Organophosphorus Chemistry

Organophosphorus Chemistry ~ Volume 1 5 A SpeciaIist PeriodicaI Report Organophosphorus Chemistry Volume 15 A Revi...

Author: D. W. Hutchinson | J. A. Miller

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Organophosphorus Chemistry ~

Volume 1 5

A SpeciaIist PeriodicaI Report

Organophosphorus Chemistry Volume 15

A Review of the Literature published between July 1982 and June 1983 Senior Reporters

D. W . Hutchinson, Department of Chemistry and Molecular Sciences, University of Warwick

B. J . Walker, Department of Chemistry, David Keir Building, The Queen's University of Belfast

Reporters

D. W. Allen, Sheffield City Polytechnic 0. Dahl, University of Copenhagen, Denmark

6. de Ruiter, University of Groningen, The Netherlands R. S. Edmundson, formerly of University of Bradford C. D. Hall, King's College, London

J . 6. Hobbs, The City University, London

J . C. Tebby, North Staffordshire Polytechnic, Stoke-on- Trent J . C. van de Grampel, University of Groningen, The Netherlands

The Royal Society of Chemistry Burlington House, London W I V OBN

ISBN 0-85186-136-9 ISSN 0306-0713

Copyright 01985 The Royal Society of Chemistry

All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems-without written permission from the Royal Society of Chemistry Typeset by Bath Typesetting Ltd., Bath, and printed by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain

In troduc t ion This year we welcome an occasional review on phosphazenes by Drs J. C. van de Grampel and B. de Ruiter of the University of Groningen, The Netherlands. For the past four years we have been unable to include a chapter on phosphazenes in these Reports and we are pleased to see the return of a review on this industrially important topic. We hope that phosphazenes will be reviewed in future on a regular basis by Professor C. W. Allen of the University of Vermont. During the past year, many papers have appeared in the field of oligonucleotide synthesis which have dealt with methodological improvement, as opposed to innovation. The development and use in enzyme studies of nucleoside polyphosphates and thiopolyphosphates continues to stimulate much activity. The elucidation of the processes by which DNA is cleaved by antitumour drugs and/or metal chelates and oxygen has also prompted much work. Studies in which phosphodiester bonds of nucleic acids are cleaved and sequence analysis of the sites of cleavage is used to provide information on nucleic acid-ligand interactions are legion. Thanks to the development of the phosphotriester methods (especially solid-phase methods), oligonucleotide syntheses which represented a huge undertaking a decade ago have become commonplace. The structures and functions of phosphoproteins have continued to attract attention in the past year, as has the development of methods which use immobilized enzymes for the synthesis, on a large scale, of biologically important organophosphorus compounds, such as nucleoside diphosphate sugars. Other active areas that are worthy of mention include investigations on the reactions of methyl metaphosphate and on the hydrolysis of cyclic phosphates. In the latter case, experiments involving leO exchange during the hydrolysis of ethyl ethylene phosphate indicate that six-co-ordinate intermediates are not involved in this hydrolytic reaction. The rapid growth of studies of p,-bonded PI'' and Pv phosphorus compounds has continued during the past year and much early confusion has been explained. Many new systems have been synthesized utilizing the now well-established principle of the presence of bulky substituents at the multiple bonds to prevent oligomerization. The past year has seen the development of phosphine oxide-based olefin synthesis into a genuinely useful method that complements the Wittig reaction. Phosphine oxide-stabilized carbanions provide stereospecific routes to both (E)- and (2)-dkenes through separation of diastereomeric intermediates; the earlier problem 2osed by the tendency for one diastereomer to predominate has been partially overcome by the development of alternative routes which provide major amounts of each isomer. Renewed interest in the mechanism of the Wittig reaction has promoted some novel suggestions, particularly those which V

V1

Introduction

attempt to explain cis-stereoselectivity. Several detailed mechanistic descriptions have appeared, but although these are individually convincing they are not, so far, totally compatible. D. W. Hutchinson B. J. Walker

Contents Chapter 1 Phosphines and Phosphonium Salts

1

By D. W. Allen

1

1 Phosphines Preparation From Halogenophosphinesand Organometallic Reagents From Metallated Phosphines By Addition of P-H t o Unsaturated Compounds By Reduction Miscellaneous Methods Reactions Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions

1 1 3 6 8 9 12 12 14 15 18

2 Phosphonium Salts Preparation Reactions

20 20 24

3 p,-Bonded Phosphorus Compounds

27

4 Phospholes and Phosphorins

32

Chapter 2 Quinquecovalent Phosphorus Compounds

35

By C. D. Hall

1 Introduction

35

2 Structure, Bonding, and Reorganization of Ligands

35

3 Phosphoranes containing a P-H Bond

39

4 Acyclic Phosphoranes

41

5 Three-, Four-, and Five-membered-ring Phosphoranes Monocyclic Systems Bicyclic Systems Tricylic Systems

44 44

6 Six-co-ordinated Phosphorus Compounds Addendum

57 58

vii

50 55

viii

Contents

Chapter 3 Phosphine Oxides and Related Compounds

59

By 8. J. Walker

1 Introduction

59

2 Preparation of Acyclic Phosphine Oxides

59

3 Preparation of Cyclic Phosphine Oxides

61

4 Structural and Physical Aspects

66

5 Reactions at Phosphorus

66

6 Reactions of the Side-chain

67

7 Phosphine Oxide Complexes and Extractants

78

Chapter 4 Tervalent Phosphorus Acids

79

By 0. Dahl

1 Introduction

79

2 Nucleophilic Reactions

79 79

Attack on Saturated Carbon Attack on Unsaturated Carbon Attack on Oxygen or Sulphur Attack on Halogen

81 84

85

3 Electrophilic Reactions

86

4 Reactions involving Two-co-ordinate Phosphorus

95

5 Miscellaneous Reactions

102

Chapter 5 Quinquevalent Phosphorus Acids

104

By R. S. Edmundson

1 Synthetic Methods General Phosphoric Acids and their Derivatives Phosphonic and Phosphinic Acids and their Derivatives

104 104 106 110

2 Reactions General Phosphoric Acids and their Derivatives Phosphonic and Phosphinic Acids and their Derivatives

117 117 120 131

Chapter 6 Phosphates and Phosphonates of Biochemical Interest

14 4

By D. W. Hutchinson

1 Introduction

144

2 Coenzymes and Cofactors

145

xi

Contents Chapter I 0 Physical Methods By J.

286

C. Tebby

1 Nuclear Magnetic Resonance Spectroscopy Biological Aspects Chemical Shifts and Shielding Effects Anisotropy Effects Phosphorus-31 8p of n8 compounds 8p of n3 compounds 8, of n4 compounds 8p of ns compounds 8p of ns compounds Hydrogen-1 Carbon-13 Nitrogen-15 and Oxygen-17 Fluorine-19 Solvation and Shift Reagents Variable Temperature Studies Studies of Configuration Spin-Spin Coupling J(PP) and J(PM) J(PF) J(P170) and J(P15N) J(W JPH) Relaxation, CIDNP, and N.Q.R. Relaxation CIDNP N.Q.R.

286 286 286 286 287 287 288 289 290 290 290 290 291 292 292 292 293 293 293 294 295 295 297 298 298 298 298

2 Electron Spin Resonance Spectroscopy

298

3 Vibrational and Rotational Spectroscopy Bond Assignments Bonding Stereochemistry Rotational Spectra

299 299 300 301 302

4 Electronic Spectroscopy

302 302 303 304

Absorption Spectroscopy Photoelectron Spectroscopy Emission Spectroscopy 5 Diffraction &Ray Diffraction Electron Diffraction

304 304 308

6 Dipole Moments, Kerr Effects, and Polarography

308

xii

Contents 7 Mass Spectrometry

309

8 Acidities and Basicities

31 1

9 Chromatography Gas-Liquid Chromatography Thin-layer and Paper Chromatography High Performance Liquid Chromatography Ion Exchange and Electrophoresis Surface Properties

313 313 314 314 314 31 4

Author Index

31 5

Abbreviations *

AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s. HMPT h.p.1.c. i.r. L.F.E.R. MIND0 MO MS-Cl MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA TfzO

bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicyclo[4.3.O]non-5-ene 1,5-diazabicyclo[5.4.0]undec-5-ene dicyclohexylcarbodi-imide [(2,2-dimethyl-1,3-dioxolan4,5-diyl)bis(methylene)]bis(dipheny1phosphine) dimethylformamide dimethyl sulphoxide 4,4’-dimethoxytrityl ethylenediaminetetra-acetic acid Extended Hiickel Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free-Energy Relationship Modified Intermediate Neglect of Differential Overlap Molecular Orbital mesitylenesulphonyl chloride mesit ylenesulphonyl-3-nitro-1,2,4-tr iazole mesitylenesulphonyltetrazole N-bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-consistent Field t-bu tyldimethylsilyl trk(diethy1amino)phosphine trifluoroacetic acid trifluoromethanesulphonic anhydride

*Abbreviations used in Chapters 6 and 7 are detailed in Biochern. J., 1970, 120, 449 and 1978, 171, 1.

xiv THF t .l.c. TPS-Cl TPS-nt TPS-tet TsOH U.V.

Abbreviations

tetrahydrofuran thin-layer chromatography tri-isopropylbenzenesulphonylchloride tri-isopropylbenzenesulphonyl-3-nitro1,2,4-triazole tri-isopropylbenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet

Abbreviations *

AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s. HMPT h.p.1.c. i.r. L.F.E.R. MIND0 MO MS-Cl MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA TfzO

bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicyclo[4.3.O]non-5-ene 1,5-diazabicyclo[5.4.0]undec-5-ene dicyclohexylcarbodi-imide [(2,2-dimethyl-1,3-dioxolan4,5-diyl)bis(methylene)]bis(dipheny1phosphine) dimethylformamide dimethyl sulphoxide 4,4’-dimethoxytrityl ethylenediaminetetra-acetic acid Extended Hiickel Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free-Energy Relationship Modified Intermediate Neglect of Differential Overlap Molecular Orbital mesitylenesulphonyl chloride mesit ylenesulphonyl-3-nitro-1,2,4-tr iazole mesitylenesulphonyltetrazole N-bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-consistent Field t-bu tyldimethylsilyl trk(diethy1amino)phosphine trifluoroacetic acid trifluoromethanesulphonic anhydride

*Abbreviations used in Chapters 6 and 7 are detailed in Biochern. J., 1970, 120, 449 and 1978, 171, 1.

xiv THF t .l.c. TPS-Cl TPS-nt TPS-tet TsOH U.V.

Abbreviations

tetrahydrofuran thin-layer chromatography tri-isopropylbenzenesulphonylchloride tri-isopropylbenzenesulphonyl-3-nitro1,2,4-triazole tri-isopropylbenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet

1 Phosphines and Phosphonium Salts BY D. W. ALLEN

1 Phosphines

Preparation.-From Halogenophosphines and Organometallic Reagents. The reactions of chlorodiphenylphosphine with Grignard reagents derived from p-halogenoalkenylbenzeneshave yielded olefinic tertiary phosphines, e.g., (1). Attempts to graft these on to polypropylene supports by y-irradiation have met with only limited su~cess.~ Grignard reagents derived from w-chloroalkyl ethers have been employed in the synthesis of phosphines bearing polyether substituents, e.g., (2), which are of interest in that the ether groups confer phasetransfer properties to metal complexes of these ligands, enabling them to function as catalysts in two-phase systems.2Interest in neighbouring-group participation involving o-methoxyphenylphosphines in the oxidative-addition reactions of transition-metal complexes has led to the synthesis of the phosphine (3) by treatment of 2,4-dimethoxyphenyldichlorophosphinewith methylmagnesium

P(CH2CH2CH20R)3

(1) n = 1 o r 2

&

\ /

Mea z M e 2

( 2 ) R = M e o r CH2CH20Me

(3)

Me 2N

R

r=>

A==

C-

\d

PR2

R2P

(W10

(4)

( 5 ) R = M e o r Ph

(6)

R

=

alkyl or Ph

F. R. Hartley, S. G. Murray, and P. N. Nicholson, J. Polym. Sci., Polym. Chem. Ed., 1982,20,2395.

* T. Okano, M. Yamamoto, T. Noguchi, H. Konishi, and J. Kiji, Chem. Lett., 1982,977. I

2

Organophosphorus Chemistry

i ~ d i d eThe . ~ naphthylphosphine (4) has been prepared by the reaction of chlorodiphenylphosphinewith the Grignard reagent derived from 1-bromo-8-dimethylA long-establishedroute to the phospholane system involving amin~naphthalene.~ the reaction of a bifunctional Grignard reagent with a dihalogenophosphine has been applied in the preparation of the o-carboranylphospholanes(5).6 The 1,Zaddition of two equivalents of chlorodialkyl- and chlorodiaryl-phosphines to the ‘magnesium-butadiene’ complex has given the chiral diphosphines (6).8 Grignard procedures have also been employed in the synthesis of silylaminophosphines,7- and a range of a,o-bis(dialky1aminophosphino)alkanes.lo The reactions of various halogenophosphines, PCl,Ph,-, (n = 1-3), with organolithium reagents have given rise to the alkynylphosphines (7),11 the o-fluorophenylphosphines (8),12 and the heteroarylmethylphosphine (9).la @

P( CCCPh ),Phg-,

3-n

[

PhP H2C

0 “ 1 2

ph2pno Me0

PPh2

The generation of organolithium reagents by o-lithiation of alkyl phenyl ethers, dialkylaminobenzenes, and benzyldialkylaminesfollowed by their reaction with halogenophosphines has afforded a range of new substituted arylphosphines, e.g., and the chiral phosphine (11).lS Directed-lithiation of l-dimethylaminonaphthalene, followed by treatment with chlorodiphenylphosphine, affords a more direct route to the phosphine (4).lSThe diphosphines (12) are formed in the reactions of chlorodiethylphosphinewith o-lithio lithium phenolate A. G. Constable, C. R. Langrick, B. Shabanzadeh, and B. L. Shaw, Znorg. Chim. Acta, 1982,65, L151.

* G. P. Schiemenz and E. Papageorgiou, Phosphorus Sulfur, 1982,13,41.

L. I. Zakharkin, M. G. Meiramav, V. A. Antonovich, A. V. Kazantsev, A. I. Yanovskii, and Yu. T. Struchkov, Zh. Obshch. Khim., 1983, 53, 90 (Chem. Abstr., 1983,98, 198 380). W. J. Richter, Angew. Chem., Int. Ed. Engl., 1982,21, 919. R. H. Neilson and P. Wisian-Neilson,Inorg. Chem., 1982, 21, 3568. B.-L. Li, J. S. Engenito, jun., R. H. Neilson, and P. Wisian-Neilson,Inorg. Chem., 1983, 22, 575. H. R. ONeal and R. H. Neilson, Znorg. Chem., 1983,22, 814. lo K. Diemert, W. Kuchen, and J. Kutter, Phosphorus Sulfur, 1983, 15, 155. l1 A. Hengefeld and R. Nast, Chem. Ber., 1983, 116, 2035. l2 H. B. Stegman, H.-M. Kuhne, G. Wax, and K. Schemer, Phosphorus Sulfur, 1982,13,331. l8 E. Lindner, H. Rauleder, and W. Hiller, 2.Nuturforsch., B: Anorg. Chem., Org. Chem., ti

’

1983, 38, 417.

Horner and G. Simons, Phosphorus Sulfur, 1983, 14, 189. L. Horner and G. Simons, Phosphorus Sulfur, 1983, 15, 165.

l P L.

l6

Phosphines and Phosphonium Salts

3

and the related reagent derived from N-methylaniline.le Dilithium reagents have been employed in the synthesis of the chelating diphosphine (13)17and the heteroarylphosphine (14), which is of interest in that it is able to form dinuclear complexes involving two metal atoms.l* The reaction of 1,2-bis(dichlorophosphino)ethane, now commercially available, with pentafluorophenyllithium (or the related Grignard reagent) affords the diphosphine (15).l9 The highly sterically crowded phosphine (16) is formed in the reaction of chlorodiphenylphosphine with tris(tr imethylsily1)methyllithium.20

Ph2P

PPh2

Ph2P[C(SiMe3)31

(16)

( R C E C ) ,PC( P h ) = C H B r

(17) R

=

Me,But,or P h

E t P ( CH2COOEt)

(18)

Alkynylsodiumreagents have been employed in the synthesis of the unsaturated phosphines (17) from a related alkenyldibromophosphine.21The reaction of ethyldichlorophosphine with the Reformatsky reagent derived from ethyl bromoacetate gives the phosphine (18), which can be easily converted into the corresponding phosphinobiscarboxylic acid with aqueous alkali.22It has been pointed out that the reaction of dimethylzinc with phosphorus trichloride has some advantages for the synthesis of small quantities of trimethylphosphine compared to the Grignard p r ~ c e d u r e . ~ ~

Preparation of Phosphines from Metallated Phosphines. This route has continued to find extensive application for the preparation of a wide range of new phosphines. The reaction of lithium diarylphosphides with tosylate esters has been employed in the synthesis of the chiral phosphines (19)2pand (20)26.In the preparation of fully alkylated chiral diphosphines in the DIOP series (21), the reactions of lithium dialkylphosphides with ditosylate precursors surprisingly give intractable products. Similar problems are encountered in the related reactions of chloromethyl, bromomethyl, and iodomethyl precursors, the main l6 l7 l8 lo 8o

81 28

aa 84 26

J. Heinicke and A. Tzschach, J . Prakt. Chem., 1983, 325, 232. A. Uehara and J. C. Bailar, jun., J. Organomet. Chem., 1982, 239, 1. J. M. Brown and L. R. Canning, J. Chem. SOC.,Chem. Commun., 1983, 460. R. L. Cook and J. G. Morse, Inorg. Chem., 1982, 21, 4103. C. Eaborn, N. Retta, and J. D. Smith, J. Chem. Soc., Dalton Trans., 1983, 905. T. N. Belyaeva, M. V. Sendyurev, A. V. Dogadina, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1983,53,475 (Chem. Abstr., 1983,98, 198 355). D. Noskovk and J. PadlahovB, Polyhedron, 1983, 2, 349. G . P. McQuillan, Synth. React. Inorg. Met.-Org. Chem., 1983, 13, 183. 3. M. Townsend and D . Valentine, jun., U.S. P. 4 343 741 (Chem. Abstr., 1983,98, 34 761). Carbo-Biochimica S.a. r.l., Jpn. Kokai Tokkyo Koho 82 32 292 (Chern. Abstr., 1982, 97, 6583).

4

Organophosphorus Chemistry CH2PPh2

Ar2pcH2LJ CH2PAr2 +

COOBu $0 Me

(21) R = Et,Pri,or

(20)

Cy

0

Ph 2P

PPh

P J(Ph2

(24) X = N or P

product being the tetraalkyldiphosphine, R2PPR2.However, the desired compounds are obtained in substantial yields when the corresponding fluoromethyl precursors are employed.2s Both 2-fluoro- and 2-chloro-tropones react with lithium diphenylphosphide in THF to give the 2-diphenylphosphinotropone system (22). However, use of isotopically labelled 2-halogenotropones reveals that these reactions are more complex than is immediately apparent, being the fist examples of tele-substitution by anionic nucleophiles in a non-protic solvent on tropones bearing nucleofugal groups.27The reaction of 1,l-dichloroethenewith lithium diphenylphosphide affords the new chelating ligand (23).28The reactions of chlorosilanes with lithiophosphide reagents have been employed in the synthesis of a range of silylphosphines, e.g., (24).2g,30 The P-H funtionality of silylphosphines derived from the reactions of fluorosilanes with reagents of the type LiPHR (R = H or But) has been utilized in their conversion into novel phosphorus-silicon heterocyclic s y s t e r n ~ . ~ ~ , ~ ~ Interest continues in the use of reagents obtained by lithiation at carbon adjacent to phosphorus. The reaction of lithiomethyldiphenylphosphine with chlorosilanes has given the phosphines (25).33Full details have now appeared of studies of lithiation at carbon of methylphosphines co-ordinated to nickeL3* 26

27

K. Tani, K. Suwa, T. Yamagata, and S. Otsuka, Chem. Lett., 1982,265. M. Cavazza, G . Morganti, C. A. Veracini, A. Guerriero, and F. Pietra, Tetrahedron Lett., 1982, 23, 4115.

28

30

31 32 33

I. J. Colquhoun and W. McFarlane, J . Chem. SOC.,Dalton Trans., 1982, 1915. P. Aslanidis and J. Grobe, Z . Naturforsch., B: Anorg. Chem., Org. Chem., 1983, 38, 280. P. Aslanidis and J. Grobe, Z . Naturforsch., B: Anorg. Chem., Org. Chem., 1983,38, 289. U. Klingebiel and N. Vater, Angew. Chem., Int. Ed. Engl., 1982, 21, 857. W. Clegg, M. Haase, U. Klingebiel, and G . M. Sheldrick, Chem. Ber., 1983, 116, 146. R. D. Holmes-Smith, R. D. Osei, and S. R. Stobart, J. Chem. SOC.,Perkin Trans. 1, 1983, 861.

34

M. Wada, K. Nishiwaki, and Y. Kawasaki, J. Chem. SOC.,Dalton Trans., 1982, 1443.


5

Many applications of sodium and potassium organophosphides have been reported in the past year. The reaction of sodium diphenylphosphide with tosylates has been employed in the synthesis of steroidal p h o s p h i n e ~ .This ~~ reagent has also been used in the synthesis of a range of carbohydrate-derived pho~phines,~~ and in the synthesis of the phosphine (26), which can be linked to a silica support by treatment with The reaction of sodium diphenylphosphide with o-difluorobenzeneaffords a convenient, one-pot synthesis of o-bis(dipheny1pho~phino)benzene.~* Sodium dimethylphosphide has been used to convert

(25)

X , Y , Z = H , Me, P h , C1

n

2-bromopyridine into the related dimethylphosphin~pyridine.~~ The reaction of sodium dihydridobis(2-methoxyethanolato)aluminate with primary phosphines generates phosphide anions, which on treatment with alkyl halides or tosylates give secondary pho~phines,~~ some of which have been converted (via the related phosphide reagents) to new, multidentate ligands, e.g., (27).41 A mixed sodium-potassium phosphide reagent has been employed in a reaction with 1,2-dichlorotetramethyldisilane to give the bicyclic phosphine (28)?2 The reaction of potassium diphenylphosphide with tosylates has been used in the synthesis of the amide-linked, polymer-bound phosphine (29).43 Treatment of a polystyrene-based polymer bearing halogenotin side-chains with potassium diphenylphosphideaffords the related stannylphosphine-functionalizedpolymer, which is of interest for the preparation of catalyst systems for oligomerization of a l k y n e ~ An . ~ ~improved route to the chiral phosphine (30) has been described, involving the reaction of potassium diphenylphosphide with a chloroalkyl precursor.4s The photostimulated reaction of 1-bromoadamantane with potassium diphenylphosphide proceeds via an & ~ mechanism l at the bridgehead, S. Gladiali, G. Faedda, M. Marchetti, and G . Botteghi, J. Organornet. Chem., 1983, 244, 289. 36 M.Yamashita, K. Hiramatsu, M. Yamada, N. Suzuki, and S. Inokawa, Bull. Chem. SOC. Jpn., 1982,55,2917. 37 T . Okano, T. Kobayashi, H. Konishi, and J. Kiji, Bull. Chem. SOC.Jpn., 1982,55,2675. 38 H. C. E. McFarlane and W. McFarlane, Polyhedron, 1983,2, 303. Y.Inoguchi, B. Milewski-Mahrla, and H. Schmidbaur, Chem. Ber., 1982,115, 3085. 40 M. Yamashita, N. Suzuki, M. Yamada, Y. Soeda, H. Yamashita, K. Nakatani, T. Oshikawa, and S. Inakawa, Bull. Chem. SOC.Jpn., 1983,56,219. 41 L. G. Scanlon, Y.-Y. Tsao, K. Toman, S. C. Cummings, and D. W. Meek, Inorg. Chern., 1982,21,2707. 48 K.Hassler, J. Organomet. Chem., 1983,246, C31. 43 R. Arshady, Makromol. Chem., Rapid Commun., 1983,4,237. 44 H.Schumann and G. Rodewald, J. Chem. Res. ( S ) , 1982,210. 46 A. De Renzi, G . Morelli, and M. Scalone, Znorg. Chim. Acta, 1982,65, L119. 35

6


resulting in the formation of 1-diphenylpho~phinoadamantane.~~ The dipotassium derivatives of a,w-diphosphinoalkanes have been used in the synthesis of a range of new, multidentate mixed-donor ligands (31)47 and the new macrocycle (32).48

I T1

(31)

ZI = 2-4 R = H or Me

(32) R = Pr

(33)

Bauder's group (and others) continue to make extensive use of alkali-metal polyphosphide reagents in the synthesis of both and acyclic polyphosphine~.~ - ~ ~range of new systems has been described in the past year, A~wide and the field as a whole has been reviewed.56 Metallation of cyclopentadienyldiphenylphosphine with thallous ethoxide proceeds quantitatively to the thallium derivative (33), which is a useful reagent for the preparation of other phosphino-substituted met a l l o ~ e n e s . ~ ~ Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. The first simple benzophosphepin (34) has been prepared by the base-catalysed

addition ofphenylphosphineto 1,Zdiethynylben~ene.~~ Two patentshaveappeared describing procedures for the synthesis of tris(2-cyanoethy1)phosphine by addition of phosphine to acrylonitrile in ethanol, in the presence of a tertiary (hydroxyalky1)phosphineand a transition metal.6g,60 The addition of diphenyl" p7 48

so

61

sp 68

64

6s s7 68

6o

R. A. Rossi, S. M. Palacios, and A. N. Santiago, J. Org. Chem., 1982,47,4654. K. Issleib and W. Gans, 2. Anorg. Allg. Chem., 1982,491, 163. M. Ciampolini, N. Nardi, F. Zanobini, R. Cini, and P. L. Orioli, Znorg. Chim. Acta, 1983,76,L17. M.Baudler and Th. Pontzen, 2. Anorg. Allg. Chem., 1982,491,27. M. Baudler and S . Klautke, 2. Naturforsch., B: Anorg. Chem., Org. Chem., 1983,38,121; M. Baudler, G. Fursternberg, H. Suchomel, and J. Hahn, 2. Anorg. Allg. Chem., 1983, 498, 57. M Baudler and Y . Aktalay, 2. Anorg. Allg. Chem., 1983,496,29. G. Fritz, K. D. Hoppe, W. Honle, D. Weber, C. Mujica, V. Manriquez, and H. G. van Schnering, J. Organomet. Chem., 1983,249,63. M.Baudler, G. Reuschenbach, J. Hellman, and J. Hahn, 2. Anorg. Allg. Chem., 1983, 499, 89. M. Baudler, Y. Aktalay, K. Kazmierzcak, and J. Hahn, 2. Naturforsch., B: Anorg. Chem., Org. Chem., 1983,38,428. M.Baudler, G. Reuschenbach, and J. Hahn, Chem. Ber., 1983,116,847. M. Baudler, Angew. Chem., Znt. Ed. Engl., 1982,21,492. M.D.Rausch, B. H. Edwards, R. D. Rogers, and J. L. Atwood, J. Am. Chem. SOC.,1983 105,3882. G. Mlrkl and W. Burger, Tetrahedron Lett., 1983,24,2545. E. V. Kuznetsov, V. A. Voskresenskii, R. K. Valetdinov, A. Sh. Sharifullin, V. Ya. Pavlov, S. I. Gol'tser, V. S. Karpov, B. D. Murdasov-Murda, and A. N. Zuikova, USSR P. 941 381 (Chem. Abstr., 1982,97,216 465). E. V. Kuznetsov, R. K. Valetdinov, and A. Sh. Sharifullin, USSR P. 941 382 (Chem. Abstr., 1982,97,216 466).


