified and the consequences of the different types of angular motion for the accurate determination of bond vector orientation, with respect to the alignment tensor, has been studied.240 Direct detection of 13C nuclei has been shown to be efficient approach to identify signals of residues that escape detection in 1H detected experiments.241 New pulse sequences Nucl. Magn. Reson., 2008, 37, 357–388 | 373 This journal is

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have been proposed that provide the couplings with the same resolution available in conventional 1H detected experiments and the method demonstrated for protein structure determination. Simultaneous determination of protein backbone structure and dynamics from residual dipolar couplings has been proposed by the use of analytical descriptions of dynamic averaging of RDCs and the method demonstrated on protein GB3.242 Simultaneous analysis of NMR relaxation data and residual dipolar couplings has been suggested to obtain information about interdomain dynamics in a multidomain protein and the approach has been demonstrated for Lys48-linked diubiquitin and for the protein VAT-N.243,244 The interference between cross-correlated relaxation and the measurement of scalar and dipolar couplings by quantitative experiments has been considered.245 It is observed that scalar and dipolar couplings of the same pair of nuclei vary depending on the type of magnetization involved. It is shown that processes of magnetization transfer originated by cross-correlated relaxation are largely responsible for these discrepancies. The accuracy of protein structure obtained from RDCs has been evaluated by analyzing a database of 100 single-domain proteins.246 An empirical formula has been proposed to estimate the accuracy of the obtained protein structures. Slow correlated motions such as those that occur in the loops, and in the b-sheet in proteins are proposed to be studied using residual dipolar couplings.247 The nature and amplitude of such motion in protein G have been identified and the results crossvalidated by hydrogen-bond scalar coupling measurements. The periodicity of residual dipolar couplings offers the possibility of determining peptide plane orientations in regular periodic protein secondary structure elements. Each peptide plane orientation can also be considered a ‘‘pixel’’ of protein structure and these features have been exploited in a method that allows determination of secondary and tertiary structure of a-helical proteins.248 This approach has been demonstrated for the structure of domain 1 of the receptor-associated protein using RDCs measured in a single alignment medium and a minimal number of NOE distance restraints. A method for rapid and accurate structure determination of coiled-coil domains using NMR dipolar couplings has been proposed and applied to cGMP-dependent protein kinase Ia.249 A strategy designed to measure simultaneously and without increased resonance overlap scalar and dipolar couplings in 13C-, 15N-labeled proteins has been presented.250 Sensitivity of RDCs to perturbations in folded and denatured states has been studied with staphylococcal nuclease as an example.251 The results suggest that RDCs are more sensitive to structural changes in folded than unfolded proteins. Protein backbone dynamics from N–HN dipolar couplings in partially aligned systems has been studied.252 A comparison of three motional models in the presence of structural noise has been made. A quick and accurate method has been described for assessing protein alignment from residual dipolar coupling measurements.253 In contrast to observing D2O resonance splitting, which reflects the orientational order of the alignment medium, it is suggested that the degree of alignment of a protein of interest may be estimated directly from 1H–1H RDCs. This approach has been demonstrated for the protein unlabeled Cp-rubredoxin. 10.4 New pulse schemes In view of the importance of magnetically aligned bicelles for the study of membraneassociated peptides and proteins, experimental aspects of the NMR study of DMPC/ DHPC bicelles have been presented with particular emphasis on approaches to enhance the sensitivity and resolution and to quantify radio-frequency heating effects.254 13C and 14N NMR studies have been discussed and an alternate proton decoupling sequence in the place of conventionally used ones has been suggested. Applications of variable-angle sample spinning to the measurement of scaled residual dipolar couplings and 15N CSA in soluble proteins has been suggested and applied to NMR spectra of ubiquitin in the presence of bicelles. Magic