7

phosphine to vinylacetylene under phase-transfer conditions is reported to lead to the formation of diphenyl-2,3-butadienylphosphine (35).s1 U.v.-induced addition of secondary phosphines to chlorovinylsilanes and allyl(ch1oro)silanes leads to the silylphosphines (36).33 A similar addition to vinyl-substituted heterocyclic silanes has given compounds such as (37).62

Ph2PCH2CH=C=CH2

(35)

(34)

R1 RB2PCH CH Si-CH2

221

CH2-

I

CH2

( 3 7 ) R1= a l k y l , v i n y l ,

R2P(CH2)nSiXYZ

( 3 6 ) R = M e or P h n = 2 o r 3 X , Y , Z = H , Me, Ph, C 1

/"" 2CH =CH \CH 2CH=CH2

MeS i- CH 2PH

(38)

(39)

or Ph R2= Me o r C F 3

Under high-dilution conditions, the primary phosphine (38) undergoes intramolecular addition to give the bicyclic system (39), the bridgehead phosphorus atom of which reacts normally with electrophilic reagenks3 Multidentate phosphines, e.g., (40), have been prepared by the radical-induced addition of primary and secondary phosphines to ally1dialkylph0sphines.B~A patent describing the free-radical addition of phosphine to C2-4alkenes to give the related trial kylphosphines has appeared.66 The addition of secondary phosphines to acrylic acid systems in the presence of acid, followed by treatment with alkali, leads to the phosphinocarboxylates (41).66Addition of P-H to carbonyl groups has been employed in the synthesis of the heterocyclic system (42):'and to C=N units in the synthesis of the formamidinophosphines (43).68 The reaction of phenyl(trimethylsily1)phosphine to

6a

66

R. A. Khachatryan, S. V. Sayadyan, and M. G. Indzhikyan, Arm. Khim. Zh., 1982,35,690 (Chem. Abstr., 1983, 98, 72 255). M. Auner and J. Grobe, Z . Anorg. Allg. Chem., 1982,489, 23. U. Kiihne, F. Krech, and K. Issleib, Phosphorus Sulfur, 1982, 13, 153. E. Arpac and L. Dahlenburg, Angew. Chem., Int. Ed. Engl., 1982, 21, 931. G. Elsner, H. Vollmer, and E. Reutel, Ger. Offen. 2936210 (Chem. Abstr., 1981, 95, 43 345).

66 67 68

J. H. Bright and M. M. Rauhut, Can. P. 1 125 306 (Chem. Abstr., 1982, 97, 182 659). V. G. Kostin, E. S. Karaulov, and M. N. Tilichenko, USSR P. 979 358 (Chem. Abstr., 1983, 98, 143 652). A. N. Pudovik, G. V. Romanov, andT. Ya. Stepanova, Zzv. Akad. Nauk SSSR, Ser. Khim., 1982, 1416 (Chem. Abstr., 1982, 97, 163 106).

8


1 (41) R = alkyl or a r y l

(40)

2

= Me o r Ph

(42) R

3

R , R = H, alkyl, ary1

[ PhN=C( NHPh ) ] ,PR3-

(43)

n = 1 or 2 R = Bu o r Ph

PhCH(OSiMeg)PHPh

Ph2PCH2NHCH( Me )COOR (45) R = H, alkyl

(44)

o r IT+

benzaldehyde proceeds with migration of the trimethylsilyl group from phosphorus to oxygen, giving the phosphine (44)as a mixture of dia~tereoisomers.~~ Mannich-type reactions between an amino-acid (or its salt or ester hydrochloride), formaldehyde, and diphenylphosphine lead to chiral aminomethylphosphines, e.g., (45).'O

Preparation of Phosphines by Reduction. Trichlorosilane has been employed in the synthesis from the corresponding phosphine oxides of a range of interesting new systems, including the chiral diphosphine (46),'l the tricyclic phospholane Ar

1

1

Ar

'PPh ,., Ph

(48) Arl=

(47)

Ar2=

o-ROC6H4 0-XC H 6 4

X = H o r OR Ph

\

(49)

(50)

(51)

6Q

A. N. Pudovik, G. V. Romanov, and T. Ya. Stepanova, Izv. Akad. Nauk SSSR,Ser. Khim., 1982, 1417 (Chem. Absfr., 1982,97, 92 430).

70

A. Tzschach, K. Kellner, W. Hanke, L. Marko, and Z. Nagy-Magos, Ger. (East) P. 149 669 (Chem. Absrr., 1982,97, 6779). H. Brunner and M. Probster, Innorg. Chirn. A d a , 1982, 61, 129.

l'

Phosphines and Phosphoniurn Salts

9

(47),72 the diphosphine (48),73the pentadienylphosphine (49),74 the cationic, water-soluble phosphine (50),7band the bicyclic phosphorinane (51).76 The latter, on treatment with acidified potassium iodide, undergoes intramolecular cyclization to form the first phosphaadamantane that has no other heteroatoms present in the skeleton. Other silicon-based reagents, whilst not as popular as trichlorosilane, have also found application. Thus, e.g., hexachlorodisilane and phenylsilane, respectively, have been used in the synthesis of the chiral phosphines (52)" and (53)78 from the corresponding chiral oxides. Polymethylhydrosiloxane has been used in the final step of a route to chiral diphosphines having a flexible alkane backbone, e.g., (54).79

(52)

R

=

Me or NR2

(53)

(54)

Polymeric phosphine oxides in which phosphorus forms part of the polymer backbone have been reduced to the corresponding phosphines in a clean, twostage, one-pot procedure : treatment with oxalyl chloride followed by di-isobutylaluminium hydride. This procedure is also applicable to simple phosphine oxides. Examples of the reduction of phosphine sulphides using either sodiumB1or lithium aluminium hydrides2have also appeared. These reagents have also been employed in the reduction of various halogenopho~phines.~~-~~ Miscellaneous Methods of Preparing Phosphines. A review of methods for the preparation of polymer-bound phosphines (and their applications) has 73 73

L. D. Quin, A. N. Hughes, H. F. Lawson, and A. L. Good, Tetrahedron, 1983, 39, 401. R. L.Wife, A. B. van Oort, J. A. van Doorn, and P. W. N. M. van Leeuwen, Synthesis,

74

C. C. Santini and F. Mathey, Can. J. Chem., 1983, 61, 21. R. T. Smith and M. C. Baird, Inorg. Chim. Acta, 1982, 62, 135. H. J. Meeuwissen, G. Sirks, F. H. Bickelhaupt, C. H. Stam, and A. L. Spek, R e d : J.R. Neth. Chem. SOC.,1982, 101, 443. W. C. Christopfel and W. S . Knowles, Ger. Offen. 3 148 098 (Chem. Abstr., 1983, 98,

1983, 71. 76 76 77

34 759). 78 79

M. Moriyama and W. G. Bentrude, Tetrahedron Lett., 1982, 23, 4547. J. C. Briggs, C. A. McAuliffe, W. E. Hill, D. M. A. Minahan, J. G. Taylor, and G. Dyer, Znorg. Chem., 1982,21,4204. S . Kobayashi, M. Suzuki, and T. Saegusa, Polym. Bull., 1982, 8, 417 N. I. Demidova, A. I. Bokanov, 0. S. Medvedev, and B. I. Stepanov, Zh. Obshch. Khim., 1982,52, 1099 (Chem. Abstr., 1982,97, 144 926). Y. Kawakami, R. A. Murthy, and Y. Yamashita, Synth. Commun., 1983, 13, 427. A. H. Cowley, E. A. V. Ebsworth, R. A. Kemp, D. W. H. Rankin, and C. A. Stewart, Organometallics, 1982, 1, 1720. A. H. Cowley and R. A. Kemp, Znorg. Chem., 1983,22,547. M . Baudler, J. Hellman, and Th. Schmidt, 2. Naturforsch., B: Anorg. Chem., Org. Chem., 1983, 38, 537. E. Niecke and R. Ruger, Z. Naturforsch., B: Anorg. Chem., Org. Chem., 1982,37, 1593.

10


appeared.87The reactions of Grignard reagents derived from chloroalkylsilanes with phosphinite esters, e.g., ( 5 9 , lead to the diphosphines (56), which may be anchored to an inorganic support via the silyl group.88The diarylphosphinite (57) is formed in the reaction of trimethylphosphite with o-tolylmagnesium Conventional crown-ether synthetic procedures have been applied to the bisphenolic phosphines ( 5 8 ) to give the monophospha-crown system (59).*O C 1Mg( CH2) 3S iMe2 (OEt )

,(EtO)Me2Si(CH2)3P(Bu)(CH2)2PBu2

Bu2P( CH2)2P( Bu)OEt (55)

R

J2

( 5 8 ) R = Ph o r But

(57)

H2C=C( R1 ) C X P P h 2

R

R2MgX 2 o r R Ag

R 2CH2C( R 1)=C=CHPPh2

( 5 9 ) n = 3 or 4

R1 P

wR

1

( 6 1 ) R'=

H o r Me

2 R = Et, Pri, Bu,

(62) R'=

R

=

1'

2 Me, Et, or Pr H or Me

The phenolic phosphines ( 5 8 ) are easily accessible by acid-cleavage of the related methyl ethers. The reactions of the enyne-phosphines (60) with Grignard or alkylsilver reagents lead to the allenic phosphines (61).91The thienylphosphines (62) are formed in the reactions of thiophenes with halogenophosphines in the presence of zinc.92,93 The chemistry of acylphosphines continues to attract attention. Reactions of acyl chlorides with silylphosphines have now been applied to the synthesis of a

89 91

B2 B3

P. Hodge, B. J. Hunt, E. Khoshdel, and J. Waterhause, N o w . J. Chim., 1983, 6, 617. 0. L. Butkova, L. I. Zvezdkina, and N. A. Pritula, Zzv. Akud. Nuuk SSSR, Ser. Khim., 1982, 2390 (Chem. Abstr., '1983,98, 72 261). A. Henne, Ger. Offen. 3 201 424 (Chem. Abstr., 1983,98,215 794). A. van Zon, G . J. Torny, and J. H. G. Frijns, Recl.: J.R. Neth. Chem. SOC.,1983, 102, 326. H. Westmijze, H. Kleijn, and P. Vermeer, J. Organomet, Chem., 1982, 234, 117. E. A. Krasil'nikova, E. S. Sharafieva, and A. I. Razumov, Zh. Obshch. Khim., 1982, 52, 2638 (Chem. Abstr., 1983, 98, 72 281). E. A. Krasil'nikova, E. S. Sharafieva, A. I. Razumov, and N. Yu. Zaslonova, Zh. Obshch. Khim., 1982, 52, 2793 (Chem. Abstr., 1983, 98, 89 518).


11

range of chloroacylphosphines, e.g., (63).94 The secondary phosphines (64) are formed in the reactions of primary phosphines with chloroformate esters. The carboxyallylphosphines in this series undergo intramolecular cyclization to form the heterocyclic systems (65).95 The reactions of halogenophosphineswith sodium carboxylates have given a series of carboxyphosphines, e.g., PhP[OC(O)Et],, which have normal phosphine-like behaviour with regard to co-ordination to transition r n e t a l ~ . ~ ~ , ~ ~

C1CH2CH2COPPh2

n

R PHCOOR

RpK 0

(63)

(64)

R 1= Ph, Cy,

O

(65)

or CH2CH2CN 2 R = E t , B u , or a l l y 1

1

( 6 7 ) R = Me or Ph

(68) R2= alkyl or Ph

The bisphosphinoindene (66) (in the form of its chromium carbonyl complex) is formed directly in a one-pot procedure by addition of bis(dipheny1phosphino)acetylene to an arylcarbene20

CH3(CF3)3PH

OC

CH3(CF3)2P

+

CF3H

n.m.r. spectra revealed a barrier (AG*zss = 59 kJ mol-l) to the intramolecular exchange of CF, groups, the largest yet reported for an acyclic quinquevalent hydride of phosphorus. Reaction of (23) with (24) gave the novel series of bicyclic phosphoranes (25) in 67-69% yield,17 and a similar displacement of a dialkylamino group from three-co-ordinate phosphorus (26) by the amidoxime (27) gave the phosphorane l6 l7

L. V. Griend and R. G. Cavell, Inorg. Chem., 1983,22, 1817. M. A. Pudovik, S. A. Terent'eva, and A. N. Pudovik, Izv. Akad. Nauk SSSR,Ser. Khim., 1982, 1408.


40

n

(23)

R =

(24)

Me, E t , or Ph

(29) ; when X = C1, however, an intramolecular (radical-cage) rearrangement of the intermediate (28) occurred to form (30).18

The first example of a stable H,B-N-P-N-BH3 sequence has been provided by the reaction of (31) with diborane to give (32), in which the BH3groups appear to be co-ordinated with the apical nitrogen atoms.19 Preliminary investigations

l8 l8

R. F. Hudson, C. Brown, and A. Maron, Chem. Ber., 1982, 115,2560. J.-M. Dupart, S. Pace, and J. G. Riess, J. Am. Chem. SOC.,1983, 105, 1052.

Quinquecovalent Phosphorus Compounds

41

of the cyclamphosphorane (33), however, which is known to be in equilibrium with the open-chain form in solution, gave a mixture from which 40% of the bis(borane)cyclamphosphorane (34) and 15% of the open bis(borane)cyclamphosphorane (35) were isolated. In solution (34) gradually isomerizes to (35). H

I

H3B,

,BH3

i +

B2H6

(34)

(33)

(35)

4 Acyclic Phosphoranes

The reaction of hexafluoroisopropyl benzenesulphenate (36) with phosphinites (37b) and phosphonites (37c) gave, as expected, hexafluoroisopropoxyphosphoranes (38b,c), but with the phosphite (37d) the intermediate phenylthiophosphorane (39) showed unusual stability and did not react with a second mole of (36).20 The variable-temperature lBFn.m.r. of (39) revealed a barrier to pseudorotation, AGlza, = 50.4 kJ mol-l (12.0 kcal mol-l), whereas the trifluoroethoxy analogue showed only broadening of the lBFn.m.r. down to 176 K. The barriers to pseudorotation in (38b) and (38c) are 67 kJ mol-' (T, = 303 K) and 55 kJ mol-1 (T, = 263 K), respectively. The significant barrier in (38c) is unusual for tetraalkoxy-phosphoranesand is attributed to non-bonded PhSP [ OCH( CF3) 2 ]

[ n = 01

D. B. Denney, D. Z. Denney, P. J. Hammond, L.-T. Liu, and Y.-P. Wang, J. Org. Chem., 1983,48,2159.

42


electron repulsions between the hexafluoroisopropoxy-groups in the squarepyramidal (sp) form of (38c). With triphenylphosphine, (36) gives triphenylphosphine oxide (40) and no phosphorane. It should be noted, however, that the desired phosphorane (38a, n = 3) is apparently obtained by the reaction of triphenylphosphine dibromide with hexafluoroalkoxide (vide infra, reference 27). The reaction of perfluorophenol (41) with PC16 in the presence of base gave perfluoropentaphenoxyphosphorane (42) along with the phosphate (43) and pefluorodiphenyl ether (44),but attempts to prepare penta(perfluorobenzy1oxy)phosphorane by a number of methods failed and analogous attempts to prepare perfluorothiophenylphosphorane (45) always resulted in fragmentation to perfluorothiophenyl phosphite (46) and bis(perfluoropheny1) disulphide (47).21 A similar reaction apparently occurred during attempts to prepare (48) from thiocatechols and phosphorus pentachloride.22

Et3N

C6F50H

+

PC15

+

( C F 0) P 6 5 5

(C6F5)20

(43)

(42)

(41)

+

(C6F50)3P0

(44)

( 4 8 ) R = H o r Me

The Mitsonubo reaction between triphenylphosphine and diethylazodito be a source of diaryloxy- or dialkoxycarboxylate (49) has been phosphoranes (51) via (50), which contradicts a recent that the key intermediate in the reaction is an 0,N-phosphorane. + Ph3P +

-

Ph3P

NO‘OOE

I

N\

___t

+ COOE t

E tOOCN=NCOOE t (49) 21 22

23

Et00CHN-NHCOOEt (50)

D. B. Denney, D. Z. Denney, and L.-T. Liu, Phosphorus Sulfur, 1982, 13, 1. D. B. Denney, D. Z. Denney, and L.-T. Liu, Phosphorus Sulfur, 1982, 13, 243. E. Grochowski, B. D. Hilton, R. J. Kupper, and C. J. Michejda, J. Am. Chem. Soc., 1982, 104, 6876.

24

R. D. Guthrie and I. D. Jenkins, Aust. J. Chem., 1982, 35, 767.

43


Bis(trifluoromethy1)nitroxyl (52) reacts with CF,PX2 (X = F, Cl, Br, or CN) at -70 "C to afford oxidative addition products (53), although with X = Br or CN the products are Substituted vinyl phosphites (54a-c) are readily chlorinated to form thermally stable phosphoranes (55a-c), which in turn may be converted into (57) via (56).26

OCMe=CCl ClnP(OCMe=CC12) 3-n

+

I

c 1.

C12

ip-

c1

,N

Ar 'N

I-Pee I ,c1 I'Cl

Ar

OCMe=CC12 (57)

Arm2, [n = 21

C1n+2P(OCMe=CC12)3-n

-

NA r

II

C12P(OCMe=CC12)

Bis(hexafluoroisopropoxy)triphenylphosphorane (38a) alkylates aromatic amines to form (58), which on heating with triethylamine give (59). The reaction has been employed to introduce the trifluoromethyl group into the desired position of heterocycles, since on using ortho-substituted anilines the alkylation products (60a-c) eliminate HF and then cyclize to form ( 6 1 a - ~ ) . ~ ~

ArNH

(38a)

2Ph3P0

A,Et3N

+

(58)

2e 27

7F3

ArNCH( CF3I2 --ArN-C=CF2 (59)

H. G. Ang and K. K. So, J. Fluorine Chem., 1982, 21, 221. T. V. Kolodka, M. I. Povolotskii, and Yu. G. Gololobov, J. Gen. Chem. USSR (Engl. Transl.), 1982. 52. 1336. T. Kubota, K: Yamamoto, and T. Tanaka, Chem. Lett., 1983, 167.

44


( 6 0 a-C)

a; XH = NH

( 6 1 a-c)

2

b ; XH = OH c ; XH = SH

A reportz8has also appeared on the alkylation of aldehydes and ketones by polyfluoroalkoxyphosphoranes (62), which in the cases of p,araformaldehyde, aromatic or unsaturated aldehydes, and hexafluoroacetone gives polyfluoroalkyl-containing acetals [e.g., (63)].

(62) n = 2,4

I r ( C 0 ) C l 2 ( PEt3)2PC12

X = H,Br

(63)

c12

I r ( CO)C12(PEt3)2PC14

(64)

(65) [6(

31

P) = +7.6,-8.6

p.p.m.1

Finally, a rare example of a metal complex (65) containing five-co-ordinate phosphorus has been prepared by chlorination of (64) and characterized by analysis and 31P{lH} n.m.r.29

5 Three-, Four-, and Five-membered-ring Phosphoranes

Monocyclic Systems.-Treatment of the betaine (50) with hydrogen peroxide at 0 "C gave phenyl diphenylphosphinate (68) ; triphenylphosphine dioxide (67), formed via (66), was suggested as the critical intermediate.30Evidence for the formation of a bisperoxyphosphorane, Ph,P(OOBu'), [S(31P)= -42.3 p.p.m.1, is presented in the same paper. Yu. G. Shermolovich, N. P. Kolesnik, Z. Z . Rozhkova, A. V. Kashkin, Yu. L. Bakhmutov, and L. N. Markovskii, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 2231. E. A. V. Ebsworth, N. T. McManus, N. J. Pilkington, and D. W. H. Rankin, J . Chern. Sac., Chem. Commun., 1983,484. so M. von Itzstein and I. D. Jenkins, J. Chem. SOC.,Chem. Commun., 1983, 164. z8

45


Ph COOE t

I

,N-NHCOOE

- (EtOOCNH)

t

Ph P 'OOH

c

11 + Ph3P-O0

In contrast to an earlier reportYS1 treatment of (69) with alkyl-lithium in saltfree THF at -78 "C did not give any detectable (by 31Pn.m.r.) quantities of either (70) or (71),32although a red colour was observed which could have been due to a low concentration of the ylid.

RLi,THF -78

or

OC

The chlorination of (72) at - 100 "C gives the trichlorophosphorane (73), which rearranges above -40 "C to the dichlorophosphate (74) with no evidence for the formation of the phosphonium salt (75).33Likewise, the halogenation of (76a,b) at low temperature gives the phosphoranes (77a,b) which, with the The latter comexception of (77b, X = Br), are stable at room ternperat~re.~~ pound, which was shown to be in equilibrium with the phosphonium salt (78), slowly gave a spirophosphorane (79) by cleavage of the ether linkage. The 31 32 33

M. Schlosser, A. Piskala, C. Tarchini, and H. B. Tuong, Chimia, 1975, 29, 341. E. Vedejs and G. P. Meier, Angew. Chem., Int. Ed. Engl., 1983, 22, 56. J. Gloede, M. Pakulski, A. Skowronska, H. Gross, and J. Michalski, Phosphorus Sulfur,

a4

J. Gloede, H. Gross, J. Michalski, M. Pakulski, and A. Skowronska, Phosphorus Sulfur,

1982, 13, 163. 1982, 13, 157.


46

C1CH2CH20P(0)C12

[6(

(74) 31 P) = +5]

c 1(75) [6(31P) = +25 (estimated)] V

(76) a ; Y = H

b ; Y = OMe

(77b,X = Br) 31P ) = -1101 [6(

=

V

(77a,b)


47

results serve to emphasize that for the reactions of phosphites with halogens in general the equilibrium for acyclic phosphoranes (80) lies in the direction of the four-co-ordinated phosphonium salt (8 l), whereas with five-membered-ring cyclic phosphoranes the five-co-ordinated structure (82) is favoured over (83).

A series of cyclic phosphoranes (86) has been obtained by the reaction of the bicyclic peroxide (84) with three-co-ordinate phosphorus compounds (85) and the products characterized by lH, 13C,and 31Pn . m . ~ .The ~ ~ increasing ring strain in cyclic pero-xides is reflected by the enthalpies of activation for the reaction of (87), (84), and (88) with triphenylphosphine; these decrease from 62.3 kJ mol-1 (14.9 kcal mol-l) through 46 kJ mol-1 to 38.5 kJ mol-1 (9.2 kcal mol-l).

(84)

(85) n = 0-3

(86) n = 0-3

(87)

(88)

4

AH ( kJrnol-l)/PhgP:

62.3

46

38.5

Phosphoranes (91) have been prepared in 21-90% yield by the reaction of (89) with various three-co-ordinated phosphorus compounds A detailed study of the reaction between methyl diphenylphosphinite and 1-nitropropene shows that at ca. -5 "C a quantitative yield of the monocyclic phosphorane (94) 35 36

E. L. Clennan and P. C. Heah, J. Org. Chem., 1982,47, 3329. S. Kobayashi, Y.Narukawa, and T. Saeguso, Synth. Commun., 1982, 12, 539.


48 0

ll

HC-COOH

+

R1R2R3P

R1= MeO, P h O , o r Ph 2

R = P h O ; R3= v a r i o u s R2-R3=

OCH2CH20,

OCMe2CMe20,

o r OCH2CH2CH2

is obtained, which may decompose to form (95) and (96) or via (93) and (97) to give (98) and (99). A combination of 31PCIDNP studies and e.s.r. evidence leads to the suggestion that single-electron transfer to form the radical-ion pair (92) is the initial step of the rea~tion.~' In another study of the interaction of Me0

0

0,

-Ph2POMe

Pb POMe \2

+

Me

MeCH=CHN02

II

+

MeCH=CHNO (96)

(95)

(94)

+.

-.

[ P h 2 P ( OMe) MeCH=CHN02]

=

+

-

Ph2PCHMeCHN02

I

OMe

OMe

I

Ph2P=CMeCH2N02

37

0

II

-Ph2PCMe=CH2

+

MeN02

R. D. Gareev. A. V. Il'yasov, Ya. A. Levin, E. I. Gol'dfarb, V. I. Morozov, I. M.Shermergorn, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1982,52, 1123.

49


three-co-ordinate phosphorus compounds with activated double bonds, the thiophosphorane (100) was detected by 31Pn.m.r. during the reaction of ethyl diethylphosphinothioite with methacrylic acid, the ultimate product being (101).38 The reaction of triethylphosphite with maleic anhydride, however, Et2PSEt

+

0

-

i"'

OC

0

II

Et2PCH2CH2COSEt

CH 3CH=CHCOOH (101) 0 (100)

31 [8( P ) = -141

gives the betaine (102)39 and not, as previouslyreported,4Othe phosphorane (103). Finally, the reaction of triphenylstibine sulphide with tetrachloro-o-benzoquinone ( EtO) 3P

CD2C12

+

-

t

0

0

OC

0 0

gives the cyclic stiborane (104); this is in contrast to triphenylphosphine sulphide and triphenylarsine sulphide, both of which undergo oxidative desulphurization to form hydrogen-bonded complexes (105) of the oxides with tetrachloro~wh01.41 Ph M=S

3

+ c1

clfJo

c1

( 1 0 4 ) M = Sb

*O

41

( 1 0 5 ) M = P or As

0. G. Sinyashin, T. N. Sinyashina, E. S. Batyeva, A. N. Pudovik, and E. N. Ofitserov, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52,2156. D. B. Denney and D. Z. Denney, Phosphorus Sulfur, 1982, 13, 315. N. D. Kazakova, Ts. A. Lyubman, and S. R. Rafikov, Izv. Akad. Nauk Kaz. SSR, Ser. Khim., 1977, 27, 75. M. M. Sidky, M. R. Mahran, and W. M. Abdou, Phosphorus Sulfur, 1983,15, 129.

50


Bicyclic Systems.-Spirophosphoranes (107) with X = Et, Ph, NEt,, NMePh, OMe, OEt, and OPr', have been prepared by the oxidative cycloaddition of dioxaphospholanes to aldehydes (106). The reactions are reversible and compounds containing the anti orientation of X with respect to R are the thermodynamically preferred X

( 1 0 6 ) R = H , Me, o r Ph

(107)

X = E t , P h , N E t 2 , N M e P h , OMe, O E t , o r OPri

A study of the reactions of amines and hydrogenphosphonates with spirophosphoranes (108) revealed that when R1 = C02R2 addition occurred at the @-carbonof the double bond to give (109) or (110), whereas with R1 = H, amines added to the a-carbon to give (1 11). The alcoholysis of the P-C bond in (109) and (110) is reported in the same paper.43

R1

I

2

-C=CHCOOR

-

R32NH

1

( 1 0 9 ) R = COOR

R~ P2

( 1 1 0 ) R1= COOR 2

43 43

R1

P(o)(oR~),

I I CH- C H C O O R ~

2

P2

I

C-CH~COOR~ 1 3 NR 2

(111) R1= H

V. V. Ragulin, A. A. Petrov, V. I. Zakharov, and N. A. Razumova, J . Gen. Chem. USSR (Engl. Trunsl.), 1982, 52, 21 1. R. Burgada and A. Mohri, Phosphorus Sulfur, 1982,13, 85.

51


Another example of five-co-ordinate phosphorus bound to a transition metal is provided by the reaction of (112) with (113) to form the spirophosphorane (114) in 91 % yield.44The 31Pn.m.r. shift at 67 p.p.m. is very broad (1100 Hz at half height) because of coupling with the manganese nucleus (spin 5/2), but 13Cn.m.r. and i.r. data serve to substantiate the structure as five-co-ordinate,

+

c1

Y

\

NaMn (CO) (113)

Further evidence for a biphilic insertion mechanism is derived from a study of the reaction of the bicyclic phosphoramidites (115) and (116) with diethyl peroxide to form (117) and (118), respecti~ely.~~ The strained l-phosphabicyclo[3.3.0]octane (115) reacts much faster than its l-phosphabicyclo[4.4.0]decane analogue (116), but the opposite reactivity is found towards diphenyl disulphide. At room temperature (116) produced (1 20) within seconds, presumably via an intermediate phosphonium salt, whereas (115) gave (119) [6 31P= - 19 p.p.m.1 after 1 h at 58 "C.As mentioned earlier, the latter appears to be the only phosphorane reported so far with two exocyclic P-S bonds.

44 45

M. Lattman, B. N. Anand, D. R. Garrett, and M. A. Whitener, Znorg. Chim. Actu, 1983, 76, L139. D. B. Denney, D. Z. Denney, P. J. Hammond, C. Huang, L.-T. Liu, and K.-S. Tseng, Phosphorus Sulfur, 1983,15,281.


52

\ PhSSPh

C

Y

m

0-P-

S

P

h

SPh

Tetraoxyazaphosphoranes[e.g., (121) and (122)]may be obtained by the reaction of (115) and (1 16) with trifluoroethoxybenzenesulphenate,and detailed n.m.r. studies suggest that (121) is the major topological isomer in the series derived from (115) whereas (122) predominates in the series from (116). When (116) was OCH2CF3

I

reacted with benzil or phenanthraquinone the tricyclic phosphorane products (123) and (124) were produced; below -34 "C, these appeared to exist as shown with the nitrogen atom apical, in sharp contrast to the adduct (125) [from (116) and biacetyl] which had nitrogen in the more conventional equatorial position,

Ph (124) (PA) = p h e n a n t h r e n e

(125)


53

Delocalization of non-bonding electrons on apical oxygen into the aromatic rings of (123) and (124), which in turn promotes interaction of the lone pair on apical nitrogen with phosphorus, is offered as a tentative explanation for the observations.4s Oxadiazaphospholines (126) have been used to prepare several monocyclic

R2XH

Cl ( 1 2 6 ) R 1= M e o r Ph

( 1 2 7 ) a ; R2= OC6H4Me-4 2

b ; R = NMePh

\ PhN=N-CCF

XN

0

AN

0

[e.g., (127a,b)] and spirocyclic [e.g.,(1 28) and (129)] pho~phoranes.~~ Triazaspirophosphoranes (132) were also produced by the reaction of oxadiazaphospholines (130) with o-azidophenol (131) and were characterized by mass spectral, i.r., and 1H/31P n.m.r. data.47Similarly, the reaction of the benzodioxaphosphole Ph

I

3

46 47

H

NR2

K. Tanaka,T. Igarashi, and K. Mitsuhashi, Heterocycles, 1983, 20, 157. A. Razhabov and M. M. Yusupov, J . Gen. Chem. USSR (Engl. Transl.), 1982,52, 1965.

54


ao>p-ph Ph H

N3CH2COOH ( 134)

‘

0

(133)

(135)

( 136)

CH2COOEt Ph

-

I

Ph

Et OOCH2C (137)

(138)

(133) with azidoethanoic acid (134) produced the spirophosphorane (135), whereas the analogous azido-ester (136) without an acidic hydrogen gave the dimeric phosphorane (1 38) via the intermediate phosphimide (1 37).48 Reaction Me

Me

Me

Me

I

I

Ph

h

H P O4 ‘Ph

(139)

(142)

Me

I

1

Rcl

Me

Me

I

I

Me

c1

I

R = P(0)PhCl \

I

Ph

R

48

M. P. Chaus, N. I. Gusar, and Yu. G. Gololobov, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 21.


55

of the spiro-(triazaphosphole) (139) with various phosphorus halides gave (140), which isomerized in part to the tricyclophosphorane (141).49Treatment of (141) with ammonia or amines gives rise to stable pentaaminophosphoranes [e.g., (142)l. The h5P-h3P diphosphorus compound (143) reacts with iron nonacarbonyl to give the novel complex (144) in which the iron atom has a tbp configuration while the geometry at five-co-ordinated phosphorus is close (> 80 %) to rp.SO

Tricyclic Systems.-In a paper dealing with a range of five-co-ordinate structures, Osman et aL51describe the reaction of (145) with biacetyl to give (146) and with phenyl azide to give the unusual bisphosphorane (147). The reaction of

/

Me COCOMe

(",.-. ' ;vt 0

nA

0-P,

'OI 0

(145)

4Q 6o

61

A. Schmidpeter, M. Naigibi, P. Mayer, and H. Tdutz, Chem. Ber., 1983, 116, 1468. J. W. Gilje, W. S. Sheldrick, N. Weferling, and R. Schmutzler, Angew. Chem., Znt. Ed. Engl., 1982, 21, 379. F. H. Osman, W. S. El-Hamouly,and M. M. A4del-Gawad,Phosphorus Sulfur, 1982,14,1.

56


(or-alkoxybenzy1idene)phosphoramidites (148) with benzoyl cyanide gives (1 50) via dimerization of the intermediate (149)52and a similar reaction between acyclic phosphoramidites (1 5 1) and acyl or aroyl cyanides (152) gives analogous

(\ 0

,P-N=C,

.Ph OEt

0

PhCOCN

Ph ( R'O)

~-N=C'

+

'R2

(153)

five-co-ordinate structures (1 53).53 Finally, the reaction of N,N'-dimethyl-N,N'bis(trimethylsily1)urea (1 54) with PCI, affords the interesting compound (1 55) with a h3P-h4P bond which undergoes oxidative addition of chloranil to form (1 56).64

MeN

MeN

I

NMe

I

Si S i Me3 Me3

\ T O=P-P /

/ \

pci3

MeN T

MeNYNMe 0

(154) 52 63

64

(155)

I. V. Konovalova, M. V. Cherkina, L. A. Burnaeva, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 189. I. V. Konovalova, M. V. Cherkina, L. A. Burnaeva, E. I. Gol'dfarb, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1982,52, 1749. H. W. Roesky and D. Amirzadeh-Asl, 2. Naturforsch., B: Anorg. Chem., Org. Chem.. 1983,38,460.

57

Quinquecovalent Phosphorus Compounds 6 Six-co-ordinated Phosphorus Compounds

Very little has been published in this area during the year. Osman reporW that (157a) reacts with the aminodiol (158) to form a product believed to have either structure (159) or (160), and that the reaction of (157b) with (158) in boiling benzene led to the formation of a mixture of (161) and (162). Denney20

uo)?-X t

'

+

0

x

BU

=

0,r

c1

/

HO (157) a ; X = C1

b; X

=

(158)

NMe2

1 9 0

0

ao'j-'oD '
SO,

Secondary aminophosphines are rare, but may be obtained in a straightforward manner, as shown for (57)4aand (58).43 The latter are also obtained, together with the tertiary aminophosphines, when (59) are treated with isopropylmagnesium chloride. [58; R = N(SiMe,),] has been made independently by Cowley, who also reports (60).44 Reduction of bis(trimethylsily1)aminodichlorophosphine gave either (61) or (62), depending on the amount of lithium aluminium hydride Experimental details for the large-scalepreparation of (sily1amino)phosphines have been published.46 ( MegSi 1,N,

LiA1H4

-*

( P r i,N),PC1

( P r i 2 N ) ,PH

/PH Me3SiNH

(57)

(Me3Si)

N

LiA1H4

‘PC1

R’ (59) R

42

=

Pri, B u t ,

(60)

(Me3Si) N ‘PH R’ (58)

CH2SiMe3,

N( S i b l e g ) , ,

Ph

R. B. King, N. D. Sadanani, and P. M. Sundaram, J. Chem. SOC.,Chem. Commun., 1983, 477.

4s

H. R. O’Neal and R. H. Neilson, Znorg. Chem., 1983,22,814.

44

A. H. Cowley and R. A. Kemp, Inorg. Chem., 1983, 22, 547. E. Niecke and R. Ruger, Z . Naturforsch., Teil By 1982, 37, 1593. R. H. Neilson and P. Wisian-Neilson, Inorg. Chem., 1982,21, 3568.

45 46

89

Tervalent Phosphorus Acids

( Me3Si)2NPC12

LiA1H4

( Me3Si)

__.__t

H C1 I I N-P-P-N( SiMe3)2

2

( Me3Si)2N-P-P-N( SiMe )

3 2

(62)

Novel reactive tervalent phosphorus acid anhydrides, phosphinosulphonates (63)-(67), have been prepared.47 The phosphorous acid derivatives (63) m d (64)are stable, but the phosphonous and phosphinous acid derivatives (65)-(67) rearrange thermally to the phosphinoyl sulphinates (68)-(70). /=N R 1 R 2 P - N d + MeS03H /

-

--*2ooc

1 2

R R P-OS02Me

(63) R (64) R

1 1

S02Me

2

=

R

=

R 2= OPr

= OEt

(68) R1= R2= Ph 1 ( 6 9 ) R = Ph, R2= B u t

(65) R1= R2= Ph (66) R 1= Ph, R2= B u t (67) R

1

=

1 2 40

R R , P

2

OMe,R = B u

( 7 0 ) X1=

OMe,R2= B u t

t

The new hexafluoro-isopropyloxyphosphorus compounds (71)-(73) have been prepared by standard methods and used for the preparation of phosphorane~.~ ~ Dibenzo-l,3,2-dioxaphosphepins and phosphocins have been prepared from bis-phenols and dichlorophosphines, and the conformations of the seven- and eight-membered rings discussed in the light of lH n.m.r. data.49

Ph2P-OCH( CF3)

(1;

P-OCH( CF3)

A general method for obtaining 1,3,2-dioxaphospholenes(74)has been devised, using the readily available masked acyloins (75) as starting materials.boThe P-chloro compounds (76)could be obtained as shown.61 p7 48 4g

s1

W. Dabkowski, J. Michalski, and Z. Skrzypczynski, J. Chem. SOC.,Chem. Commun., 1982, 1260. D. B. Denney, D. Z. Denney, P. J. Hammond, L.-T. Liu, and Y.-P. Wang, J. Org. Chem., 1983,48,2159. P. Odorisia, S. P. Pastor, J. D. Spivack, and L. Steinhuebel, Phosphorus Sulfur, 1983, 15, 9; S. D. Pastor, J. D. Spivack, L. P. Steinhuebel, and C. Matzura, ibid., p. 253. T. N. Kudryavtseva, N. B. Karlstedt, M. V. Proskurnina, N. V. Boganova, T. G. Shestakova, and I. F. Lutsenko, J. Gen. Chem. USSR,1982,52, 912. N. B. Karlstedt, T. N. Kudryavtseva, M. V. Proskurnina, and I. F. Lutsenko, J . Gen. Chem. USSR.,1982,52,1754.

90


PhCOCl

R2PC l2

R1

/

heat

OSiMe3

(74) R

(75)

2

=

2

[ R = NR21

O R , NR2

Nucleophilic substitution reactions at tervalent phosphorus centres continue to be an area of active research. Pudovik et al. have studied substitution reactions on several 1,3,2-0xazaphospholans(Scheme 5). For compounds with an exocyclic P-N bond (e.g., 77) the major reaction pathway is substitution of the exocyclic substituent.62The reactions however may not be simple substitutions since (78) is found to give first (79) derived from endocyclic P-N bond cleavage; (79) then Ph

('>

-OPh

0

Ph

Ph heat

(77)

Me

/

(>-IfMe

Me

Ph

Me 'SiMe3

iii

/

"'< (80)

-

NH

Me I

i

(:>P-OPh

MeNHCH2CH20P(OEt)2

M

,NHPh A CH CH O P 'OEt

c1-

Reagents: i, PhOH; ii, PhNH,+CI-; iii, EtOH

Scheme 5 63

M. A. Pudovik, L. K. Kibardina, and A. N. Pudovik, J. Gen. Chem. USSR, 1982, 52, 677; ibid.,1981,51,420.


91 HX

\P-NR~

/

NuH

e >P-x

H X = HC1, CH3COOH , NuH

)P-N~

= ROH,

R2NH

Scheme 6

slowly cyclizes to the usual Solely ring-opened products are observed for compounds with an exocyclic OR group (e.g., 80). According to Pudovikb2 these substitution reactions, which are catalysed by acids (R,NH,+Cl-, CH,COOH), occur by a nucleophilic catalysis mechanism (Scheme 6). 1,3,2Oxazaphospholans unsubstituted at nitrogen are usually unstable, but (81) has been obtained pure and some reactions have been Other systems studied this year include alcoholysis of some benzoxaza-, thiaza, and diazaphospholenes (82) and (83).66 A phosphorane intermediate (84) was observed H

H

H

H

- ) NJ - f

0

,OEt

EtOH =

(82) X = 0

(87) ( 8 8 ) R = alkyl,

b3

b4 b5

Ph, PhCO

M. A. Pudovik, L. K. Kibardina, and A. N. Pudovik, J. Gen. Chern. USSR,1982,52, 1310. M. A. Pudovik, S. A. Terent’eva, and A. N. Pudovik, J. Gen. Chem. USSR,1982,52,43 1. M. A. Pudovik, S. A. Terent’eva, Y. B. Mikhailov, and A. N. Pudovik, J. Gen. Chem. USSR, 1982,52, 1144.

92


(lH and 31P n.m.r.) when (82; X = 0) was treated with alcohols at room temperature; the subsequent intermediate (85), which is the result of P-0 and not the expected P-N bond cleavage, was inferred from the results of model reactions.b6In contrast to (86),66 the analogue (87) does not show any evidence for a hydroxyphosphorane during hydrolysis, although with alcohols (88) is the stable product.S7 ,CH=CMe2 ( RO) 2P-N,

MeCOOH

(RO)2P-OCOCH3

Bu (89)

+

BuN=CHCHMe2

(90)

Phosphoramidites (89), derived from enamines, react with carboxylic acids in an irreversible manner because of the low basicity of the eliminated e n a ~ n i n e . ~ ~ The anhydrides (90) may also conveniently be obtained from enol phosphite~.~~ Reactions of (89) with phenol were also studied and the kinetics found to be ‘characteristic for bimolecular processes’.68 In contrast to other carboxylic acid halides, acyl fluorides give tervalent phosphorus fluorides with tervalent esters (Scheme 7).60 i

4

0

+ RX

R’COX f-------

R’COF

-/P-F

\p-OR

/

,

+

R’COOR

Scheme 7

Further developments in the use of the phosphite coupling approach to oligonucleotide synthesis have appeared this year. CaruthersB1has examined the stability and reactivity of mononucleoside phosphoramidites (92)-(95). The (91) R = Me

DMToP (92) R = Pri

n

0-

\

,P-NR2 Me0

( 9 3 ) NR2 = N

0

u

( 9 4 ) NR2 = N

Z

3

( 9 5 ) NR2 = N

56

B. J. Walker, in ‘Organophosphorus Chemistry’, ed. D. W. Hdtchinson and S. Trippett (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1980, Vol. 11, p. 91.

57 68

0. S. Diallo and R. Mathis, Spectrochim. Actu, Part A , 1983, 39, 153. P. I. Gryaznov, A. M. Kibardin, T. K. Gazizov, and A. N. Pudovik, J. Gen. Chem. USSR, 1982,52,2152.

59 6o

T. K. Gazizov, R. U. Belyalov, and A. N. Pudovik, J . Gen. Chem. USSR, 1982,52, 1494. T. K. Gazizov, R. U. Belyalov, and A. N. Pudovik, J. Gen. Chem. USSR, 1982,52,673. L. J. McBride and M. H. Caruthers, Tetrahedron Lett., 1983, 24, 245.


93

derivatives (92) and (93) are much more stable than is the original reagent (91)s2 towards hydrolysis, but are still reactive enough after activation with tetrazole to be promising reagents. Stability problems with (91) as a reagent for oligonucleotide syntheses have been noted by otherss3who also recommend (92) as an improved reagent, and impressively demonstrate the effectiveness of the phosphoramidite method by preparing a DNA sequence with 51 units. A one-pot reaction to prepare (91), (93), and the corresponding 2-chlorophenyl derivatives (96) has been described (Scheme 8);s4 the bis-triazolyl derivatives (97) are used in order to minimize 3’,3’-coupling products.

R N

Reagents: i,HN, J

+

EtPrlN; i i , DMTo

N

‘7

; iii, R,NSiMe,

OH

Scheme 8

Although nucleoside phosphoramidites with improved stability thus have been developed it is still a drawback of the phosphite method that solutions of the monomers (91)-(96) have to be prepared and stored. Two approaches to circumvent this have been described. One uses methoxydichlorophosphine (98) to prepare the 5’-O-phosphorchloridite in situ;66 the other approach uses methoxybis(tetrazoly1)phosphine (99) in a similar way (Scheme 9)?6 Both seem to work well for larger oligonucleotides and are promising for their simplicity.

6a

68 84

6s

B. J. Walker, in ‘OrganophosphorusChemistry’, ed. D. W. Hutchinson and J. A. Miller (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1982, Vol. 13, p. 93. S. P. Adams, K. S. Kavka, E. J. Wykes, S. B. Holder, and G. R. Galluppi, J. Am. Chem. SOC.,1983, 105, 661. J.-L. Fourrey and J. Varenne, Tetrahedron Lett., 1983, 24, 1963. K. Jayaraman and H. McClaugherty, Tetrahedron Lett., 1982,23, 5377. T. M. Cao, S. E. Bingham, and M. T. Sung, TetrahedronLett., 1983,24,1019.

0rganophosphorus Chemistry

94

Reagents: i, MeOPCl,

+ Py or MeOP

(98)

OH

(99)

Scheme 9

The use of methyldichlorophosphine (100) instead of (98) for nucleoside coupling gives, after oxidation, nucleoside methylphosphonates (101), which are interesting nucleotide analogues. Two papers have appeared which describe the preparation of di- or tetra-deoxynucleotide analogues of this

MePC 1 (100)

Rd Ph

CP I

Ph

I

N

Br2

ROH

-N Me

N I Ph

67 68

,z S02C12,

(N>-oR

RX or Me1 -

I Ph

X = Cl,Br,I

J. Engels and A. Jager, Angew. Chem., Int. Ed. Engl., 1982,21, 912. N. D. Sinha, V. Grossbruchhaus, and H. Koster, Tetrahedron Lett., 1983, 24, 877.


95

2-Dimethylamino-l,3-diphenyl-l,3,2-diazaphospholane(102) reacts with primary and secondary alcohols to give crystalline derivatives (103) useful for characterization purposes; more interesting is their use to convert alcohols to alkyl halides.6eSeveral new ligands for catalysts in asymmetric redox reactions have been prepared. These include (104)and (105),the Rh complexes of which have been used successfullyin asymmetric hydrogenations,7Oand (106),which however was inferior to ‘diop’ in hydrogenation and hydroformylation reactions.71

a

-

P

N

P

h

2

I

I

PPh

PPh2

(104)

0

(,I;/.-PPh2

3 -PPh2

;I

(105)

O-PPh2

(106)

4 Reactions involving Two-cosrdinate Phosphorus

Phosphoryl chloride (107) has been prepared in a high temperature reaction between phosphoroxychloride and silver, and characterized by m.s. and i.r. spectro~copy.~~ Ab initio calculations on the simplest h3-iminophosphine, (108)’ indicate a trans-planar structure, although the cis isomer is only 0.6 kcal mol-l higher in energy.73 r (PN) 1.559

8

H ‘P=\

L HPN

10006

L HNP

11808

H (108)

One of the phosphorus substituents in aminoiminophosphines(109)and (1 10) may be displaced by lithium amides to give new aminoiminophosphines (111)(1 14).74The reactions are thought to involve the anionic intermediates (1 15), which eliminate lithium bis(trimethylsily1)amide to give the products. The reactions of (109)further involve a silyl migration to give the thermodynamically most stable isomers (1 13) and (1 14). With 2,4,6-tri-t-butylphenyl-lithium, (109) gives the h3-iminophosphine(116)which is stable enough to survive distillation at 110 0C!74As expected, (1 16)is very sensitive to hydrolysis and gives (1 17) with methanol. 6e

70

71 74

’*

74

S. Hanessian, Y. Leblanc, and P . Lavallke, TetrahedronLett., 1982,23,4411. E.Cesarotti, A. Chiesa, and G. D’Alfonso, TetrahedronLett., 1982,23,2995. W. R.Jackson and C. G. Lovel, Aust. J. Chem., 1982,35,2069. M. Binnewies, M. Lakenbrink, and H. Schnockel, 2.Anorg. Allg. Chem., 1983,497, 7. G. Trinquier, J. Am. Chem. SOC.,1982,104, 6969.