angle and off-magic angle spinning measurements lead to the determination of scalar and scaled residual dipolar 374 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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couplings, respectively.255 A sensitivity-optimized experiment for the measurement of residual dipolar couplings between amide protons in protonated protein samples has been proposed.256 The proposed pulse scheme optimized in terms of longitudinal relaxation efficiency and J-mismatch compensation for coherence transfer was found to yield a signal gain between 1.5 to 8 in comparison to previously proposed pulse schemes. A new HSQC pulse sequence based on spin-state selection has been proposed for the simultaneous measurement of several NH and CH scalar and residual dipolar couplings in double labeled proteins.257 Enhanced resolution and sensitivity enables the experiment to be used for epitope mapping and for following changes in protein conformation induced by ligand binding. A spin-state selective experiment incorporating TROSY (Transverse Relaxation Optimized Spectroscopy) has been shown to provide high resolution and sensitivity and has been applied to a protein to obtain scalar and residual dipolar couplings.258 A number of J-evolved experiments have been examined in the context of measurement of RDCs using a peptide and a protein as model systems.259 Choice of appropriate pulse sequence and the choice of suitable alignment medium by which the RDC can be scaled have been indicated as possible approaches to achieve the required resolution. A new approach based on G-Matrix Fourier transform formalism has been implemented for simultaneous measurement of correlated chemical shifts and one-bond spin–spin couplings.260 The method enables measurement of RDCs with high precision and accuracy. Simple modifications to the gradient enhanced version of the TROSY experiment has been suggested that allows residual dipolar coupling values to be obtained for medium sized proteins.261 Exploiting the E.COSY principle four correlation experiments have been proposed that enable measurement of several scalar and RDCs simultaneously.262 An improved 3D experiment for Ha–Ca–C 0 correlation has been shown to be a sensitive and accurate method to measure Ca–Ha residual dipolar couplings and its performance tested on two proteins with different secondary structures.263 Selective manipulation of spins in new 2D and 3D experiments have been proposed for accurate measurement of onebond Ca–Ha residual dipolar coupling constants in proteins.264 A fast multi-dimensional experiment proposed earlier has been investigated in detail for its performance to provide correlation spectra of proteins of different size and at different magnetic field strengths.265 Fast measurement of one-bond 1H–13C and 1H–15N scalar and residual dipolar coupling constants have also been considered. A new set of improved threedimensional NMR experiments for measuring residual dipolar couplings in proteins has been presented.266 Using spin-state selection and editing in three dimensions, the experiments allow accurate measurement of intra-residual scalar and residual dipolar couplings in proteins. A new 3D, spin-state-selective coherence transfer NMR experiment has been presented that yields accurate measurements for eight scalar or dipolar couplings involving protons and carbons within a spin system composed of a methylene adjacent to a methine group.267 Implementations of the experiment have been optimized for proteins and for nucleic acids. A set of experiments for efficient and precise measurement of residual dipolar couplings from 2D HN–N correlation spectra have been described.268 Pulse sequences with numerically optimized coherence transfer schemes for measuring 1H–1H and 1H–13C RDCs in methyl groups have been proposed and illustrated with application of the method to a 17 kDa protein weakly aligned by means of Pf1 phages.269 A novel 13C-detected 2D experiment for simultaneous correlation of one-bond and long-range 13C–13C pairs and the measurement of corresponding scalar or residual dipolar coupling constants in 13C natural abundance samples has been proposed.270 An example of this approach has been presented. 10.5 Computational methods Computational procedures have a very important role and translate the vast data collected into molecular structure which is further used for gaining knowledge about the function of the biological system. Orientational constraints obtained from solid state NMR experiments on anisotropic samples have been used for molecular Nucl. Magn. Reson., 2008, 37, 357–388 | 375 This journal is