V. D. Romanenko, A. V. Ruban, and L. N. Markovski, J. Chem. SOC.,Chem. Commun., 1983, 187.


96 NR2R3 -1

LiNR2R3 ( Me3Si)2N-P=NR1

* R 2R 3N-P=NBu

Me3Si)2NRp%R1] [R = B u

(115)

2 3 t (111) R = S i h l e 3 , R = B u 2 3 (112) R = R = Pri

R 3N = P - N ( S i M e 3 ) 2

3

(113) R = B u (114) R

3

=

' ii

( M e 3S i )2N-P=N-SiMe3-

t

1-adamantyl

B u tG p = N - s i M e 3

(109)

Bu

OMe

But

Reagents: i, But

6/ \

Li ; i i ,

But

t

I

\B u t (117)

CI-; iii, MeOH at 0 °"C C


97

Attempts to prepare h3-iminophosphines with less sterically demanding substituents on phosphorus have been less successful. Mesityldichlorophosphine (118)reacts with primary amines to give (119)which, however, gives a mixture of dimers and tetramers on treatment with base.75Remarkably, the dimers give (120), and the tetramers give (121), with diethylamine or alcohols, and (120) and (121)are not in equilibrium. Treatment of the cyclodiphosph(m)azane (122) with bulky lithium diphenylphosphinoamides gave cyclic compounds (1 23) without evidence (by n.m.r.) for any equilibrium between (123)and the aminoiminophosphines (124)6‘.

c1-P

But R I R PN-P, I ,N\ ,P-NPPh2.+ I

But I R /N\ P-C1 + 2 Ph2PNLi I -Ph

2

\N’

R Ph2PN-P=NBu I t

N

I

But

But

(122)

(123) R = Me,Et,Pri,But

(124)

Cycloaddition reactions of two-co-ordinate phosphorus compounds described this year includes the [2 21 cycloaddition of an iminoborane to aminoiminophosphines to give 1,3,2,4-diazaphosphaboretidines(125).77In an attempt to prepare hydrazino-bis-phosphaalkenes (1 26) as new candidates for hetero-Cope rearrangements, the tricyclic compounds (127) were The result is explained by a Diels-Alder rearrangement of (126), as shown.

+

B ~ B - N B +~ ~R’N=P-NR

2

--

Bu

t 1 2 R = R = SiMeQ

I BU-B

”\P-NRz2 N ’‘

R =

k1

B U ~ ,R

~ =p r i

(125)

SiMeg

%fH

I

+ 2 Cl-P=C
C1 > I.133 The Pummerer rearrangement of the 2-(diethoxyphosphinyl)ethyl sulphoxides (1 31) to give (132), has been observed and The rates of displacement of ethanethiol from OS-diethyl methylphosphonate in solution in various alcohols by fluoride anion increases with the acidity of the al coh01. ~ ~ ~ 0

0

11 II (Et0)2PCH2CH2SR

B r 2 , HCo3-

1

=-. ( E tC))2P

0

II

\SEt

(131) R = M e , E t , o r Ph

One area of noteworthy activity during the year, if only because of the number of relevant publications, has been that concerning addition reactions of (diene)phosphonic acid derivatives [particularly those of (1,2-propadiene)phosphonic 133 184 136

H. Molinari and S. B a d , Synth. Commun., 1982, 12, 749. M. Mikolajczyk, B. Costisella, and S. Grzejszczak, Tetrahedron, 1983, 39, 1189. V. E. Bel'skii, G. S. Sakulin, and Yu. P. Prostov, J . Gen. Chem. USSR (Engl. Transf.), 1981, 51, 2104.

134


acids] with halogens and with other compounds, e.g., sulphenyl chlorides, which effectively generate electrophilic halogen. The overall course of the reaction, i.e., to what extent linear or cyclic products are favoured, depends upon the nature of the substituents on phosphorus and those at the terminal carbon atom of the diene In the halogenation of the (1,3-butadiene)phosphonicesters (133), the reaction might conceivably proceed via the resonance-stabilized tertiary carbocation (134). However, since the products are actually 1,2-oxaphosphorins (136), it would appear that the initial formation of the secondary carbocation (135) is preferred.13s

r

c1

c1

c1 - RX

A generalized scheme for the interaction of (1,2-propadiene)phosphonic esters (137) and R3YCl (Y = S or Se) is depicted in Scheme 17.140 Addition at position 1 or position 3 leads to equilibrium between the stereoisomers (138) and (139), and between (140) and (141) respectively. Ring opening, by attack at C-1, would thus lead to the (E) or (Z) alkenes (142) and (143), respectively. lS6

13'

lS6 laS

N. G. Khusainova, L. V. Naumova, E. A. Berdinkov, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 904. N. G. Khusainova, L. V. Naumova, E. A. Berdnikov, G. A. Kutyrev, and A. N. Pudovik, Phosphorus Sulfur, 1982, 13, 147. I#. M. Angelov, K. V. Vachkov, M. Kirilov, and V. B. Lebedev, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 412. Kh. M. Angelov, V. Khristov, and M. Kirilov, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 181.

l P oC.

M. Angelov, K. Vachkov, J. Petrova, and M. Kirilov, Phosphorus Sulfur, 1983,14,7.

Quinquevalent Phosphorus A cidr

I35 Me

@yHC1

,Me

@C H C l

0

Y

=

S or Se

PR" I -

R"

11

YR3

C1-

+*,R"

YR3

I

@C H = C - C = C H ~ 0 '

1

Me (147)

Scheme 17

Alternatively, dealkylation can lead to the A3-l ,2-oxaphospholens (146) or (148), or, by loss of a proton, to a (1,3-diene)phosphonate (147). The ratio of acyclic to cyclic product, and of (142) to (143) depends on the bulk of the group R2,an increase of which causes the equilibrium between (138) and (139) to shift towards (138) with consequent increase in the ratio of (142) to (143).

136


Relative to the structures (138) and (139), structures (140) and (141) will be favoured by stabilizing effects of Me and R2.The trans relationship between the carbocation charge and the polar phosphoryl group in (145) renders the decomposition route (141) + (145) -+ (148) unlikely, and hence breakdown takes place preferentially via the route (140) + (144), and the stereoisomeric A3-l,2oxaphospholens can be formed together with the phosphonates (142) and (143). For reactions with MeSCl, the ratio of (146) to (148) was found to be dependent on temperature, and the total yield of (142) (143) was only 8-15%.140 A similar scheme might be written in which R3Y is replaced by C1, and indeed, hints of such a representation have already been given (see ‘Organophosphorus Chemistry’, Vol. 10, p.144, and also ref. 146). A feature which might be added is an equilibrium between the carbocation and a phosphonium salt s t r u ~ t u r e . ~In ~ ~this J ~ ~respect, cyclic 1,2-propadienyl esters represent an interesting case. The intermediate in the highly stereoselective halogenation of the 1,3,2-dioxaphospholans(149; R1, R2 = H or Me, R3 = Me or Et, R4 = H generally, X = C1 or Br) might exist as a spiro phosphonium salt possibly in equilibrium with a carbo~ation.’~~

+

R4

Me

p4

The scope of the Scheme can be extended to include (1,2-propadiene)phosphonic dichlorides when an additional equilibrium between the dichlorophosphonium chloride and a trichloro pentaco-ordinate compound can be considered. Thus, the chlorination of the 3-phosphylated-penta-1,2,4-triene compound (150: R1= X = Cl) yields the linear (hexa-l,3,5-triene)-phosphonic dichloride (153: R1 = X = Cl) via the proposed intermediate equilibrium 141 142

V. K. Brel’, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1983, 52, 234 (Chem. Abstr., 1983, 98, 215 674). C. M. Angelov and C. Zh. Christov, Heterocycles, 1983, 20, 219 (Chem. Abstr., 1983, 98, 143 542); C. M. Angelov and C. Zh. Christov, Phosphorus Sulfur, 1983, 14, 205.

I37

Quinquevalent Phosphorus Acids r

/.I=

alkoxy

2 (153)

( 154 1

between (151) and (152) :143 when the phosphonic esters (150: R1= alkoxy) are used, dealkylation can then occur, and A3-l ,Zoxaphospholens (1 54) result.l** Direct anti-Markownikoff addition of phenylsulphenyl chloride to the phosphonic dichloride (155: R1= H) gives the (E)-alkene (156). For the case 0

0

II

1 C12PCH=C=CR

+

ti ,SPh C12PCH=C ‘CH2C1

PhSCl a

(155) (156)

r

1

0

( R20) 2POS143

V. K. Brel’, B. I. Ionin, and A.

1

(159)

A. Petrov, J . Gen. Chem. USSR (Engf. Trunsl.), 1981, 51,

2264. 144

Kh. M.Angelov, N. M. Stoyanov, and B. I. Ionin, J. Gen. Chem. USSR (Engl. Transf.), 1982, 52, 162.

138


when R2 = (CH2)5, the intermediate loses HCl to give the diene (157). When the electrophilic reagent is a phosphoranesulphenyl chloride and R1 is Me, the intermediate is evidently (158) and release of phosphorochloridothioate affords the chloro chloride (159).137 The addition of HC1 or HBr to (160: R1 = alkoxy, R2 = Me) occurs readily to give (161); the much slower chlorination of the phosphonic dichloride (160: R1 = C1) yields (162).145 MeOCH2

F-

*=CRZ2

m -

R12P

HX (X =

II 0

c1

or B r )

> 'c I:rp

R1 2P

II

0

0

c Me

The structure of one of the diastereoisomeric products from the; ester (163) and PhSeCl has been established by X-ray ana1~sis.l~~ Recent Russian work on the addition of electrophiles to dienephosphonateshas been reviewed (59 refs.).147 Under acidic conditions at 100 "C, the acids (164) cyclize to 2-ethenyl-2-0x0A3-l ,2-oxaphospholens(165).148 0

II

( MeO) 2PCBut=

=CHBut

The esters (160: R2 = H) add ethylthiolate anion in EtSH to give the very labile (166) which easily tautomerize to (167). Both (166) and (167) yield (168: R2 = SEt) when treated with sodium m e t h o ~ i d e A . ~ similar ~~ reaction 145

146

V. K. Brel', B. I. Ionin, and A. A. Petrov, J . Gen. Chem. USSR (Engl. Transl.), 1982,52,709. R. S. Macomber, G . A. Krudy, K. Seff, and L. E. Rendon-Diazmiron, J. Org. Chem., 1983,48, 1425.

14' 14* 140

C . M. Angelov, Phosphorus Sulfur, 1983, 15, 177. T. N. Belyaeva, M. V. Sandyurev, A. V. Doyadina, B. I. Ionin, and A. A. Petrov,J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 2184. V. K. Brel', A. V. Dogadina, B. I. Ionin, and A. A. Petrov, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 456.

Quinquevalent Phosphorus Acids

139 0

II

R12p SEt

MeOCH2

1

SEt

MeOCH,

\" I R1=

/CH-C=CH2

alkoxy

R1 2P

Meo-

II

2 R = H

0

(166)

\ M R1 2P

Me C=C-C=CHMe 2

II

O = P1( O R 1 ) 2

0

(1691

(168) R

4

@CH=o =CR2 2

( R ~ O2)

H2°

H2°

____c

H

(175) 0

@

=

(RlO),P

II

R2

.Ph ~ ~ 'R4

R = Ph

c = ~

2

=

SEt

140


takes place when (160: R2= H) is treated with diethylamine.lS0Alcohols, RBOH,add to the phosphonates (150: R2 = Me, R1 = alkoxy) in the presence of alkoxide to give the butadiene derivatives (169).151 Reactions between the allenic phosphonates (170) and the methylene amidophosphites (171 : R4 = Ph) initially afford unstable phospholens (172) which can be hydrolysed to (173) and ultimately to (174).152When (171 : R4 = NEt,) is employed, another reaction pathway is followed with elimination of diethylamine giving [(azaphosphorin-3-yl)methyl]phosphonates (17 3 , which are hydrolysable to (176). The product from (170: R2 = H) and (171 : R4 = NEt,) is 1-dimethoxyphosphinylpropyne.This last, as well as other esters of (l-propyne)phosphonic acid, reacts further with (171 : R4 = NEt2) to give (177) and thence (178).163 0

0

OH

0

II I

(Et0)2P-CPh

1

D

Et (177)

(178)

(180) a ; R = OMe , b ; R = OCH2CMe3

,

c ; R = OPh , d ; R = N E t 2 R

The unusual feature of carbocations which are thought to be formed during the solvolysis of the 0-mesylates of the esters (179: R = H or Me), is the close proximity of the phosphoryl group and the cation positive charge.164 The hydrolytic behaviour of the 2-0x0-A3-1,2-oxaphospholens (180) has been compared to that of the phosphonate (137: R1 = R2 = Me). The latter is inert to neutral and acid conditions, but, as might be expected, loses one Me group under basic conditions ; it also undergoes simultaneous isotope exchange of the olefinic hydrogen. The esters (180: a, b, and c) hydrolyse autocatalytically in aqueous methanol. In alkaline solution they undergo ring opening followed by ring closure and loss of the R group to give (180 : R = OH). The amide (180 : d) is labile only in acid.166 The course of alcoholysis of the 1,2-oxaphospholan-5-one system has been examined and shown to depend on experimental conditions, including order of lli0 V.

K. Brel', B. I. Ionin, and A. A. Petrov, J. Gen. Chem. USSR (Engl. Transl.), 1981, 51,

2263.

Yu. M. Dangyan, G. A. Panosyan, M. G. Voskanyan, and Sh. 0. Badanyan, J. Gen. Chern. USSR (Engl. Trunsl.), 1982,52,240. lSaN. G. Khusainova, Z. A. Bredikhina, and A. N. Pudovik, J. Gen. Chem. USSR (Engl. Transl.), 1982, 52, 1139. N. G. Khusainova, Z. A. Bredikhina, A. D. Sinitsa, V. I. Kal'chenko, and A. N. Pudovik, J. Gem Chem. USSR (Engl. Transl.), 1982, 52, 684. 164 X. Creary, C. C. Geiger, and K. Hilton, J. Am. Chem. Suc., 1983, 105, 2851. R. S. Macomber, G. A. Krudy, M. Zaki Amer, J. Org. Chem., 1983,48, 1420.

llil

Quinquevalent Phosphorus Acidr

141

mixing and temperature control. Attack on (181) by the alcohol ROH occurs at either the carbonyl carbon or the phosphoryl phosphorus, a result also observed during hydrolysis (see 'Organophosphorus Chemistry', Vol. 2, p.1 14).lS6

ocp/o < II

0

Et PCH2CH2COOH

ROH

AR 0

tE' (181 1

II I

EtPCH2CH2COOR (182)

OH

Some of the general principles governing the reactivity of tetraco-ordinate phosphorus compounds have been discussed. While rates of reaction of compounds ABP(0)X depend on A, By and X, they can be described, with some degree of success, by the use of the Hammett equation, and Taft and Kabachnik constants, but a correlation is not always achieved. If substances react by the same mechanism, the effects of the substituents A and B are additive. When reaction conditions change thenlog k[bP(O)X]- log k[B,P(O)X] = constant and this was illustrated by reference to the esters (XCH,),P(O)OR (X = C1 or I; R = Et or Bu). This relationship does not hold if the reactions differ mechanistically; thus, for the series R1R2P(0)OEt, (a) R1 = R2 = Et, (b) R1 = Et, R2 = ClCH2, and (c) R1 = Ra = CICH2, in water at 100 "C, compound (c) hydrolyses.by G O cleavage. In alkaline solution, all the compounds react by the same mechanism, and the relationship log kb = OS(1og k , log k,) h01ds.l~~ The effects of changes in structure, temperature, and reaction medium on the kinetics of alkaline hydrolysis of aryl esters of phosphinothioic acids (182: R1 = R2 = Me or Ph; R1= Me, R2= Ph; X = H, Br, Me, or NO2) have been i n v e ~ t i g a t e dThe . ~ ~ ~effect of the nature of the leaving group on the kinetics of alkaline hydrolysis of aryl diphenylphosphinates has also been reported Indirect evidence has been advanced for the participation of the azaphospholidines (183) in the solvolysis of N-[amino(methyl)phosphinyl]-L-phenylalanine derivatives, and it includes the transfer of the P-amino group to the phenylalanyl carbonyl.160J61The products from the hydrolysis or ammonolysis of fosfomycin have the threo structure and have been shown to possess no antibiotic

+

A. N. Pudovik, M. A. Vasyanina, I. K. Pokrovskaya, and V. K. Khairullin, J . Gen. Chem. USSR (Engf. Transl.), 1982, 52, 682. 16' M. G. Gubaidullin, J. Gen. Chem. USSR (Engl. Transf.), 1981, 51, 2297. lS8 B. I. Istomin and G. D. Eliseeva, J. Gen. Chem. USSR (Engf. Transf.), 1981,51,2063. 160 N. A. Sukhorukova, B. I. Istomin, and A. V. Kalabina, J. Gen. Chem. USSR (Engf. Transf.), 1982, 52, 1706; B. I. Istomin, N. A. Sukhorukova, A. V. Kalabina, and Yu. I. Sukhorukov, ibid., p. 1787. l60 N. E. Jacobsen and P. A. Bartlett, J. Am. Chem. SOC.,1983,105,1613. lS1 N. E. Jacobsen and P. A. Bartlett, J. Am. Chem. SOC.,1983,105,1619. Y. Vidal, B. Clin, A. Cassaigne, and E. Neuzil, Bull. SOC.Pharm. Bordeaux, 1982, 121, 3 (Chem. Abstr., 1983, 98, 72 259). lS6


142 CH2Ph

X

0

-1 ( 1 8 3 ) Z = 0 o r NH

X = NH Y = OMe

a; X

=

Y = OMe

NH-,

b ; X = 0 - , Y = NH

+

3

Photolysis of the azides (184) in methanol results in a Curtius-like migration of Ph or R from P to N. The ease of migration of the group R decreases in the order R = But > Pr' > Et > Me, and in all cases is slightly faster than Ph.le3 When a methanolic solution of (185) is photolysed, the main product is the phosphate (187), the formation of which was explained by postulating the involvement of the oxaphosphiran intermediate (1 86).164 Ph

R

Ph

\p/o

MeOH, hv

/\ R

/

/"\NHR

Me0

N3

+

/ \ NHPh

Me0

(184) R = a l k y l

i2/OMe E t2NS02CP

a\

0

163

0

-

MeOH

hv

M. J. P. Harger and S. Westlake, Tetrahedron, 1982, 38, 3073. P. A. Bartlett and N. I. Carruthers, J . Chem. Soc., Chem. Coltlmun., 1982, 536.

Quinquevalent Phosphorus A c i h

143

The dipolar addition of (diazoalky1)phosphonic esters to (isopropeny1)phosphonates gives the di(phosphonates) (188) in their trans form. When these are heated, a mixture of cis and trans cyclopropanes (189) is formed, evidently via intermediates having a substantial life-time. By contrast, the photolysis of the esters (1 88) yields (1 89) with complete retention of geometry, presumably by way of intermediates having very short life-times, e.g., biradicals.166

1*6

R. D. Gareev, A. V. Chernova, E. A. Ishmaeva, E. A. Berdnikov, R. R. Shagidullin, E. N. Strelkova, G. M. Dorozhkina, I. I. Patsanovskii, and A. N. Pudovik, J . Gen. Chern. USSR (Engl. Transl.), 1982,52,2161.

Phosphates and Phosphonates of Biochemical Interest BY D. W. HUTCHINSON

1 Introduction*

The structure and function of phosphoproteins has provoked much interest in the past year. The application of 31Pn.m.r. to the study of protein structure and function has been reviewedl while the stereochemistry of enzymic phosphoryl transfer2and the enzymology of kinases3have been described in recent volumes of Methods in Enzymology. The identification of the sites of phosphorylation on phosphoproteins is an important prerequisite in attempting the elucidation of the functions of these compounds and methods have been described for the detection of 0-phosphoserine*and 0-phosphotyrosine6residues in proteins. The enzymic phosphorylation6 and depho~phorylation~ of tyrosine residues in proteins has been investigated, and a simple synthesis of 0-phospho-L-tyrosine from the amino acid and a phosphoric oxide/orthophosphoric acid mixture has been described.a There has been a continued interest in the chemistry and biochemistry of coenzymes, particularly phosphoenolpyruvate, and a book devoted to pyridine nucleotide coenzymes has been published as a tribute to Professor N. 0. Kaplan’s work on these compounds.BAmong new techniques which have been applied recently to biologically interesting compounds is fast atom bombardment mass spectrometry, which has been used in the structural elucidation of underivatized phospholipids.lo

*Abbreviationsused in Chapters 6 and 7 are described in Biochemical Nomenclature and Related Documents published in 1978 by the International Union of Biochemistry. B. D. Sykes, Can. J. Biochem., 1983,61, 155. ‘Methods in Enzymology’, ed. W. A. Wood, Academic Press, New York, 1982, Vol. 90. ‘Methods in Enzymology’, ed. D. L. Purich, Academic Press, New York, 1982, Vol. 87. W. D. Annan, W. Manson, and J. A. Nimmo, Anal. Biochem., 1982,121, 62; H. J. Vogel and W. A. Bridger, Biochemistry, 1982,21,5825. T. M. Martensen, J. Biol. Chem., 1982, 257, 9648. C. Erneux, S. Cohen, and D. L. Garbers, J. Biol. Chem., 1983,258, 4137. D. Horlein, B. Gallis, D. L. Brautigan, and P. Bornstein, Biochemistry, 1982,21, 5577. P. F. Alewood, R. B. Johns, R. B. Valerio, and B. E. Kemp, Synthesis, 1983, 30. ‘The Pyridine Nucleotide Coenzymes’, ed. J. Everse, B. Anderson, and K . 4 . You, Academic Press, New York, 1982. lo H. E. May and D. M. Desiderio, J. Chem. Soc., Chem. Commun., 1983, 72. a

’

144

Phosphates and Phosphonates of Biochemical Interest

145

2 Coenzymes and Cofactors

Phosphoenolpyruvate (1) has been the subject of many investigations during the past year and a number of new syntheses of this compound have been reported. For example, trimethylsilylation of pyruvic acid followed by bromination gives a product which can undergo a Perkow reaction to give (1) in high yield (Scheme 1).l1 Analogues of (l), e.g., (2), can be prepared by a similar route. In these

-

OSiblle3

I

i

MeCOCOOH

CH2=C-COOSiMe

3

BrCH2COCOOSiMeg iv, v

H203P’

C ‘COOH

(Me0)2P

II

0

(1)

Reagents: i, Me3SiBr/(4-dimethy1amino)pyridine; ii, Br2/CH2CI2; iii, (MeO),POSiMe,;

iv, Me3SiBr; v, NaOEt/H20

Scheme 1 syntheses, P-OMe groups are demethylated using trimethylsilyl bromide rather than the more conventional iodide. A large scale synthesis of (1) based on the method of Clark and Kirby12has been developed and glucose 6-phosphate has been prepared on a large scale using the immobilized enzymes pyruvate kinase and hexokinase and (1) to regenerate the ATP required in this synthesis.ls The synthesis of nucleoside triphosphates using (1) and insolubilized pyruvate kinase has also been used as a convenient route to the synthesis of nucleoside diphosphate sugars on a large scale.14 [32P]-labelled(1) can be prepared by making use of GTP-dependent phosphoenolpyruvate carboxykinase which catalyses the following reaction :Is

+

+

[ySaP]-GTP oxaloacetate 7+ [32P]-(1) C02

+ GDP

The acid-catalysed exchange of oxygen from the phosphoryl and carboxyl CHB r

II

HOOC /c\

*l

W3H2

M. Sekine, T. Futatsugi, K. Yamada, and T. Hata, J. Chem. SOC.,Perkin Trans. 1 , 1982, 2509.

la l3

l4

l5

V. M. Clark and A. J. Kirby, Biochem. Prep., 1966,11,101. B. L. Hirschbein, F. P. Mazenod, and G. M. Whitesides, J. Org. Chem., 1982,47,3765. C.-H. Wong, S. L. Haynie, and G. M. Whitesides, J. Am. Chem. SOC.,1983,105, 115. F. Parra, Biochem. J., 1982, 205, 643.