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dynamics (MD) simulations for determining the structure and dynamics of several different membrane-bound molecules.271 The method was tested on three systems of increasing complexity and the MD simulations were able to reproduce the NMR parameters within experimental error. The alignment of the three membrane-bound molecules and some aspects of their conformation were also derived from the NMR data. An algorithm for protein backbone structure determination from solution NMR data has been presented.272 It is shown that residual dipolar coupling data can be used in conjunction with very sparse NOE data to obtain a polynomial-time algorithm for structure determination. Different strategies of using residual dipolar couplings in NMR-based protein structure calculations have been suggested and illustrated with application to Lys48-linked di-ubiquitin.273 Residual dipolar couplings provide valuable information about the orientation of each internuclear vector in a macromolecule with respect to the static magnetic field. However, structure determination utilizing RDC still remains challenging without additional restraints such as NOE. In this context, a novel approach has been developed to efficiently extract structural information from RDC by successive application of singular value decomposition method in the course of structure determination.274 The efficacy of this approach is illustrated by showing that by using only RDC restraints in the molecular dynamics simulations, it is possible to arrive at the appropriate structure given an initial distorted one. Ensembles obeying the laws of statistical thermodynamics describe the proteins undergoing dynamic excursions away from their average three-dimensional structure. An unrestrained molecular dynamics ensemble of ubiquitin using the AMBER99SB force field has been reported, which reproduces experimental residual dipolar couplings in multiple alignment media.275 The impact of static and dynamic deviations from the idealized A-form helix of RNA as it propagates into errors in the principal order tensor parameters determined using residual dipolar couplings has been examined.276 A 20-ns molecular dynamics simulation of the HIV-1 transactivation response element RNA together with a survey of spin relaxation studies of RNA dynamics reveals that pico-to-nanosecond local motions in non-terminal Watson-Crick base-pairs will uniformly attenuate base and sugar one bond RDCs by approximately 7%. The study also confirms earlier findings that the two TAR helixes undergo large changes in both their mean relative orientation and dynamics upon binding to different targets. A toolkit for the analysis of residual dipolar couplings for macromolecular structure determination is available.277 The program allows experimental RDC values to be loaded using simple data formats and can perform several useful RDC analyses such as alignment tensor estimation and order tensor analysis by singular value decomposition. It can also import from and export to several different commonly used programs for further analysis of RDC data and RDC-based refinement of macromolecular structures. The possibility of predicting the alignment tensor of a molecule from the molecule’s 3D charge distribution and shape has been explored for alignment of proteins in liquid crystalline phases.278 Residual dipolar couplings predicted by this electrostatic model for the B1 domain of protein G in fd phage and for the protein ubiquitin in the presence of a positively charged surfactant system are shown to fit well with the experimental values. A structural model for unfolded proteins from residual dipolar couplings and small-angle X-ray scattering has been proposed and the model validated by considering a natively disordered protein as well as proteins unfolded by the addition of urea.279 The wave like periodic behavior of residual dipolar couplings arising from nucleic acid and protein secondary structures has been shown to be more complex and information-rich.280 A procedure to extract peptide plane orientation information from the RDC data and an assessment of errors using Monte-Carlo simulations have been presented. The utility of the approach has been demonstrated for model systems. 376 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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10.6 Structure, conformation, orientation and dynamics studies Proteins. In this section literature on the use of distance and angular constraints obtained from weak ordering of proteins is presented. Reports on structure and dynamics of proteins and their complexes have been included. While some of the reports have a major emphasis on the NMR results, others use such constraints along with other measurements. RDCs, J-couplings, and NOE have been measured in construct K18 of tau, an unstructured protein that regulates the organization of neuronal microtubules.281 Analysis of the dipolar couplings combined with molecular simulations indicated strong tendencies to form turn conformations and these localized sequence-dependent conformational tendencies have been considered to interrupt the propensity to sample more extended conformations. The precision of the techniques used and factors affecting the interpretation of residual dipolar couplings in the analysis of the spatial structures of partially aligned proteins have been examined.282 With the protein barstar considered as an example, it is concluded that molecular dynamics calculations provide a reasonable description of internal motions and lead to accurate determination of protein spatial structures from NMR data. The structure of 13C- and 15N-enriched silk from two Australian spider species has been studied. 13C and 15N spectra from alanine- or glycine-labeled oriented dragline silks have been acquired with the fiber axis aligned parallel or perpendicular to the magnetic field.283 The relative fraction of ordered alanine was found to be higher than the fraction of ordered glycine and the higher degree of crystallinity observed for one of the species correlated with its superior mechanical properties. It has been shown that the relative orientation and stoichiometry of coiled-coil proteins in solution can be determined by comparison of residual dipolar couplings measured in charged liquid crystalline media with values predicted from the three-dimensional charge distribution of the protein.284 The method was used to identify the coiled-coil region of the cGMP-dependent protein kinase I as a parallel homodimer ruling out other possibilities. Though the study of bound-state conformations of ligands interacting with proteins is important to the understanding of protein function, the use of residual dipolar couplings for ligand-binding applications has been limited due to the absence of appropriate methodologies. This problem has been addressed and an approach has been presented which rests on association of a Histadinetagged protein with a nickel-chelate-carrying lipid inserted into the alignment media used in the acquisition of RDCs.285 The approach has been validated through the observation of bound-state RDCs for the disaccharide, lactose, bound to the carbohydrate recognition domain of the mammalian lectin, galectin-3. The conventional view of denatured proteins as random coils has been challenged and from residual dipolar coupling measurements it is argued that a denatured protein is not a random coil.286 Natively unfolded proteins in weakly aligned media have been considered. It is observed that the variation of dipolar couplings and heteronuclear relaxation rates in them closely follows the variations of the bulkiness of amino acids along the polypeptide chain.287 Deviations from this random coil behavior are attributed to residual secondary structure and long-range transient interactions. Possibility of obtaining long-range information with high sensitivity and precision in the unfolded state of a protein from HN–HN residual dipolar couplings and hydrogen bond scalar couplings has been demonstrated for urea-denatured ubiquitin.288 The RDCs indicate the persistence of native-like structure in ubiquitin’s first hairpin. Heat-Induced Dimerization of BCL-xL has been studied.289 From the measurements of residual dipolar couplings the solution structure of the dimer is shown to be very close to the crystal structure. The structure in a denatured nuclease has been considered by measuring RDCs with multiple alignment tensors.290 The RDCs have been analyzed by singular value decomposition to infer the ensemble average structure of the denatured nuclease. Magnetic field induced alignment and the need to consider residual anisotropic chemical shifts (RACS) while estimating pseudocontact shifts has been highlighted.291 Using a 30 kDa protein–protein Nucl. Magn. Reson., 2008, 37, 357–388 | 377 This journal is