146


groups of (1) with solvent water has been used for the preparation of [180]labelled (1).l6 [(S)-160,170]-thiopho~phoen~lpyruvate, generated in situ from 2-[(S)-l6O, 170]-thiopho~pho-~-glycerate in the presence of enolase, has been used as a substrate in the phosphoenolpyruvate carboxylase reaction carried out in [180]-labelled water. From the absolute configuration of the [160,170,180]thiophosphate produced, it was deduced that this reaction proceeds by a stepwise mechanism involving the intermediate formation of carboxyphosphate (Scheme 2).17 This deduction is, however, at variance with a mechanism proposed on

H2C=C-

\coo-

0

H OOCCH

// C ‘cooScheme 2

kinetic grounds which favours a concerted pr0cess.I Phosphoenol-3-bromopyruvate (3) is an excellent competitive inhibitor [with respect to (l)] of phosphoenolpyruvate carboxylase and can form a covalently bound adduct with the enzyme.19 The stereochemical course of reactions catalysed by the bacterial phosphoenolpyruvate: glucose phosphotransferase system has been investigated l).20 with the aid of [(R)-160,170,180]-( Nicotinamide 1 ,“%henoadenine dinucleotide, prepared from NAD+ and chloroacetaldehyde,21 has been converted into 3-aminopyridine 1 ,Wethenoadenine dinucleotide (4) by a pyridine base exchange reaction which was catalysed by the venom of Bungurus fasciutus. Yeast alcohol dehydrogenase was C. C. O’Neal, jun., G. S. Bild, and L. T. Smith, Biochemistry, 1983,22, 611. D. E. Hansen and J. R. Knowles, J. Biol. Chem., 1982,251, 14 795. C. A. Hebda and T. Nowak, J. Biol. Chem., 1982,257, 5515. l* M. H. O’Leary and E. Diaz, J. Biol. Chem., 1982,257, 14 603. 2o G. S. Begley, D. E. Hansen, G. R. Jacobson, and J. R. Knowles, Biochemistry, 1982, 21, 5552. 21 J. R. Barrio, J. A. Secrist, 111, and N. J. Leonard, Proc. Natl. Acad. Sci. USA, 1972,62,2039. l6

l7


147

rapidly and reversibly inactivated by (4) and one mole of the coenzyme analogue bound to each catalytic sub-unit of the enzyme.22Sulphydryl groups appear to be involved in this binding as one SH group was lost for every mole of (4) which bound to the enzyme. 2-~-~-Ribofuranosylthiazole-4-carboxamide is active against certain murine tumours when it is anabolized into the thiazole-4carboxamide adenine dinucleotide (5). The latter, which is a potent inhibitor of IMP, dehydrogenase, has recently been synthesized chemically by the phosphoromorpholidate Since NAD pyrophosphorylase catalyses nucleotidyl transfer from adenosine (R)-5'-[d70]-triphosphateto NMN+ with inversion of configuration, it has been proposed that the adenylyl group is transferred directly from ATP to NMN+by an in-line mechanism.24It has also been shown that the phosphodiesterase from Crotalus adamanteus hydrolyses NAD+ regiospecifically at the adenylyl terminus of the pyrophosphate bond. HO

OH

HO

(4)

R1 =

OH

a'*" N +

I

9

R2 =

Ade

A number of FAD analogues containing modifications in the isoalloxazine moiety have been prepared by incubation of the riboflavin analogues with the flavokinase/FAD synthetase system of Brevibacterium arnrn~niagenes.~~ All 22

23 24 25

D. A. Yost, M. L. Tanchoco, and B. M. Anderson, Arch. Biochem. Biophys., 1982,217,155. G. Gebeyehu, V. E. Marquez, J. A. Kelley, D. A. Cooney, H. N. Jaryaram, and D. G. Johns, J . Med. Chem., 1983,26,922. G. Lowe and G. Tansley, Eur. J. Biochem., 1983,132, 117. G. Zanetti, V. Massey, and B. Curti, Eur. J. Biochem., 1983, 132, 201.

OrganophosphorusChemistry

148

derivatives supported the NADPH-ferricyanide reductase activity of the ferredoxin-NADP+ reductase of spinach and their catalytic activity was found to be directly proportional to the redox potentials of the flavins. However, no such relationship was found when ferredoxin was used as acceptor. Phosphoric acid esters of riboflavin and its analogues can be prepared by a variety of chemical or enzymic methods. However, all published procedures lead to the formation of significant quantities of non-5’-phosphate isomers. Recently, h.p.1.c. conditions have been published which allow for the isolation of > 99 % pure 5’-FMNtogether with the 3’4’-, 4’,5’-, and 3’,5’-bi~phosphates.~~ The last bisphosphate binds tightly to the apoflavodoxin of Megasphaera elsdenii and has a high catalytic activity. This appears to be the first reported instance of a bisphosphate of FMN having biological activity.

(6) ;“2

0

where R =

Reduction of thiamine pyrophosphate with borohydride gives rise to tetrahydro derivatives (6) containing a thiazolidine ring.27Four stereoisomers of (6) exist comprising two diastereomers each of which is a racemic mixture. The mixture of stereoisomers inhibits the pyruvate dehydrogenase of Escherichia coli, the cis-isomers binding more tightly to the enzyme complex than either the trans-isomers or thiamine pyrophosphate itself. The X-ray crystal structure of racemic methyl 2-hydroxy-2-(2-thiamine)ethylphosphonate chloride (7), an analogue of 2-(ct-lactyl)thiamine, shows that the hydroxyl group at position 2 lies close to the methylene bridge between the two heterocyclic rings.28Thus, it seems probable that maximum orbital overlap can readily occur during the decarboxylation of lactylthiamine with the minimum divergence from a favourable conformation of the lactylthiamine. A scheme for the biogenesis of the thiazole moiety of thiamine from glycine and 2-pentulose 5-phosphate has been proposed.2g A phosphonate analogue (8) of pyridoxal 5’-phosphate (9) which contains a 5’-phosphonomethyl group has been prepared by a Michaelis-Becker reaction from the protected pyridoxyl chloride Both (8) and its monoethyl ester x6 27

28

P. Nielsen, P. Rauschenbach, and A. Bacher, Anal. Biochem., 1983,130, 359. P. N. Lowe, F. J. Leeper, and R. N. Perham, Biochemistry, 1983,22, 150. A. Turano, W. Furey, J. Pletcher, M. Sax, D. Pike, and R. Kluger, J. Am. Chem. SOC., 1982, 104, 3089.

2B 30

R. L. White and I. D. Spenser, J. Am. Chem. Soc., 1982,104, 4934. C.-N. A. Han, C. Iwata, and D. E. Metzler, J. Med. Chem., 1983,26, 595.

149


bind to aspartate aminotransferase but lack catalytic activity. Pyridoxal 5’-diphospho-( 1)-a-D-glucose (1l), prepared by the diphenyl phosphorochloridate method, combines both the coenzyme [(9)] and the substrate (glucose l-phosphate) of glycogen phosphorylase. When bound to the enzyme in the absence of substrate, (11) is slowly cleaved to (9) which activates the enzyme.31 Addition of maltose or glycogen alters the mode of cleavage and (11) is then broken down to pyridoxal 5’-pyrophosphate. These observations are taken to support a proposal for the catalytic mechanism in which (9) interacts directly with the phosphoryl group of the substrate. CHO

H

P03H-

i, i i , iii

Me

Me

Reagents: i, NaPO,Et,;

ii, Mn02/H20; iii, H 3 0 +

HO

Me (11)

3 Sugar Phosphates

The synthesis and analysis of carbohydrate phosphates have been and phosphodiesters formed between 2-aminoethanol and polyhydroxylated alcohols or sugars have been synthesized using acetoin enediol pyrophosphate 31

39

M. Takagi, T. Fukui, and S. Shimomura, Proc. Natl. Acad. Sci. USA, 1982,79, 3716. ‘Methods in Enzymology’, ed. W. A. Wood, Academic Press, New Y a k , 1982, Vol. 89.

150


(12) as phosphorylating agent.33From the analysis of the products of the hydrolysis of x-D-ribofuranose l-[leO4]-phosphateit has been shown that while acids cleave the C-O bond both acid and alkaline phosphatases cleave the P-0 bond.34 From a study of the 31Pn.m.r. spectra of phosphoribosyl diphosphate in the presence of magnesium ions, it has been deduced that the mono- and pyrophosphate residues act as independent binding sites for these The anomeric composition and mutarotation rate of fructose 1,6-bisphosphatehas been determined by 31Pn.m.r., and it has also been observed that magnesium and zinc ions bind preferentially to the 1-phosphoryl group when it is in the a-anomeric position. 36 CHZOOCR

I

Me

Me

0

0

RCOOcC-H

OH

4 Phospholipids

Several syntheses of nucleotidephospholipids have been reported recentl~.~~-*O For example, phospholipid-araC conjugates have been prepared and tested as prodrugs of araC as inhibitors of the growth of a murine myeloma cell line.39 The most effective inhibitor was [13, n = 1, R = Me(CH,),,]: solubility difficulties may have affected the testing of other analogues. The preparation and spectroscopic properties of chiral thiophospholipids have been r e p ~ r t e d . ~ 1,2-Dipalmitoyl-sn-glycero-3-thiophosphocholine l*~~ [14, R1= Me(CH2)14,R2 = Me] was shown by 31Pn.m.r. to be a mixture of two diastereoisomers. Phospholipase A2 hydrolysed one isomer specifically while phospholipase C hydrolysed the These observations were exploited in the synthesis of each isomer from the diastereomeric mixture. 31Pand 14Nn.m.r. 33 34

F. Trigalo and L. Szabo, J. Chem. SOC.,Perkin Trans. 1, 1982, 1733. F. Jordan, D. J. Kuo, S. J. Salamone, and A. L. Wang, Biochim. Biophys. Acta, 1982,704, 427.

35

36 37 3e

40

41

G. W. Smithers and W. J. O'Sullivan, J. Biol. Chem., 1982,257,6164. G. B. Van den Berg and A. Heerschap, Arch. Biochem. Biophys., 1982,219, 268. F. Ramirez, S. B. Mandal, and J. F. Marecek, Synthesis, 1982, 402. F. Ramirez, S. B. Mandal, and J. F. Marecek, J. Am. Chem. SOC.,1982,104, 5483. E. K. R p , R. J. Ross, T. Matsushita, M. MacCoss, C. I. Hong, and C. R. West, J. Med. Chem., 1982,25, 1322. P. P.N. Murthy and B. W. Agranoff, Biochim. Biophys. Acta, 1982,712,473. K. Bruzik, R. T. Jiang, and M. D. Tsai, Biochemistry, 1983,22,2478.


151

studies with chiral (14) and model membranes suggest that these membranes could be chiral at p h o s p h ~ r u s . Diastereomers ~~ of [14, R1 = Me(CH2)14, R2 = HI have also been prepared.44 Spin-labelled phosphocholines, e.g., (15),45 rival phosphocholine as ligands for C-reactive proteins from a variety of sources and their binding to these proteins has been studied by e.s.r. spectroscopy. CH200CR 1

I* I in 1

1

R COO-C-H

CH20-P-0

Me

nogI 0

Me3N+

0.

0-

+N(R 2 ) 3

Me

0-

(14)

(15 1

Dihydrogen phosphate esters which contain conjugated or nonconjugated double bonds have been prepared by a route which probably involves monomeric metaphosphate as the phosphorylating agent. Thus, the steroids are phosphorylated by treatment of (1-phenyl-l,2-dibromoethyl)phosphonicacid with base in an aprotic solvent. An advantage of this method is that few side reactions occur as is often the case with acidic phosphorylating A simple procedure for the preparation of [32P]-labelledphosphorus oxychloride by equilibration of the unlabelled oxychloride with [32P]-orthophosphoric acid has been de~cribed.~' This procedure should be extremely useful for the preparation of a vwiety of [s2P]-labelled compounds and, for example, [32P]-labelleddolichyl phosphate has been prepared using this reagent. The structures of teichoic acid-glycopeptide complexes from cell walls of BaciZZus cereus have been inve~tigated,~~ a proteolipid which can bind and transport inorganic phosphate into an organic phase has been isolated from kidney brush-border mernbrane~,~~ and chemically synthesized galactosyl ficaprenyl diphosphate has been used as an intermediate in the biosynthesis of the O-antigenic polysaccharide of SaZmo~zeZla.~~ N-Acylphosphatidyl serines are a newly identified class of phopholipids which account for up to 40% of the cellular phospholipids of Rhodopseudomonas s p h a e r ~ i d e s .N-Acylphosphatidyl ~~ serine which has been chemically synthesized using palmitic anhydride as acylating agent is very similar to the natural material. However, the natural phospholipids contain a high proportion of vaccenic acid (16) as has been 4a 4a

44 46

46 47

48

49 6o

51

K. Bruzik, S. M. Gupte, and M. D. Tsai, J. Am. Chem. SOC.,1982,104,4682. M. D. Tsai, R. T. Jiang, and K. Bruzik, J. Am. Chem. SOC.,1983,105,2478. G. A. Orr, C. F. Brewer, and G. Heney, Biochemistry, 1982,21,3202. F. A. Robey and T.-Y. Liu, J. Biol. Chem., 1983,258,3895. F. Ramirez, J. F. Marecek, and S. S. Yemul, J. Org. Chem., 1983, 48, 1417. R. W. Keenan, R. A. Martinez, and R. F. Williams, J. Biol. Chem., 1982,257, 14 817. Y. Sasaki, Y. Araki, and E. Ito, Eiir. J. Biochem., 1983,132,207. R. J. Kessler, D. A. Vaughn, and D. D. Fanestil, J. Biol. Chem., 1982, 257, 14 311. S. Kanegasaki, A. Wright, and C. D. Warren, Eur. J. Biochem., 1983, 133,77. T. J. Donohue, B. D. Cain, and S. Kaplan, Biochemistry, 1982,21, 2765.

152


observed for other phospholipids from R. sphaeroides. Conditions for the efficient hydrolysis of polyprenyl pyrophosphates have been established using potato acid phosphatase in 60% (E)-Me(CH,),CH=CH(CH,)gCOOH

(16)

5 Phosphonates

The purification of a 2-aminoethylphosphonate aminotransferase from Pseudomonas aeruginosa should allow the catabolism of 2-aminoethylphosphonic acid (17) to be studied in detail.53This enzyme, which requires (9) as cofactor, catalyses the conversion of (17) to phosphonoacetaldehyde (18). The next enzyme in the catabolic pathway which catalyses the breakdown of (18) should be of general interest as few enzymes are known which can cleave a C-P bond. H3NCH2CH2P03H

OHCCH2P03H2

0

0

,OAc

As mentioned in Volume 13 of these Reports, 4-oxoazetidin-2-yl phosphonates and phosphinates (19) can be prepared by Arbusov-like reactions between Pnl compounds and 4-acetoxyazetidin-2-one (20). Acid hydrolysis of (19) yields phosphono- and phosphino-aspartic acids (21) which can be converted into peptides with antibacterial Diastereomeric mixtures of phosphonodipeptides,whichcanbe prepared from racemicdialkyl 1-aminoalkylphosphonates, can be separated by ion-exchange chromatography. It appears that it is easier to synthesize phosphonodipeptides from these phosphonates as their P-dialkyl esters rather than as the free phosphonic acids.6SPhosphonic acid analogues of N-Cbz-alanine and -phenylalanine can be converted into ester and amide fluoridates, e.g., (22, R = OMe or NHCHMe,). These fluoridates are the most potent inhibitors of elastase and chymotrypsin yet reported and seem to mimic the natural substrates of these enzymes.56

56

H. Fujii, T. Koyama, and K. Ogura, Biochim. Biophys. Acta, 1982,712,716. C. Dumora, A.-M. Lacoste, and A. Cassaigne, Eur. J. Biochem., 1983,133,119. M. M. Campbell, N. I. Carruthers, and S. J. Michel, Tetrahedron, 1982,38,2513. P . Kafarski, B. Lejczak, P. Masterlerz, J. Szewczyk, and C. Wasielewski, Can. J. Chem.,

56

L. A. Lamden and P. A. Bartlett, Biochem. Biophys. Res. Commun., 1983,112, 1085.

64

J53 54

1980,60, 3081.


153

0 0 P h C H 2 0 CIIN H C H ( M e ) PII -R

I

F

6 Enzyme Mechanisms

Hydrolysis of [(R)-17080]-4-nit rophenyl t hymidine 5’-phosphate by staphyI oc o d nuclease in H,laO yields [(S)160,170y180]-4-nitrophenyl phosphate, indicating that this reaction proceeds with inversion of configuration at phosp h o r ~ Alkaline ~ . ~ ~ phosphatase from E. coli which had been grown in the presence of l13Cdnions contains l13Cd in place of zinc and has a similar catalytic activity to the natural enzyme.s8The presence of phosphoenzyme intermediates during the catalytic reaction has been shown by 31Pn.m.r. using the l13Cd-containing enzyme.s0 Purine nucleoside phosphorylase has also been studied by 31Pn.m.r. spe,ctroscopywhich revealed that the C-0 bond of a-D-ribofuranose 1-phosphate is cleaved by this enzyme. There was no evidence of Z s O e 1 8 0 exchange from orthophosphate to water indicating that no phosphoryl enzyme intermediate is involved in this reaction.6O 02NCH CH

‘COOH

-

[02NCH=CHCOOH]

+

H2P03-

Pyruvate kinase catalyses the phosphorylation of 2-hydroxy-3-nitro-propionate by ATP to the 2-phosphate (23). The latter can eliminate inorganic phosphate nonenzymatically to give a product, presumably (24), which inactivates the enzyme irreversibly.6l Phosphorothioate analogues of ATP have been employed in the kinetic analysis of the metalloenzymes arginine kinasesa and 3-phosphoglycerate kina~e.6~ These experiments indicate that the metal ion in arginine kinase is bound to both the 01- and P-phosphoryl groups of ATP at a ratedetermining step in the reaction.sz On the other hand, the metal ion of glycerate 3-phosphate kinase does not chelate with the P-phosphoryl group of ATPF3 A phosphapyrimidine analogue (25) of cytidine has been prepared by a modification of a previously published r ~ ~ t eThe . ~ analogue * (25) can be regarded as a transition-state analogue of cytidine deaminase and is a potent competitive inhibitor of the deaminase from E. cokaS 67 68 6s 6o

68

63 84 65

S. Mehdi and J. A. Gerlt, J. Am. Chem. SOC.,1982,104,3223. P. Gettins and J. E. Coleman, J. Biol. Chem., 1983, 256, 396. P. Gettins and J. E. Coleman, J. Biol. Chem., 1983,258,408. S . J. Salamone, F. Jordan, and R. R. Jordan, Arch. Biochem. Biophys., 1982,217, 139. D. J. T. Porter, D. E. Ash, and H. J. Bright, Arch. Biochem. Biophys., 1983,222,200, M . Cohn, N. Shih, and J. Nick, J. Biol. Chem., 1982,257, 7646. E. K. Saffe, J. Nick, and M. Cohn, J. Biol. Chem., 1982,257,7650. P . A. Bartlett, J. T. Hunt, J. L. Adams, and J.-C. E. Gehret, Bioorg. Chem., 1978,7, 421. G. W. AshIey and P. A. Bartlett, Biochem. Biophys. Res. Commun., 1982, 108, 1467.


154

The role of enediols in the conversion of L-glyceraldehyde3-phosphate (26) into either dihydroxyacetonephosphate (27) or inorganic phosphate plus methylglyoxal (28) has been postulated for some time.66Triose phosphate isomerase, which does not react with (26) directly, can convert it into dihydroxyacetone phosphate by

o=c

/CH20H

\CH20P032-

HO ( 2 9 ) a;

R 1= O H , R 2 = H

b ; R 1= H ,

R 2= OH

reacting with the cis-enediol phosphate (29a) formed during the base-catalysed enolization of (26). Methylglyoxal synthetase can accept the trans-enediol phosphate (29b) and it has been proposed that the latter may be an intermediate in the catalytic reaction of this enzyme with dihydroxyacetone phosphate (Scheme3).67

7 Other Compounds of Biochemical Interest An asymmetric synthesis of the enantiomers of cyclophosphamide (30) has been developed which makes use of a highly stereospecificring closure and the use of 66

67

R. Iyengar and I. A. Rose, Biochemistry, 1981,20, 1229. R. Iyengar and I. A. Rose, J. Am. Chem. SOC.,1983,105,3301.


155

sulphuric acid in toluene rather than hydrogenolysis to cleave N-benzyl groups.68 Polycyclic aromatic hydrocarbons can be metabolized to epoxides, e.g., (31), which are often potent carcinogens. While these epoxides appear to react primarily with DNA bases, it has recently been shown that phosphodiesters can also react with these epoxides to give adducts such as (32).gBThus, the internucleotide phosphodiester link may also be a natural site of attack by these epoxides.

I Me CH

I

Ph

Reagent : i, H2S0,/PhMe

pijg? -Ho + ( R 0 ) 2 P 0 2-

OR

Me

where R = adenosine 5'-phosphoryl

68 gg

T. Sato, H. Ueda, K. Nakagawa, and N. Rodor, J. Org. Chem., 1 9 8 3 , 4 8 , 9 8 . P. Di Raddo and T. H. Chan, J. Chem. SOC.,Chem. Commun., 1983, 16.

156


Newly laid eggs of the locust Locusta migratoria contain as the major ecdysteroid 22-(adenosine 5’-monophosphoryl)-2-deoxyecdysone (33).70 During embryonic development (33) is hydrolysed to the free deoxyecdysone which is subsequently metabolized to 3-dehydro-2-deoxyecdysone and 2-deoxy-3epiecdysone. The latter accumulates at a late stage of development as the 3-phosphoric acid ester. The 22-phosphoric ester of 2-deoxyecdysone is also present during embryonic development but it is uncertain whether the latter arises from the hydrolysis of (33) or by de novo phosphorylation of the 2-deoxyecdysone. The separation of phosphohydroxyimino acids by h.p.1.c. has been described.71 A very sensitive method for the determination of inorganic phosphate has been described which is based on the formation of a Rhodamine B-phosphomolybdate complex,72and the continuous enzymic removal of inorganic phosphate from reactions has been achieved by means of the nucleoside phosphorylase-catalysed phosphorolysis of nicotinamide riboside, when the product is ribose 1-phosphate.73 Some of the proceedings of the French National Conference on Phosphorus Chemistry which was held in Montpellier in September 1982 have been published as a special issue of Phosphorus and Sulfur. Papers of biochemical interest include those on organophosphorus compounds as antiviral aminophosphinic the synthesis of optically active 2-aminopropylphosphoric acid,7s and 0-phosphobiotin models.77

70

G . Tsoupras, C. Hetru, B. Luu, E. Constantin, M. Lagueux, and J. Hoffmann, Tetrahedron, 1983,39, 1789.

71 72

73 74 76

76 77

J. C. Yang, J. M. Fujitaki, and R. A. Smith, Anal. Biochem., 1982,122, 360. I. Debruyne, Anal. Biochem., 1983,130,454. J. W. Shriver and B. D. Sykes, Can. J. Biochem., 1982,60,917. D. W. Hutchinson, P. A. Cload, and M. C. Haugh, Phosphorus Sulfur, 1983,14,285. L. Maier, Phosphorus Sulfur, 1983, 14, 295. F. Sauver, N. Collignon, A. Guy, and P. Savignac, Phosphorus Sulfur, 1983,14, 341. G. Etemad-Moghadam, C. Blonski, M. B. Gasc, J. J. Perie, and A. Klaebe, Phosphorus Sulfur, 1983, 14, 367.

7 Nucleotides and Nucleic Acids BY J. B. HOBBS

1 Introduction Regular readers of this Chapter will note that some change has taken place since last year’s Report : the sections on ‘Affinity Chromatography’ and ‘Sequencing’ have been reduced in size, and are now covered, along with ‘Affinity Labelling’ under the heading of ‘Other Studies’. The burgeoning demand for the synthesis of oligonucleotides of defined sequence for hybridization, mutagenesis, etc., has spurred much research on improvements in triester methods of oligonucleotide synthesis, and syntheses which were almost unthinkable a decade ago have now become commonplace. Two volumes of symposium reports1B2must be cited for their high content of relevant papers. The Journal of Carbohydrates, Nucleosides and Nucleotides, a small but important contributor to this field, has undergone binary fission to give a new and regrettably elusive daughter journal, Nucleosides and Nucleotides.

2 Mononucleotides Chemical Synthesis.-Purine nucleoside 5’-monophosphates enriched with 170 or le0on the phosphate group are conveniently prepared by treating phosphorus pentachloride in dry triethyl phosphate with one equivalent of the appropriately labelled water to give [170]-or [1sO]POC13,which is not isolated but mixed with adenosine or guanosine in the same solvent. Work-up of the resulting 5’-phosphorodichloridate in similarly labelled water permits the formation of [170]or [180]AMP (or GMP) in fair yield with good enri~hment.~ The 5’-monophosphates of the 5‘-C-methyl uridines derived from 6-deoxy-~-alloseand 6-deoxy-~talose have been prepared via phosphorylation of the 2’,3’-O,O-ethoxymethylidene derivative of the nucleosides (1) with P-cyanoethyl phosphate and DCC or TPS-Cl.4 The same method has been used to phosphorylate N6-benzoylated 2’,3’-O,O-isopropylidenederivatives of various 5’-C-alkyladenosine species (2) and also 4’-allyladenosine (3) as part of a study in which derivatives of AMP

Nucleic Acids Symp. Ser., 1982, Vol. 11. Proc. Int. Round Table Nucleosides, Nucleotides, Their Biol. Appl., 4th, 1981, ed. F. C. Alderweireldt and E. L. Esmans. R. S. Goody, Anal. Biochem., 1982, 119, 322. M. Ya Karpeiskii, S. N. Mikhailov, and N. Sh. Padyukova, Bioorg. Khirn., 1982, 8, 933 (Chem. Absfr., 1982,97, 182 782).

157


158

Bz Ade

HoJ5? /

OH

OH

(1) R

=

Me, B

(2) R

=

Me, E t , o r P r ” , B = Ade

=

OH

Ura

OH

(3)

with substituents or group replacements at any of eleven positions on base, sugar, and phosphate were examined for their selective effects in inhibiting rat adenylate kinase iso~ymes.~ Some differential inhibition was observed using AMP analogues substituted at C-2, or on the sugar ring. Trichloropyrophosphopyridinium chloride, formed from phosphoryl chloride, pyridine, and water in acetonitrile (the Sowa-Ouchi method) was used to phosphorylate 3’-O-methyladenosine to 3’-0-meth~l-5’-AMP,~ and gave far better results than did phosphoryl chloride-trimethyl phosphate in phosphorylating 2-P-~-ribofuranosylselenazole-4-carboxamideto its 5’-phosphate(4).s Compound (4) shows significant antitumour activity, while the corresponding thiazole nucleotide (9,which is formed when cells in culture are treated with the corresponding nucleoside, seems to be converted in vivo to thiazole-4-carboxamide adenine dinucleotide,? an analogue of NAD+ and a powerful inhibitor of IMP dehydrogenase.8 0

II I

ROOC-P-0-(

Urd-5 ’ )

HO ( 6 ) I? = E t (7)

R = H

(Me3Si0)2P-O-(Urd-5’ OH ( 4 ) X = Se

(5)

x

=

)

OH (8)

s

Treatment of tris(trimethylsily1)phosphite with ethyl chloroformate followed by pyridine affords pyridinium ethoxycarbonylphosphonate which upon condensation with 2’,3’-O,O-isopropylideneuridineusing tosyl triazole affords 2’,3’-O,O-isopropylidene 5’-(ethoxycarbonyl)phosphonate, which may be

’

T. T. Hai, D. Picker, M. Abo, and A. Hampton, J. Med. Chem., 1982,25,806. P. C . Srivastava and R. K. Robins, J. Med. Chenz., 1983,26,445. R. Kuttan, R. K. Robins, and P. P. Saunders, Biochem. Biophys. Res. Commun., 1982,107. 862. R. K. Robins, Nucleosides Nucleotides, 1982, 1, 3 5 .

1 59

Nucleotides and Nucleic Acids

deblocked with formic acid to give (6). Such nucleoside ethoxycarbonylphosphonates serve as the synthetic equivalents of the phosphites fixed in the phosphonate form. Treatment of (6) with aqueous alkali affords (7), which on treatment with bis(trimethylsily1)acetamide undergoes simultaneous decarboxylation and silylation to afford the silyl phosphite (8), the synthetic uses of which have been described in previous Reports. Several methods have been described for preparation of 2’(3’)-O-phosphonylmethyl derivatives of ribonucleosides.l* In the most effective and convenient procedure, treatment of base-protected 5’-O-tritylnucleosides with chloromethanephosphonyl dichloride and pyridine in 1,2-dichloroethane, followed by deblocking, gave (9) (and its 2’-isomer), which on hydrolysis with aqueous alkali gave (10) (and its 3’-isomer), presumably via a clean and rapid cyclization to (11) followed by hydrolysis. No 2’(3’)hydroxymethanephosphonyl by-products were observed. The 5’-chloromethanephosphonate isomer of (9) was by contrast stable to aqueous alkali; cyclization would require the formation of a sterically disfavoured sevenmembered ring. B

HoY? OH

0

OCH2P03H2

OH

w Hols? I

O=P-OH

I

(9)

CH2Cl

B

2o Fs

OH

OH

( 1 2 ) B = Ade

/”

”\

O=P

( 1 3 ) B = Hyp

I

The 5’-deoxy-5’-thioanaloguesof AMP and IMP, (12) and (13), have been prepared by condensing trisodium phosphorothioate with the appropriate 5’-iodo-5’-deoxynucleoside.11Both are hydrolysed by weak acetic acid, or by alkaline phosphatase, to give the 5’-thionucleosides, but are stable to snake

lo

l1

M. Sekine, H. Mori, and T. Hata, Bull. Chem. SOC.Jpn., 1982,55, 239. I. Rosenberg and A. Holy, Collect. Czech. Chem. Commun., 1983, 48, 778. E. F. Rossomando, G. A. Cordis, and G . D. Markham, Arch. Biochern. Biophys., 1983, 220, 71.


160

venom 5’-nucleotidase. Base-protected 5’-iodo-5’-deoxynucleosideshave been coupled to S-P-cyanoethylphosphorothioateusing DCC to give mononucleotide units of type (14),12 and the rates of reaction of these (or 5’-iodo-2’-deoxynucleosides) with 2’-deoxynucleoside-3’-phosphorothioatesin DMF solutions have been studied in the development of a general method for synthesis of 5’-S-phosphorothioate analogues of oligodeoxyribonucleotides.13 A number of methyl esters of N-benzyloxycarbonylamino acids and dipeptides bearing a hydroxy group in the side chain have been condensed with 5’-mOnOnucleotides (UMP, dAMP, dCMP, dTMP) using DCC or diphenyl phosphorochloridate, and the resultant phosphodiestersdeblocked by standard methods and examined as simple models of covalent protein-nucleic acid The resultant nucleotidyl (P -+ 0)amino acids are stable in acid and neutral media, but are cleaved in alkali via @-elimination.The analogous nucleotidyl and oligonucleotidyl (P -+ N) amino acids are acid-labile, with the carboxyl group of the amino acid promoting intramolecular catalysis of hydrolysis of the phosphoramidate link, an effect which is much more marked in 2’-deoxythymidylyl(5’ -+ N) phenylalanine than in the corresponding 3’-isomer.I5 B

0

I

H

O=P-SCH2CH2CN

I

OH (14)

@

A c0 A c0

(15)

Treatment of adenosine 2’,3’-monophosphate with bromoethanol and hydrogen chloride in dioxan affords a mixture of the 2-bromoethyl esters of 2’- and 3’- AMP, with the latter isomer being favoured. 5’-(2-Bromoethyl)-AMP has been prepared by coupling bromoethanol to AMP using mesitylenesulphonyl chloride (MS-Cl). The bromoalkyl esters are reasonably stable in neutral media but react with nucleophilic side chains of amino acids, particularly cysteine, and should find application as affinity labels.“ 8-Sulphoadenosine-5’-phosphate has been prepared by heating 8-bromo-AMP with aqueous sodium s~1phate.l~ la

V. P. Kumarev, V. S. Bogachev, V. F. Kobzev, and L. V. Baranova, Bioorg. Khim., 1982, 8, 1516 (Chem. Abstr., 1983, 98, 107 663).

lS

l4 l6 l6 l7

V. P. Kumarev, V. S. Bogachev, V. F. Kobzev, L. V. Baranova, M. I. Rivkin, and V. N. Rybakov, Bioorg. Khim., 1982,8, 1525 (Chem. Abstr., 1983,98, 107 664). B. Juodka, V. Kirveliene, and P. Povilionis, Nucfeosides Nucleotides, 1982, 1, 111; Bioorg. Khim., 1982, 8, 326 (Chem. Abstr., 1982, 97, 110 367). B. Juodka, L. Liorancaite, and V. Baltenas, Khim. Prir. Soedin., 1982, 740 (Chem. Abstr., 1983, 98, 198 675). R. A. Bednar and R. F. Coleman, J. Protein Chem., 1982, 1, 203. S. G. Zavgorodnii, B. P. Gottikh, and V. L. Florent’ev, Bioorg. Khim., 1982. 8. 1421 (Chem. Abstr., 1983, 98, 161 089).


161

The a- and p-L-fucosyl esters of UMP and dTMP have been prepared as anomeric mixtures by treating the nucleotides with orthoester (15) in DMF.I8 In the absence of methylenetetrahydrofolate cofactor, thymidylate synthetase has been observed to catalyse nucleophilic addition reactions at the ethynyl moiety of 5-ethynyl-2’-deo~yuridylate.~~ On the basis of isotope effects and other kinetic studies, it has been suggested that addition of a thiol group of the enzyme at C-6 of the nucleotides results in formation of the allenic intermediate (16), followed by addition of 2-mercaptoethanol, morpholine, or other nucleophiles at the sp-hybridized carbon of the allene, and subsequent elimination of the enzyme. A number of studies concerning mononucleotide components for use in ‘phosphotriester’ oligonucleotide syntheses have been reported. As a possible means of avoiding the loss of adenine base during detritylation steps in oligonucleotide synthesis,compounds containing adenine N1-oxide have been investigated. 5’-O-Dimethoxytrityl-NB-benzoyladenosineN1-oxide was treated successively with 2-chlorophenylphosphorobis(lH-l,2,4-triazolide) and 2-cyanoethanol to give (17). On treatment with 2 % benzenesulphonic acid in methylene dichloridemethanol, quantitative detritylation occurred without depurination, showing that the glycosidic bond had been stabilized.20The N-1 oxygen atom is removed from (17), albeit slowly, by hexachlorodisilane or trimethyl phosphite-methanol. NHBz

0

$O )(/-

1

H S-Enz H

2

DMTrO

Ade

w I

0

0

A de

1 1 R O-P=O

I

R20 (18) R

1

= R2 = 2-C1C6H4

TBDMSO ( 2 0 ) R1 = P h ; R2 = 4-NO C H

2 6 4

(19)

l8

M . A. Salam and E. J. Behrman, Nucleosides Nucleotides, 1982, 1, 155. P. J . Barr, M. J. Robins, and D. V. Santi, Biochemistry, 1983, 22, 1696.

2o

C. Morin, Tetrahedron Lett., 1983, 24, 53.


162

An unusual approach to nucleoside phosphorylation consists in activating the hydroxyl group to be phosphorylated using strong base. Thus, 5’-O-TBDMS-2’deoxyadenosine, treated successively with t-butyl-lithium in pentane-hexane at - 78 “C and bis(2-chlorophenyl)phosphorochloridate, affords (18) in high yield.21 The corresponding 5’-phosphates are prepared similarly, using an activated 5’-hydroxyl group as in (19). Adenine-, thymine-, and uracil-containing species may be used without necessarily protecting the base, but cytosine requires to be protected at N4, and the reaction fails with guanosine. This procedure could also be employed to construct internucleotidic links, the reaction of (20) with (19) forming the link by expulsion of 4-nitrophenolate and affording ApA after deblocking. If a methylarylphosphorochloridate is added to a solution of a 5’-0-dimethoxytritylated-2’-deoxynucleosidein pyridine, a triester of type (2 1) is the principal product. If, however, the nucleoside is added to the phosphorochloridate in pyridine solution, the dealkylated phosphodiester (22) is formed in a process catalysed by tertiary amines, particularly 1,5-dimethyltetrazole. Evidence obtained using 31Pn.m.r. suggests that in the latter case displacement of the halogen by pyridine, followed by dealkylation, generates the phosphopyridinium species (23), which is the true phosphorylating agent.22Studies involving variation B

0

I

O=P-OR

I

Thv

OAr

(21) R

Me

=

(22) R = H B ( 2 7 ) R1 (38)

R1

=

DFdTr; R2 = B z

=

R2

= H

0

I

MeO-P-R (24) R

=

1-(1,2,4-triazole)

R

=

NMe2

(25)

(26) R = N ( C H 2 C H 2 > a 0

22

Y. Hayakawa, Y. Aso, M. Uchiyama, and R. Noyori, Tetrahedron Lett., 1983, 24, 1165. N. T. Thuong, C. Barbier, and U . Asseline, Phosphorus Sulfur, 1983,14.357.


163

of the aryl group, and of the halogen, have shown that the 4-chlorophenyl methylphosphorochloridate-pyridine-dimethyltetrazole system rapidly places the arylphosphodiester group at the 3’- or 5’-hydroxy groups of properly protected nucleosides. Treatment of methoxyphosphorodichloridite with lH-l,2,4-triazole in THF at -78 “C affords methoxyphosphorobis(triazo1idite)which reacts with 5 ’ 4 dimethoxytrityl-2’-deoxynucleosides to give (24), which in turn affords (25) and (26) on treatment with excess N-trimethylsilyl-dimethylamineor -morpholine, re~pectively.~~ This preparation of deoxynucleoside phosphoramidites avoids the use of chlorodialkyl aminomethoxyphosphines, which are unstable and difficult to prepare. Little or no 3’-3’ dinucleoside phosphite is formed in this case, although if the methyl group is replaced by 2-chlorophenyl, some 3’-3’linked by-product is found. Species of type (24)-(26) are of central importance in the ‘phosphite’ method of oligonucleotide phosphotriester synthesis. Treatment of methyldichlorophosphine with successive equivalents of 5’-O-trityl-2’-deoxythymidine and 3’-O-benzoyl-2’-deoxythymidinein THF at -78 “C,and oxidation of the product with t-butyl hydroperoxide affords a onepot synthesis in high yield of the dinucleoside methylphosphonate (27), along The diastereoisomers of with a small quantity of the 3’-3’-coupled by-produ~ts.~~ (27), which are formed in unequal quantities, are separable using t.l.c., and deblocking with t-butylamine and boron trifluoride etherate affords (28). Oxidation of the intermediate phosphonite with sulphur or selenium offers a route to the corresponding thiophosphonate or selenophosphonate analogues. The diastereoisomers of (29), easily synthesizedusing phosphotriester methods, have been separated chromatographically, and a tentative assignment of the absolute stereochemistry made on the basis of their polarity and lH and 31P n.m.r. data.25The phosphite (30) is easily prepared starting from methyl phosphorodichloridite and the appropriate blocked nucleosides [cf. (27)] and oxidized to the phosphotriester (31) using aqueous iodine. However, while the diastereoisomer mixture of (31) could not be separated, demethylation with t-butylamine to (32) followed by treatment with triphenylphosphine-carbon tetrachloride and aniline affords (33), which is easily separable into its diastereoisomers using t .l.c. on silica gel. Treatment of each separate diastereoisomer of (33) with sodium hydride and carbon disulphide in DMF affords the corresponding diastereoisomer of phosphorothioate (34), in a reaction in which configuration is known to be retained. An alternative rapid route to these compounds lies in oxidation of (30) using elemental sulphur, separation of the diastereoisomers of (35), and demethylation as above (during which the configuration at phosphorus is retained) to give (34). Detritylation of (34) with 80% acetic acid then affords the separate diastereoisomers of d[Tp(S)T], which are readily distinguished enzymically; snake venom phosphodiesterase stereoselectively hydrolyses the (Rp) phosphorothioate diester. This result also allows

23 24 28

J.-L. Fourrey and J. Varenne, Tetrahedron Lett., 1983, 24, 1963. J. Engels and A. Jager, Angew. Chem., Int. Ed. Engl., 1982,21, 912. W. Michels and E. Schlimme, Liebig’s Ann. Chem., 1982, 1398.

164


assignment of absolute stereochemistry in (34), (39, etc.2sThe (Rp) isomer of d[Tp(S)T] exhibited a signal at lower field in the 31Pn.m.r. spectrum than the (Sp) isomer, a result which may be useful in assigning absolute configuration. Since the anilido group of (33) may be replaced by oxygen on treatment with sodium hydride and carbon dioxide (or benzaldehyde), a route to stereochemically defined dinucleoside phosphates containing oxygen isotopes at phosphorus is defined. Alternative routes to these and similar compounds have been described; successive replacement of the oxybenzotriazole groups of (36) by 5’449phenylxanthen-9-y1)-2’-deoxythymidine and 3’-O-acetyl-2’-deoxythymidine affords a separable mixture of diastereoisomeric thiophosphorotriesters which in turn yields the separate diastereomers of (34) following a conventional deblocking pro~edure.~’ The phosphorylating agent (36) is formed by heating 2,5-dichlorophenyl phosphorodichloridite, thiophosphoryl chloride, and sulphur in the presence of activated charcoal, and treating the resultant 2,5-dichlorophenylphosphorodichloridothioatewith 1-hydroxybenzotriazole.

4;: 4;

JHa

JH

MMTrO DMTrO

0-P-0

0-P-0

OMMTr

OAc

0

C6H4C1-4 (29)

c1

(30) R = OMe, X a b s e n t (31) R

=

OMe, X = 0

(32) R

=

OH, X

= 0

(33) R = PhNH, X ( 3 4 ) R = OH, X

=

0

= S

(35) R = O V e , X = S

c1 (36)

Successive condensations of S-(2-~yanoethyl)thiophosphate with 5’-0monomethoxytritylthymidine and N6,3’-O-dibenzoyl-2’-deoxyadenosineusing TPS-CI, followed by deblocking, affords a mixture of d[Tp(S)A] diastereoisomers, which is separable using reverse-phase h.p.l.c., and the absolute stereochemistry assignable using snake venom phosphodiesterase, as above. When T4 DNA polymerase was used to copolymerize the (Sp) isomer (37) of dATPctS and dTTP on a poly d(A-T) template, and the resultant copolymer degraded using the 5’-exonuclease activity of DNA polymerase I from Escherichia coli and alkaline phosphatase, the d[Tp(S)A] formed was shown to possess the (Rp) configuration (38) by comparison with the authentic material, thus showing 26 27

B. Uznanski, W. Niewiarowski, and W. J . Stec, Tetrahedron Lett., 1982, 23, 4289. 0. Kemal, C. B. Reese, and H. T. Serafinowska, J. Chem. SOC.,Chem. Commun., 1983, 591.


I65

that polymerization had proceeded with inversion of configuration at Hydrolysis of the (Sp) isomer (39) of d[Tp(S)A] in H2lsO using nuclease S1 at pH 6.5 affords an isomer of [180]AMPS, which, on phosphorylation using myokinase, (which phosphorylates the pro-R oxygen atom of AMPS), pyruvate kinase, ATP, and PEP yields an isomer of [cc-ls0]dATPccS,in which 31P n.m.r. shows that the l80atom is in the non-bridging position (40). Hydrolysis by the nuclease thus occurs with inversion of config~ration.~~ The (Rp)(41) and (Sp)(42) isomers of d[Tp(S)T] may be oxidized with NBS in dioxan containing HzleO.

,

Ths 0

0

II

HO-P-0-P-0

I

HO

S

\ x”’

Ado-5 ’ )

,P-o-(

I

HO

(37)

x

(40)

X = l8O

= 0

O( Ado-5

I

’

0-P=O

OH ( 3 8 ) B = Ade, Y = S , X = 0 ( 3 9 ) B = Ade, Y = 0, X = S

( 4 1 ) B = Thy, Y = S , X = 0 ( 4 2 ) I3 = T h y , Y = 0 , X = S ( 4 3 ) B = Thy, Y = l 6 0 , X

=

HO l80

( 4 4 ) B = T h y , Y = l 8 0 , X = l6O (45) B

=

Thy, Y

=

0

(47)

Me160, X = l80

( 4 6 ) B = T h y , Y = l6O, X = Me

180

When the product obtained from this oxidation of (41) is subsequentlyhydrolysed by snake venom phosphodiesterase in [170]Hz0,a process in which the configuration at phosphorus is retained, and the chirality of the resulting 2’-deoxythymidine 5’-[160,170,1*0]phosphate analysed by cyclization to the 3’,5’-monophosphate, methylation and examination by 31P n.m.r., it is seen that the replacement of sulphur in (41) by l*O proceeds with inversion at phosphorus, giving (43). Similarly, oxidation of (42) affords (44).Methylation of the potassium 18-crown-6 salt of (43) with methyl iodide gives the (Rp)(45) and (Sp)(46) diastereoisomers of the methyl phosphotriester, and (45) gives a signal at higher field in the n.m.r. spectrum than (46). The results show that little, if any, 28

2B

P. J. Romaniuk and F. Eckstein,J. Biol. Chem., 1982,257, 7684. B. V. L. Potter, P. J. Romaniuk, and F. Eckstein, J. Biol. Chern., 1983,258, 1758.

)

166


racemization occurs during oxidation, and also that isotopomers of the (Rp) diastereoisomers exhibit resonances at higher field than those of the (Sp) diastereoisomers, thus allowing the configuration of the non-isotopicallylabelled methyl phosphotriesters to be assigned unequi~ocally.~~ This conclusion agrees with the tentative assignment made for the diastereoisomers of (29). Hydrolysis of (44)using nuclease P1 in [170]H20,followed by analysis of the 2’-deoxythymidine 5’-[160,170,1aO]phosphate as described above, shows that the (Sp) isomer is formed, and thus that hydrolysis occurs with inversion of configuration at p h o s p h o r u ~ . ~ ~ Condensation of N4,5‘-O-diacetylcytidine 2’,3’-phosphate with 8-bromoguanosine using TPS-Cl, followed by hydrolytic work-up, deblocking, and column separation, affords the 2’-5‘- and 3’-5’-linked isomers of cytidylyl 8-bromoguanosine, while 2’-deoxycytidylyl(3’-5’) 8-bromoguanosine has been prepared by phosphodiester meth0ds.~1Spectroscopic studies on base stacking and complex formation in these compounds suggest that (3’4’) Cp(br8G) may form left-handed helical (2‘)dimers. Phosphodiester methods have also been used to prepare a number of dinucleoside monophosphates containing 2’-halogeno-2’-deoxynucleosides,32~33 which have been investigated by n.m.r. and other spectroscopic methods in order to determine the influence of the halogen substituents on oligonucleotide c o n f ~ r r n a t i o n s . ~ Intramolecular ~-~~ stacking in dinucleoside monophosphates containing 1-methyladenosine residues has been investigated by spectroscopic and thermal denaturation The major ecdysteroid conjugate in newly-laid eggs of Locusta migratoria has been identified by spectroscopic methods as the 22-adenosine-5’-monophosphate ester of 2-deoxyecdysone (47).36 Cyclic Nuc1eotides.-An extensive review of the chemistry of cyclic nucleotides and their analogues has been p~blished.~? 8-Substituted analogues of adenosine 3’,5’-monophosphate (CAMP) have been prepared by treatment of 8-bromo-CAMPwith nitrogen, oxygen, sulphur, and selenium nucleophiles, and subsequently treated with phenyldiazomethane to give benzyl esters of type (48).38The diastereoisomers of (48) have been separated chromatographically, and the stereochemistry assigned by 31P n.m.r. The esters were found to elicit similar responses to dibutyryl CAMP, but at lower concentration. The 2’-phosphate of CAMP has been prepared in modest yield by coupling N6-benzoyl-CAMPwith 2-cyanoethyl phosphate using DCC, 30 31

a8 33 34

s6

B. V. L. Potter, B. A. Connolly, and F. Eckstein, Biochemistry, 1983, 22, 1369. S. Uesugi, T. Shida, and M. lkehara, Biochemistry, 1982,21, 3400. S. Uesugi, T. Kaneyasu, and M. Ikehara, Biochemistry, 1982,21, 5870. S. Uesugi, T. Kaneyasu, J. Tmura, M. Ikehara, D. M. Cheng, L . 4 . Kan, and P. 0. P. Ts’o, Biopolymers, 1983,22, 1189. D. M. Cheng, L. S. Kan, P. 0. P. Ts’o, S. Uesugi, Y . Takatsuka, and M. Ikehara, Biopolymers, 1983, 22, 1427. Y. Takeuchi, I. Tazawa, and Y . Inoue, Bull. Chem. SOC.Jpn., 1982,55, 3598. G. Tsoupras, C. Hetru, B. Luu, E. Constantin, M. Lagueux, and J. Hoffmann, Tetrahedron, 1983,39, 1789.

s7 38

G. R. Revankar and R. K. Robins, Handb. Exp. Pharmacol., 1982,58, 17. J. Engels and A. Jaeger, Arch. Pharm. (Weinheim, Ger.), 1983, 315, 368 (Chem. Absrr., 1982,97,24 144).


167

followed by conventional d e b l o ~ k i n gPsicofuranine .~~ 4’,6’-monophosphate (49) has been made by phosphorylation of the orthoester (50) using phosphoryl chloride in trimethyl phosphate, and subsequent cyclization of the psicofuranine 6’-monophosphate formed using DCC.40Treatment of cAMP and cGMP with isatoic anhydride or N-methylisatoic anhydride affords novel fluorescent analogues which are stable at neutral pH, and are substrates for beef heart cyclic nucleotide phosphodie~terase.~~ The positions of the emission maxima, and in particular the quantum yields of these analoguesvary with solvent,making them potentially useful fluorescent probes of hydrophobic microenvironments in enzyme studies. NH,

Ade

(49)

Ph CHZO

(48) R = OH, SMe, S B z l , S e B z l , N H B z l , NMeBzl, e t c . Ade

N6-Octyl-CAMP has been prepared by treatment of 6-chloropurine-g-P-~ribofuranoside 3’,5’-monophosphate with octylamine, and 3-deaza-CAMP and 7-deaza-CAMP have been made by phosphorylation of the corresponding nucleosides at the 5’-position using trichloromethylphosphonyl dichloride in triethyl phosphate, followed by cyclization using potassium t - b u t o ~ i d e . ~ ~ These and many other analogues of cAMP have been used to investigate the characteristics of the CAMP-binding sites on the regulatory sub-units of the M. Ya. Karpeiskii, S. N. Mikhailov, and N. Sh. Padyukova, Bioorg. Khim., 1983, 9, 132 (Chem. Abstr., 1983, 98, 161 095). 40 P. A. Sturm, E. J. Reist, and J. P. Miller, J. Org. Chem.. 1982, 47, 4367. *l T. Hiratsuka, J. Biol. Chem., 1982, 257, 13 354. 42 S. 0. Darskeland, D. Ogreid, R. Ekanger, P. A. Sturm, J. P. Miller, and R. H. Suva, Biochemistry, 1983, 22, 1094. as

168


isozymes of CAMP-dependent protein k i n a ~ e . ~In~ one -~~ which utilized the (Rp) and (Sp) diastereoisomers of adenosine 3',5'-phosphorothioate, a marked preference for binding the (Sp) isomer (51) to site 2 of bovine cardiac muscle CAMP-dependent protein kinase regulatory sub-unit was observed, and it is thought that preferential hydrogen bonding of a functional group on the enzyme to the exocyclic oxygen, as opposed to sulphur, of the thiophosphate group may account for this selectivity. Analogues of cAMP modified in base, sugar, or phosphate moieties have also been used to explore the substrate specificities of cyclic nucleotide phosphoNeither diesterase from beef heart and from Dictyosteliurn di~coideurn.~~ diastereoisomer of the electrically neutral N,N-dimethyl cyclic phosphoramidate analogue of cAMP is hydrolysed by these enzymes, and, while (51) is hydrolysed at one-hundredth the rate of CAMP,its (Rp) diastereoisomer is cleaved far more slowly still. These observations, coupled with the known fact that hydrolysis proceeds with inversion at phosphorus, and the results of quantum-mechanical calculations on the energetics of the supposed intermediates, have led to the following course of hydrolysis being proposed : exo-attack by a nucleophilic group of the enzyme molecule gives initially a pentaco-ordinate phosphorus intermediate (52) with the cyclophosphate ring positioned diequatorially, which undergoes pseudorotation to (53) and expulsion of the 3'-OH group to give (54), after which in-line expulsion of the enzyme by incoming water gives the inverted product (55).