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complex, the RACS effects are shown to be significant for heteronuclear spins with large chemical shift anisotropies, lanthanide ions with large anisotropic magnetic susceptibility tensors, and measurements at high magnetic field. Residual dipolar couplings have been used for the study of the following proteins. Structure of Na,K-ATPase Regulatory Protein FXYD1 in Micelles;292 Solution structure of the catalytic domain of RICH protein from goldfish.293 Structure of the complex of Calmodulin with a Ryanodine Receptor Target.294 Conformational Dynamics in Ig domains from the elastic filament Titin in vertebrate muscle.295 Structural Plasticity of Peptidyl-Prolyl Isomerase sFkpA.296 The interaction between calcium- and Integrin-binding protein 1.297 Interaction of a -Synuclein with divalent metal ions.298 Long-Range Order and Local Disorder in Native a-Synuclein.299 High-resolution structure of the membrane Protein OmpA.300 Quaternary structure of carbonmonoxyhemoglobins and the structural changes induced by the allosteric effector inositol hexaphosphate.301 Characterization of saposins-lipid-binding and membrane-perturbing glycoproteins.302 Refinement of the model for the structure of acireductone dioxygenase.303 Solution structure of an oncogenic Mutant of Cdc42Hs.304 Structure and Orientation of Peptide Inhibitors LPFFD and DPFFL Bound to Beta-amyloid Fibrils.305 Structure and dynamics of micelle-associated human immunodeficiency virus gp41 fusion domain.306 Refined NMR structure of a-sarcin.307 Structural comparison of the unstable Drosophila adapter protein Drk and its stable mutant.308 The solution structure of a stably phosphorylated form of the cytoplasmic B domain of the mannitol-specific transporter of the Escherichia coli phosphotransferase system.309 Structure of a homotrimeric phosphotransferase protein IIAChitobiose.310 Solution structure, stability, and nucleic acid binding of the hyperthermophile protein Sso10b2.311 Structure of the peptidoglycan binding domain of bacillus subtilis cell wall lytic enzyme.312 Structure of the membranebound form of the juxtamembrane domain of the epidermal growth factor receptor.313 Solution structure of the sulfite reductase flavodoxin-like domain from Escherichia coli.314 Structure of IIAMannose-HPr Complex of the Escherichia coli Mannose Phosphotransferase System.315 Investigations of allosteric processes in a two-domain thermus thermophilus Hsp70 molecular chaperone.316 Structure of calmodulin complexed with a fragment of the olfactory cyclic-nucleotide gated channel.317 Solution Structure of trimeric Escherichia coli enzyme IIAChitobiose.318 Structure of the mercury transport membrane protein MerF in micelles, a membrane protein with two transmembrane helices.319 Structure, stability, and flexibility of a hyperthermophile coiled-coil DNA-binding protein, Sso10a.320 Structure and dynamics of a fragment of a G-protein-coupled receptor from yeast.321 Structure and activity of a two-domain antifreeze protein RD3.322 Solution structure and dynamics of ribosomal protein L11 from Thermotoga maritima.323 Orientation and structural studies of Deoxyhemoglobin at High Magnetic Fields.324 Ultrahigh-resolution backbone structure of perdeuterated protein GB1.325 Residual Dipolar Couplings analysis of the third Ig binding domain (GB3) of streptococcal protein G.326 Study of slow motions in ubiquitin.327 Structural differences in putidaredoxin investigated as a function of oxidation state of the iron cluster.328 Paramagnetism-based restraints and study of Cytochrome b562.329 Peptides. The analysis of 1H residual dipolar couplings of zwitterionic tetraalanine in the lyotropic system cesium pentadecafluoroctanoate in water (CsPFO/D2O) showed that the internal peptide residues adopt a polyproline II helix conformation and that the long molecular axis is tilted by an angle of 560 with respect to the surface of the micelles formed by CsPFO.330 Ab initio calculations have been carried out to compute all of the tensor elements and the asymmetry parameter of the electric field gradient for each carbon–deuterium bond in the ring of deuterated 3-methylindole.331 The perpendicular tensor components have been used to analyse 2H NMR 378 | Nucl. Magn. Reson., 2008, 37, 357–388 This journal is