(55)

(54)

( O x y g e n atoms a r e m a r k e d w i t h i d e n t i f y i n g s y m b o l s ) 43

44 45

J. D. Corbin, S. R. Rannels, D. A. Flockhart, A. M. Robinson-Steiner, M.C. Tigani, S. 0. Dsskeland, R. H. Suva, and J. P. Miller, Eur. J. Biochem., 1982,125,259. C. A. O'Brian, S. 0. Roczniak, H. N. Rramson, J. Baraniak, W. J. Stec, and E. T. Kaiser, Biochemistry, 1982, 21, 4371. P. J. M. van Haastert, P. A. M. Dijkgraaf, T. M. Konijn. E. G. Abbad, G. Petridis, and B. Jastorff, Eur. J. Biochem., 1983, 131, 659.


I69

3 Nucleoside Polyphosphates

If an aqueous solution of AMP is stirred with chloroform containing the dichloride salt of N1,N4-bis(n-octadecy1)-1 ,4-diaza[2.2.2]bicyclooctane(56) and the organic phase then separated, treated with phosphoryl chloride and potassium carbonate (or some similar base) and subsequently back-extracted with aqueous sodium perchlorate, ADP and ATP are found to have been formed in moderate yields.46The agent (56) has thus extracted AMP into the chloroform layer, where it reacts with P0Cl3 forming species such as (57) which may be hydrolysed to ADP by adventitious water or phosphorylated further to ATP. If ammonium carbonate is employed as buffering base, the phosphoramidate (58) is obtained in high yield, giving a useful alternative synthesis for this species. In a novel simple route to ATP and dATP, the corresponding nucleosides are phosphorylated with phosphoryl chloride in trimethyl phosphate, and the products treated, without isolation, with bis(tributy1ammonium) pyrophosphate, and subsequently with aqueous triethylammonium bicarbonate to give good yields of the tripho~phates.~~ Mixtures of ribonucleoside triphosphates may be obtained from yeast RNA as starting material by using nuclease P1 to hydrolyse the RNA to oligonucleotides. These are then phosphorolysed using polynucleotide phosphorylase and orthophosphate to afford a mixture of ribonucleoside-5’-diphosphates, which are converted immediately to the corresponding 5’-triphosphates using pyruvate kinase and PEP.48 Degradation of commercial ATP samples using sodium periodate and methylamine, followed by analysis of the products by h.p.l.c., has demonstrated that they may contain up to 1 % of dATP, probably derived from DNA contaminating the RNA used as starting material for the preparation of ATP.4QCare must therefore be taken if ATP of high purity uncontaminated by dATP is required.

n

0

0

II II X-P-O-P-O-(AdO-5’ I I OH

OH

(56)

(57)

)

x

=

c1

( 5 8 ) X = NH2

Treatment of adenosine 5’-[p-morpholino]diphosphate with [1s04]orthophosphate affords [y-la0,]ATP, which has been used to study nonenzymatic hydrolytic pathways of ATP.60Upon hydrolysis, the orthophosphate released was isolated, converted to trimethyl phosphate, and the isotope content analysed by mass spectrometry. In 1~ and 0 . 1 HCl, ~ the data suggest addition-elimination as the hydrolysis mechanism, with attack occurring predominantly at P, to 46 47

I. Tabushi and J. Imuta, Tetrahedron Left., 1982,23, 5415. J. Ludwig, Acfa Biochim. Biophys. Acad. Sci. Hung., 1981, 16, 131 (Chem. Abstr., 1982, 97, 56 177).

48 40 50

C.-H. Wong, S. L. Haynie, and G. M. Whitesides, J . Am. Chern. Soc., 1983,105, 115. A. Yashioka, K. Tanaka, Y. Wataya, and H. Hayatsu, Chem. Pharrn. Bull., 1982,30,2651. S . Meyerson, E. S. Kuhn, F. Ramirez, and J. F. Marecek, J . Am. Chern. Soc., 1982, 104, 723 1.

170


1

OH ( 5 9 ) 0 = l80

afford the intermediate oxyphosphorane (59) in which the leaving group, ADP, is apical. Any attack at P, would require that adenosine becomes an equatorial ligand in the intermediate, a situation which is sterically disfavoured. The predominant hydrolysis of ADP via attack at Pp at these pH values may be rationalized similarly. The small proportion of attack at Pp of ATP which is observed results only in hydrolysis to ADP and orthophosphate, suggesting that orthophosphate is preferred as apical ligand in the intermediate. At pH 8.3, hydrolysis of ATP proceeds exclusively by cleavage of Pp-0-P,, at a much slower rate than in acid. An elimination-addition mechanism is thought to operate, with Py being eliminated as metaphosphate. Over the entire pH range 0-8.3, no oxygen exchange between water and ATP, ADP, or orthophosphate was detected. Non-enzymatic hydrolysis and isotopic analysis of the orthophosphate formed are thus reliable methods for assaying isotopic enrichment of [y1*0]ATPspecies used in studies of enzymatic processes. A comparative study of the rates of hydrolysis of ATP and dATP, ADP and dADP over the same pH range shows that similar rates and mechanisms of hydrolysis occur in each series, except that at lower pH values the cleavage of the glycosidic bond becomes the dominant initial process in hydrolysis of the deoxyribonucleotides.61A kinetic study of the anaerobic hydrolysis of ATP at 60-80 “C in the pH range 3.2-10.1 has furnished specificrate constants and the associated thermodynamic data for hydrolysis of all the ionic species of ADP and ATP Treatment of bromomethyl acetate with the sodium salt of a dialkyl phosphite, followed by deacetylation with methoxide affords the corresponding dialkyl hydroxymethanephosphonate. If this is tosylated with tosyl chloride, and the product treated with nucleosides [protected at the 3’- (and 2’-, if present) hydroxy groups] and sodium hydride in DMF, the monoalkyl ester of a 5’-O-phosphonylmethyl nucleoside (60) is obtained after deblocking the sugar, and subsequent dealkylation with TMS-iodide affords (61).53Like alkyl esters of 5’-mononucleotides, (60) is resistant to acid and alkaline hydrolysis, while (61) is stable in acidic and alkaline media, and is also resistant to hydrolysis by alkaline phosphomonoesterase and snake venom 5’-nucleotidase. Treatment of (61) with DCC and niorpholine, and subsequently with orthophosphate or pyrophosphate, affords (62) and (63), respectively. Alkaline phosphomonoesterasefrom E. coli hydrolyses the pyrophosphaie links in (62) and (63) to give (61) and orthophosphate. The UTP and CTP analogues (63 ; B = U or C) are inhibitors of uridine kinase from 51

63 53

F. Ramirez, J. F. Marecek, and J. Szamosi, Phosphorus Sulfur, 1982, 13, 249. H. Seki and T. Hayashi, Chem. Phnrm. Bull.. 1982, 30, 2926. A. Holy and I. Rosenberg, Collect. Czech. Chem. Commun., 1982, 47, 3447.


171

mouse leukaemic and are also more potent competitive inhibitors of DNA-dependent RNA polymerase from E. coli than the purine nucleotide analogues (63; B = A or G).55None of the analogues was a substrate for the latter enzyme. 0

(60) R = M e

or E t

(61) R = H ( 6 2 ) R = P03H2

( 6 3 ) R = P206H3

P-D-Glucose 6-phosphate has been coupled to ADP and ATP using carbonyltriphosphate, and the diimidazole to afford P1-(adenosine-5’)-P3-(glucose-6) analogous tetraphosphate, which are inhibitors (but not substrates) for yeast hexokinase and isozymes of rat hexokinase. Similarly, treatment of ADP with carbonyldiimidazole and then with dTMP affords A(S’)ppp(S’)dT, which was a powerful inhibitor for thymidine kinase from rat mitochondria, but inhibited the same enzyme from cytoplasm only weakly.56If 8-ethylthio-ATPis cyclized to the 5’-trimetaphosphate using DCC, and then treated with piperidine, the 8-ethylthioadenosine 5’-[y-piperidino]triphosphate formed reacts readily with ADP to afford the unsymmetrical dinucleosidyl pentaphosphate, 8-EtS-A(5’)ppppp(5’)A. This procedure gives fewer by-products than simple treatment of the trimetaphosphate with ADP.K7Accordingly, unsymmetrical pentaphosphates of this type have been prepared from 8-ethylthio-ATP and the 5’-diphosphates prepared from nucleosides (2), and investigated as potential two-site competitive inhibitors of adenylate kinase isozymes from rat tissues. The 5’-triphosphates of (2) have also been prepared from the corresponding 5'-mono phosphate^^ using carbonylidiimidazole and pyrophosphate, and investigated as inhibitors of adenylate kina~e.~’ Many of the monophosphates described in Ref. 5 , including those of (2) and (3), have been converted to the corresponding 5’-diphosphates using the same condensing agent, and tested as inhibitors of isozymes of pyruvate kinase from rat 54 55

56 67 58

J. Vesely, 1. Rosenberg, and A. Holy, Collect. Czech. Chem. Commun., 1982, 47, 3464. K. Horska, I. Rosenberg, A. Holy, and K. Sebcsta, Collect. Czech. Chem. Commun., 1983, 48, 1352. A. Hampton, T. T. Hai, F. Kappler, and R. R. Chawla, J. Med. Chem., 1982,25, 801. F. Kappler, T. T. Hai, M. Abo, and A. Hampton, J. Med. Chem., 1982,25, 1179. T. T. Hai, M. Abo, and A. Hampton, J. Med. Chem., 1982,25, 1184.

172


The use of phosphorothioate analogues of nucleotides for the investigation of biochemical processes has been newly reviewed.s0When unprotected 2’-deoxynucleosides are treated with excess phosphorous acid, and one equivalent of N,N’-bis(4tolyl)carbodiimide in pyridine, the corresponding 5’-monophosphites are formed almost exclusively, in good yield, and on treatment with sulphur, TMS-chloride, and trialkylamines in pyridine, the corresponding 2’-deoxynucleoside 5’-phosphorothioates are formed almost quantitatively.60These are readily converted to the corresponding 5’-[a-thio]triphosphates using diphenyl phosphorochloridate and pyrophosphate, the diastereoisomers separated by ion exchange chromatography on DEAE-Sephadex, and their absolute configuration assigned using 31Pn.m.r. T4 DNA polymerase converts (Sp)[a-l8O2]dATPaSto [a-180]dAMPSif poly[d(A-T)] template primer is present, although the (Rp) isomer is unaffected.61 The reaction thus appears to involve incorporation by the polymerase of the thioadenylate opposite a thymine base on the template,followed by excision by the associated 3’ -+ 5’ exonuclease activity. After phosphorylation of the product using adenylate kinase and pyruvate kinase, to give (Sp)[a-1801]dATPaS, 31Pn.m.r. showed that l80was entirely in the non-bridging position, i.e., that (40) had been formed, and thus that overall retention of configuration at phosphorus had occurred. Since incorporation of the thiotriphosphate by this enzyme involves inversion at phosphorus,28hydrolysis by the exonuclease A more must also proceed with inversion, possibly by direct di~placernent.~~ complicated, but general, route to chiral 2’-deoxynucleoside 5’-[a-thioltriphosphates is exemplified by a synthesis of dTTPaS : 2’-deoxythymidine-Y-phosphorothioate is coupled to AMP using diphenyl phosphorochloridate, the diastereoisomersof the resultant A(S’)pp(S)( 5’)dT separated chromatographically, the adenosine moiety removed using sodium periodate and triethylamine, and the resultant diastereoisomers of dTDPaS phosphorylated using acetate kinase and acetyl phosphate to give the required products.62Polymerization of (Sp)dTT’PaSusingavianmyeloblastosisvirus reverse transcriptaseand poly(A) - d(pT)l, template primer affords poly(d[p(S)T]) in which the thiophosphate group has (Rp) configuration, as shown by the degradation of the polymer by snake venom phosphodiesterase, and the coincidence of the chemical shift in the 31Pn.m.r. spectrum with that of (41). Polymerization by the enzyme thus proceeds with inversion of configuration at Pa. The procedure described above for A(S‘)pp(S)(5’)dT has also been used to prepare A(S’)pp(S)(S’)I and A(S’)pp(S)(S’)A and separate their diastereoisomers, the absolute configuration being assigned by oxidation with a single equivalent of periodate, isolation of the IDPaS (or, in the latter case, ADPaS) formed, and investigation of its substrate properties with pyruvate kinase, which phosphorylatesonly (Sp)nucleoside a-thiodipho~phates.~~ Incubation of (Sp)A(S‘)pp(S)(S’)I with ApApA and T4 RNA ligase afforded ApApAp(S)I as product, which could be degraded totally by snake venom phosphodiesterase, showing that the phosphorothioate bond in the ApApAp(S)I 8o 82

83

F. Eckstein, Angew. Chem., Int. Ed. Engl., 1983,22,423. J.-T. Chen and S. J. Benkovic, Nucleic Acids Res., 1983, 11, 3737. A. Gupta, C. DeBrosse, and S. J. Benkovic, J. Biol. Chem., 1982, 257, 7689. P. A. Bartlett and F. Eckstein, J. B i d . Chem., 1982, 257, 8879. F. R. Bryant and S. J. Benkovic, Biochemistry, 1982, 21, 5877.


173

possessed (Rp) configuration, and that the ligase had catalysed displacement of AMP from the substrate with inversion at phosphorus. Also, if adenosine 3’-phosphate 5’-phosphorothioate (prepared, with the 2’-isomer, by phosphorylating adenosine 2’,3’-monophosphate with thiophosphoryl chloride and subsequentlyopening the cyclophosphatering by acidic hydrolysis) was incubated with ATP and T4 RNA ligase, only (Sp)A(S’)pp(S)(S’)A was formed: the chiral product formed from the prochiral reactant thus possesses the configuration required for the subsequent ligation step. When ADPaS is oxidized with excess cyanogen bromide in H2180at pH 10.6, [180]ADP is formed in which analysis reveals that l80has been incorporated at Pa and Pp in equal amounts. Similarly, oxidation of ATPPS in H2l80at pH 7 affords [180]ATP in which equal quantities of the label are incorporated at Pp and P,, but none at Pa. These curious observations have been further investigated by studying the same oxidation process in water, using [a-l*O, a,P-lsO]ADPaS (a), analysis of the products showing that some [a-1802]ADP (65) is formed in addition to the expected product (66). This finding has prompted the suggestion that in addition to direct displacement of thiocyanate from (67) by water, some of the cyclodiphosphate intermediate (68) is formed, and that hydrolysis of (68) occurs exclusively at Pp, resulting in transfer of part of the bridging oxygen isotope of (64) to While Pp is the more ccowded atom, it is equally strained and electrically neutral, and it seems curious that no attack at Pa,evidenced by transfer of l80to a non-bridging position on Pp, occurs. It seems possible that the cyclophosphate ring of (68) could cleave to give a phosphorylmetaphosphate, which would be quenched by water to give the observed products. 0

S

II

II

-O-p-O-P-O-

-1

(Ado-5’ )

-1

0

0

0

0

0

0

TI II -0-p-0-P-0-1

0

-I

(Ado-5

)

0

(65)

Reagents: i, CNBr, pH 10.6; ii, H,O 64 R. D. Sammons, H.-T. Ho, and P. A. Frey, J. Am. Chem. Soc., 1982, 104, 5841.

174


If, in contrast, (Sp)ADPaS is oxidized using bromine in [170]H20,analysis of the [a-170]ADP formed shows it to have the (Rp) configuration with 93% inversion having This result contrasts strongly with those reported above: possibly the leaving group formed at Pa during oxidation using bromine leaves more efficiently than thiocyanate, being displaced by water before the cyclodiphosphate intermediate has time to form, or else the P-phosphate group is a better nucleophile at the high pH employed in the previous study than at the lower pH of bromine-water-dioxan, and thus favours cyclodiphosphate formation. The (Rp)[a-170]ADP has been converted to (RP)[~-~~O]ATP using pyruvate kinase, and used as a substrate for isoleucyl-tRNA synthetase, together with [1802]isoleucine.The isoleucyl adenylate formed was ammonolysed using hydroxylamine, and the [1s0,170,180]AMPformed was cyclized, methylated, and analysed by methods reported previously to show that the (Rp) isomer had been formed, and thus that the formation of the isoleucyl adenylate had occurred with inversion of configuration at P,. Upon incubation of [p-l80,]ATP with the enzyme in the absence of isoleucine, no isotopic scrambling to the Pa-O-Pp bridge position was observable, suggestingthat no adenylyl-enzyme or metaphosphate intermediate is formed, while in the presence of the isoleucine, scrambling and tumbling (resulting in transfer of l80to P, by rotation of pyrophosphate) were seen. A similar study using methionyl-tRNA synthetase from E. coli afforded the same results as the isoleucyl-tRNA synthetase.ss Phosphoglycerate kinase will phosphorylate only the (Sp) diastereoisomer of GDPaS, a property which has been used to prepare (Sp)GDPaS from the racemic mixture via the corresponding (Sp)GTPaS. Oxidation of (Sp)GDPccS with NBS in H2I8Oand dioxan affords (Rp)[a-180]GDP, which has been converted to (Rp)[a-180]GTP using pyruvate kinase and PEP, and used as a substrate for guanylate cyclase from bovine lung.s7Methylation of the [l80]cGMP formed and analysis using 31Pn.m.r. shows l80to be in the axial position on the 1,3,2-dioxaphosphorinan ring, and thus that cyclization proceeded with inversion of configuration. This result was confirmed using (Sp)GTPaS as substrate and analysing the cGMPS formed. Treatment of (Sp)2’,3’-di-O-acetyladenosine5’- [160,170,1 80]phosphate with sulphur trioxide-triethylamine, and subsequent deacetylation using acetyl esterase affords the isotopomers of (Sp)adenosine 5’-[160,170,180]phosphosulphate. On treatment of this species with ATP sulphurylase and magnesium pyrophosphate, the sulphate group, which includes the bridging oxygen to which the sulphur atom is attached, is displaced by pyrophosphate. Analysis of the resultant isotopically labelled ATP species by hydrolysis in [170]H20 using snake venom phosphodiesterase, chemical cyclization to CAMP, methylation and analysis of the isotopic configuration using 31Pn.m.r. shows that the displacement by pyrophosphate occurs with inversion of configuration at phosphorus, indicating that the double displacement mechanism previously

65 66 13’

G. Lowe, B. S. Sproat, G. Tansley, and P. M. Cullis, Biochemistry, 1983, 22, 1229. G. Lowe, B. S. Sproat, and G. Tansley, Eur. J . Biochem., 1983, 130, 341. P. D. Senter, F. Eckstein, A. Mulsch, and E. Bohme, J. B i d . Chem., 1983, 258, 6741.


175

ascribed to this enzyme may be untenable.68Adenosine 5’-[a,p-l8O,pJaO2]triphosphate and (Sp)adenosine 5’-[y-160,170,180]tripho~phate have been incubated with pyruvate kinase to test a suggestion that enzyme-bound ATP loses the terminal phosphate group by a dissociative rnechani~m.~~ If this were the case, rapid positional scrambling between the P-non-bridge oxygen atoms and the P,y-bridge oxygen should be observable in the former species, and racemization at P, in the latter, but the experimental data show that scrambling is 104 times faster in the presence of co-substrate pyruvate than in its absence, and the rate of racemization at P, is very slow. It has been concluded that an associative, rather than a dissociative, mechanism is involved in phosphoryl transfer from pyruvate kinase. The rate of loss of la0from Mg,[y-1a04]ATPduring the hydrolysis and re-association of this species catalysed by myosin has been measured using native myosin, and also myosin modified at reactive sulphydryl or lysine groups.7oModification suppressed oxygen exchange by increasing the rate of hydrolysis and decreasing the rate of re-association,possibly by perturbing the conformational changes in the protein believed to be coupled to the catalytic mechanism. The rate of labelling of adenine nucleotide a-phosphoryl groups with l8O in intact blood platelets equilibrated with H2180is accounted for primarily or solely by the phosphodiesterase-catalysed hydrolysis of CAMP, and not by transfer to P, from [180]-labelledy-phosphoryl groups, or orth~phosphate.~~ A review on the use of phosphorothioate analogues of ATP as substrates of enzymic reactions, with particular regard to studies involving stereoselectivity in metal chelate structures, and the displacement of equilibrium in kinase reactions using ATPFS and similar species as substrates, has A brief description of a principle used in such studies may be given as follows: consider the B, or (Rp) isomer, of ATPPS chelated by a divalent metal ion (69). A soft metal ion, such as cadmium(rI), will bind preferentially to the sulphur atom at Pp, conferring a right-handed helical screw sense on the direction of the triphosphate chain (A), while a hard metal ion, such as magnesium(@, binds to the oxygen atom, conferring the left-handed (A) screw sense. For the A, or (Sp) isomer (70), the cadmium complex has the A configuration, and the magnesium complex the A configuration. Then, an enzyme which binds Mg.ATP2- as a P,y-chelate with A configuration will show a higher V,,, with the Mg2+complex of (70) than with the Cd2+complex, and a higher V,,, for the Cd2+complex (69) than for the Mg2+complex; one binding the A,p,y-chelate will show the opposite preferences. If a single diastereoisomer of the phosphorothioate is preferred regardless of the nature of the metal ion, the phosphate group in question may not be ligated to the metal ion. This point is discussed further below. Studies using the methods outlined above have concluded that rat

68

69

‘O

71 72

R. Bicknell, P. M. Cullis, R. L. Jarvest, and G. Lowe, J. B i d . Chem., 1982, 257, 8922. A. Hassett, W. Bliittler, and J. R. Knowles, Biochemistry, 1982, 21, 6335. K. K. Shukla, H. M. Levy, F. Ramirez, and J . F. Marecek, J. Biol. Chem., 1982,257, 8885. T. F. Walseth, J. E. Gander, S. J. Eide, T. P. Krick, and N. D. Goldberg, J. Biol. Chern. 1983,258, 1544. M. Cohn, Acc. Chern. Res., 1982, 15, 326.

176


muscle hexokinase and rat liver glucokinase bind Mg.ATP2- as the A,P,ybidentate and that pyridoxal kinase from brain74and adenylate kinase from baker's yeast7sare stereoselectivefor the A,P,y-chelate. In arginine kinase from lobster muscle, the metal-ATP substrate is thought to be the tridentate or,P,y-chelate.78 In a study of 3-phosphoglycerate kinase, metal-dependent stereospecificity was observed for the diastereoisomers of ATPcrS and ADPorS, but not for ATPPS, and in addition the diastereoisomers of the substitution-inert P,y-bidentate Cr"'.ATP- complex gave no reaction, suggesting that the metal ion is chelated to Pa, but not to Pp, in a rate-determining step of the With porcine liver adenylate kinase, by contrast, metal-dependent stereospecificity was observed for the diastereoisomers of ATPPS, but not for the ATPorS, with the preference of the enzyme for the magnesium complex of (70) showing that thepro-R oxygen of Pp of ATP is chelated to the metal ion in the rate-limiting step, while no chelation is thought to occur at Information concerning the mode of chelation may be obtained by alternative means: oxidation of (Sp)ATPPS (67) in [l70]H20using one of the methods described previously affords (Rp)[PJ70]ATP (71) while (69) affords (Sp)[P-170]ATP (72). 0

0

I

I

A-

0

P-0

/I

0

0

X-M'

0-(

5 ' -AMP)

\I

0

0-(5'-AMP) A

A M i s a metal i o n ( 6 9 ) X = S,

Y

= 0

(70) X = 0, Y = S

x (72) x (74) x (71)

0

-

74

7B 76 77 78

0

= l60, =

Y

x

l6o

= l7o

= l60

0

II II II O-PP-O-P-O-P-O~(A~O-~' -1 -I I 0

73

0

= l70, Y =

)

SM e

M. K. Darby and I. P. Trayer, Eur. J. Biochem., 1983, 129, 555. J. E. Churchich and C. Wu, J. Biol. Chem., 1982, 257, 12 136. A. G. Tomasselli and L. H. Noda, Eur. J. Biochem., 1983, 132, 109. M. Cohn, N. Shih, and J. Nick, J. Biol. Chem., 1982, 257, 7646. E. K. JafTe, J. Nick, and M . Cohn, J. Biol. Chem., 1982,257,7650. H.-R. Kalbitzer, R. Marquetant, B. A. Connolly, and R. S. Goody, Eur. J. Biochein., 1983, 133,221.