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spectra from well-oriented, hydrated peptide/lipid samples. For each of the four tryptophans of membrane-spanning gramicidin A channels this is shown to change the deduced ring tilt by nearly 100 and increase the ring principal order parameter. 1 H–13C residual dipolar couplings have been used to obtain the structure of Glu– Cys–Gly in a lyotropic medium.332 Conformational preference of polyglycine in solution has been studied and it is observed that glycine in short segments exhibits a strong preference for an extended conformation.333 Three-dimensional structure of the selenium complexes of phytochelatin analog has been obtained.334 A systematic investigation of the influence of amino acid substitutions on the conformation of unfolded model peptides as monitored by the RDCs detected at natural abundance of 15N and 13C in strained polyacrylamide gels has been reported.335 The results have been compared with statistical models of unfolded peptide conformations derived from the protein data bank. The structure of hormaomycin in DMSO has been investigated from residual dipolar couplings by dissolving the depsipeptide in a polyacrylamide gel compatible with DMSO.336 Refinement of structure of cyclosporin A in chloroform by using RDCs measured in a stretched gel.337 Nucleic acids. An approach for NMR structure determination of large, modular RNAs has been proposed.338 It combines the conventional short-range, distance, and torsion angle NMR restraints with long-range, angular restraints derived from residual dipolar couplings to improve both the local and global precision of the structure. The approach was demonstrated for the domain II of the hepatitis C viral internal ribosome entry site (HCV IRES), a 25-kDa RNA. A protocol for determining the relative orientation and dynamics of A-form helices in 13C/15N isotopically enriched RNA samples using NMR residual dipolar couplings has been presented in which NOE and trans-hydrogen bond connectivity has been used for modeling the idealized A-form helix geometry.339 Subsequent RDC analysis enabled the average relative orientation of helices and order parameters describing the amplitude and asymmetry of interhelix motions to be obtained. Regulatory RNAs undergo large changes in structure upon recognition of proteins and ligands. Residual dipolar couplings have been used to characterize Na+-induced changes in the structure and dynamics of the HIV-1 transactivation response element RNA that mirrors changes induced by small molecules bearing a different number of cationic groups.340 A general, time- and cost-effective methodology for the preparation of 13C/15N labeled RNAs from a single plasmid has been proposed.341 Applying this method to a 25 kDa RNA, it was possible able to almost double the number of available RDC restraints in comparison to the conventional labeling scheme. The difference in the resonance frequency of the 13C TROSY component of the 13C-{1H} doublet in an aligned and isotropic oligonucleotide sample has been named as residual pseudoCSA (RPCSA). Use of RPCSA has been demonstrated for structure refinement of the helical region of a 24-nucleotide stem-loop segment of ribosomal helix-35.342 Chemical shift tensors for all ribose and protonated base carbons in A-form helical RNA and B-form DNA have been determined by liquid crystal NMR.343,344 The measurement of NMR residual dipolar couplings in partially aligned systems has provided new insights into the structural plasticity of RNA and the RDC methodology for studying RNA structural dynamics has been reviewed.345 Residual dipolar couplings have been used for the study of the following nucleic acids. Structure of the full-length linear dimer of stem-loop-1 RNA in the HIV-1 dimer initiation site.346 Assessment of the global shape of DNA duplexes containing a tandem of G-T mismatches.347 Structural studies and Mg2+ binding of RNase P P4 helix.348 Structure and dynamics of the Dickerson DNA Dodecamer in Solution.349 Sequence-specific interaction of DNA with a threading bisintercalator consisting of two intercalating 1,4,5,8-naphthalenetetracarboxylic diimide units connected by a rigid, tricyclic spiro linker.350 Structural and kinetic aspects of the interaction of the Nucl. Magn. Reson., 2008, 37, 357–388 | 379 This journal is

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HoxD9 homeodomain with a nonspecific, 24-base pair DNA duplex.351 Structural study of elements of Tetrahymena telomerase RNA stem-loop IV.352 Structural study of DNA dodecamers with locked topology.353 Global dynamics RNA bound to charged molecules.354 Structure of viral DNA at the binding-processing site of HIV-1 integrase.355 Global structure and dynamics of tRNAval.356

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Nuclear Magnetic Resonance: Volume 37 (Specialist Periodical Reports)

Photochemistry, Volume 37 (Specialist Periodical Reports)

Nuclear Magnetic Resonance

Catalysis, Volume 22 (RSC Specialist Periodical Reports)

Organometallic Chemistry, Volume 36 (Specialist Periodical Reports)

Organometallic Chemistry, Volume 31 (Specialist Periodical Reports)