177

When these form a chelate with manganese@) at the active site of an enzyme, superhyperfine coupling between the nuclear spin of oxygen-17 and the paramagnetic Mn” ion produces a characteristic inhomogeneous broadening of the e.p.r. signals when the 170is in the first co-ordination sphere of the metal ion. For porcine liver adenylate kinase, line-broadening was observed with (71), but not with (72) or with other ATP species stereospecifically labelled with 170at P,, or at P,, providing further evidence that Mg.ATP2- exists predominantly as the p-monodentate complex at the active site of the enzyme with the metal chelated by the pro-R oxygen atom.78In a comparable study on creatine kinase using (Rp) and (Sp)[aJ70]ADP in the presence of Mn“, line broadening was only observed with the (Sp) isomer, and this, together with previous results, establishes the stereoselectivity of the enzyme for the A configuration of the a,P-chelate of Mn .ADP-.’@ In an attempt to determine whether a lack of reversal of stereoselectivity on replacing Mg2+by Cd2+in studies with diastereoisomers of ATPaS genuinely means that the metal is not co-ordinated to oxygen at Pa, the diastereoisomers of ATPaS have been methylated with methyl iodide to give the corresponding diastereoisomers of adenosine 5’-[a-methylthio]triphosphate (73) in which the a-phosphate group, being electrically neutral, should bind metal ions only weakly, if at While (73) was unstable at physiological pH, decomposing mainly to adenosine 5’-(S-methyl)phosphorothioate [AMPS(Me)] and pyrophosphate, and partly to ATP and methylthiol, it was more stable at lower pH. The (Sp) diastereoisomer of (73) was a substrate for hexokinase and acetate kinase, and both diastereoisomers were actitre with fructose 6-phosphate kinase, the products in each case being the corresponding sugar or acyl phosphate, AMPS(Me) and orthophosphate, the latter arising via breakdown of the presumably highly unstable intermediate adenosine 5’-[or-methylthio]diphosphate. If metaphosphate is generated at the active site of the enzyme during this breakdown process, (73) may behave as an affinity label for those enzymes which recognize it as a substrate. No measurable substrate activities were obtained for (73) with creatine kinase and 3-phosphoglycerate kinase, and it has therefore been suggested that these enzymes require Mg2+ to be co-ordinated to the or-phosphate for catalytic activity. Attempts to methylate ATPPS and ADPaS similarly were unsuccessful, with ADPPS and AMPS(Me) being the major products isolable. The @,y-bidentatechromium(ur).ATP complex (74; M = CP+) has been separated into four diastereoisomers by reverse-phase h.p.1.c. 81 The six-membered rings of the A and A forms are puckered, with the adenylate able to adopt an axial conformation (which is stabilized by transannular hydrogen bonding) or an equatorial conformation, in each. CD spectroscopy was used to identify the screw sense of the resolved isomers, and the interconversion rates measured, the axial-equatorial interconversion rates for the A and A isomers being more rapid than the A-A isomerization. Both (74; M = Crs+)and the corresponding

’* 8o

T.S. Leyh, R. D. Sammons, P. A. Frey, and G. H. Reed, J. Biol. Chem., 1982.257,15 047. B. A. Connolly and F. Eckstein, Biochemistry, 1982, 21, 6158. K. J. Gruys and S. M. Schuster, Anal. Biochem., 1982,125,66.

178


tetraamminocobalt(I1I) complex are competitive inhibitors with regard to Mn .ATP2- for Ca2+-ATPasefrom sarcoplasmic reticulum and Mg2+-ATPase and (Na+ K+) ATPase from kidney medulla, while the cobalt complex is also a substrate for the first two enzymes.82The behaviour of the diastereoisomers of ATPPS as substrates for Ca2+-ATPasefrom sarcoplasmic reticulum has been examined.83 Curiously, although the free energy of hydrolysis of the thionucleotides is some 2.5 kcal mo1-1 greater than that of ATP, the isomers are hydrolysed at the same rate as each other, and as ATP, and the rate of Ca2+ uptake by vesicles was the same for each. The cc,@-methyleneanalogues of ADP and ATP have been found to act as substrates for creatine kinase, and 31P n.m.r. has been used to measure the equilibrium constant of the reaction, revealing that the standard free energy of hydrolysis of the terminal phosphate group in the ATP analogue is less favourable by 2.8 kcal mol-1 than that for ATP. 84 P3-[1-(2-Nitro)phenylethyl]adenosine-5'-triphosphate, prepared by treating ADP-morpholidate with 1-(2-nitro)phenylethyl phosphate,86 has the useful property that upon illumination with laser light at 347 nm, the 2-nitrophenylethyl group is lost to afford ATP. Photolysis of muscle fibres perfused with this 'caged' ATP thus removes limitations in resolving the time course of muscle fibre relaxation by creating an instantaneous concentration of ATP.8s A water-soluble carbodiimide has been used to couple 1 -aminonaphthalene5-sulphonate to the y-phosphate groups of dTTP, CTP, UTP, ATP, GTP, dCTP, and dGTP by forming a phosphoramidate link. The change in fluorescence exhibited by the resulting analogues on cleavage of the M-P pyrophosphate bond permits a convenient assay of enzymes active in this pH range which cleave this bond, such as snake venom phosphodiestera~e.~~ GTP and GDP have been coupled to 4-azidoaniline and N-met hyl-(4-azido)benzylamine, and GTP to 4-[N-(2-chloroethyl)-N-methylamino]benzylamine,using a similar agent, and the interaction of these analogues with elongation factor Tu investigated.s8 ADP has been treated with carbonyldiimidazole and N-acetylalanyl-O-(phosphory1)serine methyl ester to afford the y-O-(N-acetylalanylserine methyl ester) ester of ATP, as a potential inhibitor resembling the putative transition state involved in associative phosphoryl transfer from ATP to protein catalysed by CAMP-dependent protein kinases.89 Treatment of 8-(6-aminohexylamino)ATP with 2,4-dinitrofluorobenzene affords (79,which, despite being a ribonucleotide, is a substrate for calf thymus terminal deoxynucleotidyl transferase and DNA polymerase I from E. coli, and

+

82

83 84

85 86

M. L. Gantzer, C. Kleevickis, and C. M. Grisham, Biochemistry, 1982, 21, 4083. E. Pintado, A. Scarpa, and M. Cohn, J. Biol. Chem., 1982, 257, 11 346. E. J. Milner-White and D. S. Rycroft, Eur. J . Biochem., 1983, 133, 169. J. H. Kaplan, B. Forbush, 111, and J. F. Hoffmann, Biochemistry, 1978, 17, 1929. Y. E. Goldman, M. G. Hibberd, J. A . McCray, and D. R. Trentham, Nnrure (London). 1982, 300, 701.

13' 88 89

S. E. Pollack and D. S. Auld, Anal. Biochem., 1982,127,81. G . T. Babkina, J. Jonak, and 1. Rychlik, Biochirn. Biophys. A d a , 1982, 698, 116. P. R. Lashmet, K.-C. Tang, and J. K. Coward, Tetrahedron Lett., 1983,24, 1121.


179

may thus be incorporated into DNA.goThe 2,4-dinitrophenyl group, a hapten, can then bind to suitable antibodies, affording a method for isolating DNA which has incorporated (75).

0

2

N

q H( CH2 1 6 N H < l h

O2

I

N R

=

2,4,6-(Me2CH)3C6H2

(80) R

=

2,4,6-Me3C6H2

(79)

‘

N

I

0

(82) R = 3‘-0-laevulinyl-dThd-5’

(83) R = 5‘-O-trityl-dThd-3‘

The presence of an activated ester between the phosphodiester and l-hydroxybenzotriazole during internucleotide bond formation using benzotriazol-l-yloxytris(dimethy1amino)phosphonium hexafluorophosphate (81) has been demonstrated using 31P n.m.r.,lZoand optimum conditions for the use of (81) 11* ll8

F. Himmelsbach and W. Pfleiderer, Tetrahedron Lett., 1982, 23, 4793. E. Ohtsuka, Z.Tozuka, S. Iwai, and M. Ikehara, Nucleic Acids Res., 1982, 10, 6235. D. Molko, A. Guy, R. Teoule, B. Castro, and J. R. Dormoy, Nouv. J. Chim., 1982, 6 , 277 (Chem. Abstr., 1982, 97, 163 395).


183

have been defined.121The effects of nucleophilic catalysis on the reactions of arylsulphonyl condensing agents with 4-chlorophenyl nucleotide esters during internucleotidic bond formation have also been investigated using 31P n.m.r.lz2Jza Condensation by TPS-Cl to form the symmetrical pyrophosphate intermediate (82)lz2is very sluggish unless excess pyridine or N-methylimidazole is present, the rate of catalysis of the condensation appearing inversely proportional to base strength. Tetrasubstituted pyrophosphates such as (83), which are formed during treatment of the 4-chlorophenyl nucleotide esters with many of the arylsulphonyl condensing agents in common use, fail to react with hydroxy-groupbearing components in the absence of a nucleophilic cata1y~t.l~~ In the presence of nucleophilic reagents such as N-methylimidazole, powerful phosphorylating species such as (84) are formed, which complete the condensation by phosphorylating the hydroxy-group-bearing component.lz4N-Methylimidazole has been found to be particularly effective as a condensation c a t a l y ~ t . ~ ~ ~ J ~ ~ Bis(5-chloro-8-quinolyl)-2’-O-tetrahydropyranylribonucleoside5’-phosphates may be obtained by coupling bis(5-chloro-8-quinolyl) phosphate to the 3’3’unprotected nucleosides using 8-quinolinesulphonyl tetrazolide (QS-tet) without appreciable quantities of the 3’-phosphorylated or 3’3-bisphosphorylated byproducts being formed.lz6The product may then be extended at the 3’-position by oligonucleotide phosphotriester methods, and the 5-chloro-8-quinolyl groups removed with zinc chloride in pyridine during terminal deblocking to give the 5’-phosphorylated oligonucleotide. 8-Quinolinesulphonyl chloride-tetrazole has been used in a one-pot preparation of protected deoxyribodinucleotide blocks for use in oligonucleotide synthesis,lz7and it has been claimed that the use of this mixture, and of QS-tet itself,12*avoids the formation of detritylated products and of 06-phosphorylated guanosine by-products. A number of 5’-O-pixyl-2’-deoxythymidine3’-arylmethyl (2-chlorophenyl) phosphates (85) have been prepared by coupling the substituted benzyl alcohols to (86) using MS-nt in pyridine, in order to study the effect of substitution in the benzyl group on nucleophilic deben~y1ation.l~~ The 2,4-dinitrobenzyl group is removed very rapidly by toluene-4-thiolate, and rather slowly by pyridine, and appears to be a promising group for protecting 3’-terminal phosphate groups during oligonucleotide synthesis. The 2-cyanoethyl group, which is frequently used for this purpose, can be removed rapidly by hindered primary amines such as t-butylamine, without removing acyl groups protecting cytosine or adenine or 4-chlorophenyl groups protecting phosphate in the process.13oThe 2,2,2-triD. Molko, A. Guy, and R. Teoule, Nucleosides Nucleotides, 1982, 1, 65. V. F. Zarytova, E. M. Ivanova, and V. P. Romanenko, Dokl. Akad. Nauk SSSR, 1982, 265, 878 (Chem. Abstr., 1983, 98, 54 377). 12* E. M. Ivanova, L. M. Khalimskaya, V. P. Romanenko, and V. F. Zarytova, Tetrahedron Lett., 1982, 23, 5447. la4 A. L. Kayushin, Yu. A. Berlin, and M. N. Kolosov, Bioorg. Khim., 1982, 8, 660 (Chern. Abstr., 1982, 97, 127 986). lZ5 T. Wakabayashi and S. Tachibana, Chem. Pharm. Bull., 1982,30,3951. H. Takaku, K. Karnaike, and K. Kasuga, J. Org. Chem., 1982,47,4937. H. Takaku, K. Karnaike, and M. Suetake, Chem. Lett., 1983, 111. la* H. Takaku, M. Yoshida, andT. Nomoto, J . Org. Chem., 1983,48,1399. C . Christodoulou and C. B. Reese, Tetrahedron Left., 1983,24, 951. I3O H. M. Hsiung, TetrahedronLett., 1982,23,5119; H. Hsiung, S. Inouye, J. West, B. Sturm, and M. Inauye, Nucleic Acids Res., 1983,11,3227. lal

la2


184

H4C1-4

(85) R = ArCH2 Me

(86) R

(84)

=

H

OTh p

MeO-

0

II

DMTrO

O-P-OR

P-R

I

c1

I

OH (87)

R

=

N

(89) R =

N(CHMe2)2

(91))R

N

5-chloro-8-quinolyl,

C13CCH2, CN(CH2)2,

n \p

(88) R =

4-C1C6H4, or Et =

3

chloroethyl group, which has also enjoyed wide usage, is removed by treatment with zinc, and the zinc ions formed during this process may be conveniently removed as the zinc anthranilate complex by adding anthranilic acid as coreagent.131In a study of the effects of phosphate-protecting groups on coupling using a variety of reactions, (87) was condensed with 2’,3’-di-O-benzoyluridine condensing agents (QS-tet, TPS-tet, MS-triazole, QS-Cl, and TPS-Cl), and it was found that reaction was fastest using QS-tet or TPS-tet, and that little or no 5’-O-sulphonated dibenzoyluridine by-product was observed if the phosphate in (87) was protected by an aryl group, while an appreciable quantity was formed if an alkyl group was The use of alkyl groups to protect phosphate during coupling is therefore not recommended. The number of novel groups designed for the protection of phosphate during the phosphotriester approach to oligonucleotide synthesis includes the 9-fluorenylmethyl group (removed using tr iethylamine),13 34 the 2-(4-nitrophenyl)t hioethyl group (removed by oxidation with 3-chloroperbenzoic acid, followed by 9

133

A. Wolter and H. Koster, Tetrahedron Lett., 1983, 24, 873. H. Takaku and T. Kono, Chem. Pharm. Bull., 1982,30,2991. C. Gioeli and J. Chattopadhyaya, Chem. Scr., 1982, 19, 235 (Chem. Abstr., 1982, 97,

134

N. Balgobin and J. Chattopadhyaya, Chem. Scr., 1982, 20, 133 (Chem. Abstr., 1983, 98,

131

132

182 794). 89 801).


185

@-elimination using triethylamine),l35~136 the 2-phenylsi1 l ~ h o n y l e t h y land ~~~ 5-benzisoxazolylmethylene138groups (also removed using triethylamine), and the 2-oxymethyleneanthraquinonegroup (removed using sodium dithionite in a neutral pyridine buffer).139Some of these have been used in conjunction with unusual groups for protecting the 5’-hydroxy functions of nucleosidic units, such as the 2-(dibromomethyl)benzoyl group,136 the 2-(4-chlorophenyl)sulphonylethoxywbonyl group,l 36$140 the fluoren-9-yl-methoxycarbony1 group,l the pixy1 (9-phenylxanthen-9-y1) group,14oand its close relatives the 9-phenylthioxanthen-9-yl and 7-chloro-9-phenylthioxanthen-9-yl groups.141 B

(91) R1 = N(CHMe2)2, R 2

3

(92) R1 = N

(93) R1 = C1, R2

, R2 =

=

=

Me

Me

C13CC(Me)2

Several methoxyphosphor amidochl or idites [e.g., (88)-(go)] have been prepared either by direct treatment of methoxyphosphorodichloridite with the corresponding amine, or with its N-trimethylsilyl derivative, the latter method affording slightly better yields. Treatment of base-protected 5’-O-dimethoxytrityl-2’-deoxynucleosides with (88)-(90) in dichloromethane containing diisopropylamine affords (26), (91), and (92), respectively. While (92) is rather unstable, (91) shows moderate stability and high reactivity upon treatment with tetrazole for coupling to a 3’-O-polymer-bound 2’-deoxynucleoside, and (26) shows high stability and is only a little less reactive. Consequently (26) and (91) are the reagents of preferred to the dimethylamidite (25) which has KG

N. Balgobin and J. Chattopadhyaya, Chem. Scr., 1982, 20, 144 (Chem. Abstr., 1983, 98, 34 897).

N. Balgobin, C. Welch, and J. Chattopadhyaya, Chem. Scr. 1982, 20, 196 (Chem. Abstr., 1983, 98, 89 807).

S. Josephson and J. Chattopadhyaya, Chem. Scr., 1981, 18, 184 (Chem. Abstr., 1982, 97, 6726). 13* N. Balgobin and J. Chattopadhyaya, Chem. Scr., 1982, 20, 142 (Chem. Abstr., 1983, 98, 13’

34 896).

N. Balgobin, M. Kwiatkowski, and J. Chattopadhyaya, Chem. Scr., 1982,20, 198 (Chem. Abstr., 1983,98, 89 808). M. Kwiatkowski and J. Chattopadhyaya, Chem. Scr., 1982, 20, 139 (Chem. Abstr., 1983,

laO

140

98, 54 379). 141 142

N. Balgobin and J. Chattopadhyaya, Chem. Scr., 1982, 19, 143 (Chem. Abstr., 1982, 97, 24 145). L. J. McBride and M. H. Caruthers, Tetrahedron Lett., 1983, 24, 245.

186


hitherto enjoyed wide usage, and both have been used to advantage in solidphase syntheses of oligohucleotides.143144 2,2,2-Trichloro-1,l -dimethylethyl phosphorodichloridite is reported to react selectively with 5’-O-protected deoxynucleosides in THF at -78 “C,with complete replacement of the first chlorine atom taking place to give (93), which may then be used in oligonucleotide syntheses which use the ‘phosphite’ a p p r 0 a ~ h .The l ~ ~trichloroalkyl group is removed efficiently from oligonucleotide phosphotriesters, both in solution and on solid supports, by tributylphosphine in DMF-triethylamine at 80 “C. 3’-O-Formyl-(N-acyl)-2’-deoxyribonucleosides have been described as units for use in the synthesis of oligodeoxyribonucleotides.146The formyl group is introduced using formic acetic anhydride, and removed using triethylamine in methanol-THF prior to phosphorylation by 2-chlorophenylphosphorobis(triazolidate) or methoxyphosphorodichloridite.147Methyl groups protecting the internucleotidic linkage are reported to be removed efficiently by aqueous pyridine without internucleotidic cleavage occurring.147 Cyclic orthoester functions have been explored as protecting groups for nucleoside hydroxy functions, and the 1,3-benzodithiol-2-y1 group, which may be introduced at the 5’-position of an unprotected nucleoside (94) using 1,3-benzodithioliurn tetrafluoroborate in pyridine, and is removed rapidly by 2% trifluoroacetic acid at 0 “C,can be used during oligonucleotide synthesis.14*The tetrahydrofuranyl group has been used to protect the 2’-position in a synthesis involving block condensation of ribo-oligonucleotides, in which the phosphate function was blocked as the 4-ani~idate.l~~ The use of zinc bromide in dry solvents for detritylation is essential, since the tetrahydrofuranyl group is otherwise lost. In a study of the detritylation of fully protected 3’-mononucleotides using zinc bromide and methanol or isopropanol in chloroform or methylene dichloride, it was found that under certain conditions, while analysis by t .l.c. indicates complete detritylation to have occurred, work-up affords a quantity of the tritylated compound, suggesting that the trityl cation may not separate from the zinc-nucleotide complex, but recombines. Optimum detritylation requires the use of a large excess of saturated zinc bromide solution in the alcohol-chlorohydrocarbon mixture. After reaction, the zinc bromide is conveniently removed as a complex with 4-t-b~tylpyridine.1~~ Trifluoroacetic acid and aluminium trichloride have also been used as reagents for detrit~1ation.l~~ One of the more remarkable ideas to have emerged during the past year concerns the use of colour-coded triarylmethyl protecting groups in oligonucleotide If, after each coupling of a mononucleotide to an 9

T. Dorper and E.-L. Winnacker, Nucleic Acids Res., 1983, 11, 2575. S. P. Adams, K. S. Kavka, E. J. Wykes, S. B. Holder, and G. R. Galluppi, J. Am. Chem. SOC.,1983,105, 661. 145 R. L. Letsinger, E. P. Groody, and T. Tanaka, J. Am. Chem. SOC.,1982,104,6805. 146 J. Smrt, Collect. Czech. Chem. Commun., 1982, 47, 2157. 147 H. Vecerkova and J. Smrt, Collect. Czech. Chem. Commun., 1983, 48, 1323. 148 M. Sekine and T. Hata, J. Am. Chem. SOC.,1983, 105, 2044. ld9 E. Ohtsuka, A. Yamane, and M. Ikehara, Nucleic Acids Res., 1983, 11, 1325. 150 F. Waldmeier, S. De Bernardini, C. A. Leach, and C. Tamm, Helv. Chim. Acta, 1982, 65, 2472. 151 V. Butkus, S. Klimasauskas, and Yu. A. Berlin, Bioorg. Khim., 1982, 8, 1343 (Chem. Abstr., 1983, 98, 72 649). 152 E. F. Fisher and M. H. Caruthers, Nucleic Acids Res., 1983, 11, 1589. 143

144


187

oligonucleotide during stepwise addition, a detritylation step is required before the next round of coupling, the colour developed due to the trityl cation may be used as an index of the success of the previous coupling stage. If, therefore, a set of triarylmethyl groups can be found which can be removed from a sugar oxygen function at acceptable rates using standard detritylating reagents, and which generate different coloured carbocations during the process, a different triarylmethyl group may be assigned to each of the four mononucleotidic units used in synthesis. This has been done: the bis(4-anisy1)phenylmethyl (i.e., dimethoxytrityl) group gives an orange cation, and is assigned say, to a guanosine unit ;the 4-anisyl-1-naphthylphenylmethyl,red, to thyrnidine; the bis(2-anisyl)-lnaphthylmethyl, blue, to cytidine; and the 4-tolyldiphenylmethyl, yellow, to adenosine. Then, for instance, the development of a blue colour during the detritylation step indicates the successful attachment of a cytidine unit during the last coupling round, and its intensity allows a rough quantitation. The phthaloyl group, introduced at the Ns-position by treating 2’-deoxyadenosine with trimethylsilyl chloride followed by phthaloyl chloride, confers increased stability on the glycosidic bond.153 The rate of depurination of Ns-phthaloyl-2’-deoxyadenosinein 80% acetic acid at 30 “C is four times slower than that of the Ns-benzoylated compound, and the phthaloyl group is stable during the processes of oligodeoxyribonucleotide synthesis, thus suppressing the common complication of depurination. The group is readily removed using hydrazine hydrate. The primary amino groups of 2’-deoxyadenosine, 2’-deoxycytidine, and 2’-deoxyguanosine have been blocked as benzylcarbamates via treatment of the nucleosides with l-(benzyloxy)carboxyl-3-ethylimidazolium tetrafluoroborate, and the protected nucleosides used in oligonucleotide synthesis by standard phosphotriester methods.154 Debenzylation was performed by hydrogenolysis using cyclohexadiene and a palladium-carbon catalyst. The guanine base of an N2-isobutyryl-2’-deoxyguanosinemononucleotidic unit for oligonucleotide synthesis may be protected by condensation with glyoxal followed by acylation with isobutyric anhydride to introduce the 1,2-diisobutyryloxyethylenegroup as in (95).155At the completion of synthesis,the protecting group is removed with concentrated ammonia and pyridine. The trityl group has also been used to protect N 2 of guanosine during oligonucleotide The 2-phenylthioethy1l6’ and 4-nitr0phenylethyll~~groups have been used to protect Os of 2’-deoxyguanosine residues from sulphonation by coupling agents during phosphotriester syntheses. The former is removed by oxidation to the sulphoxide using periodate, followed by P-elimination with ammonia, and the latter by P-elimination using DBU. The simplicity of the latter procedure commends 4-nitrophenylethyl as the group of choice. Treatment of 5 ’ 4 dimethoxytrityl-2’-O-TBDMS-uridinewith 4-chlorophenylphosphorodichloridate and excess lH-l,2,4-triazole, followed by 2-cyanoethanol, affords (96) as a 153 154

lS5 lS6

15’ 158

A. Kume, M. Sekine, and T. Hata, TetrahedronLett., 1982,23,4365. B. E. Watkins, J. S. Kiely, and H. Rapoport, J. Am. Chem. SOC.,1982, 104, 5702. M. Sekine, J. Matsuzaki, and T. Hata, Tetrahedron Lett., 1982,23, 5287. T. Hata, N. Gokita, N. Sakairi, K. Yamaguchi, M. Sekine, and Y. Ishido, Bull. Chem. SOC.Jpn., 1982, 55, 2949. S. Kuzmich, L. A. Marky, and R. A. Jones, Nucleic Acids Res., 1982, 10, 6265. S. Kuzmich, L. A. Marky, and R. A. Jones, Nucleic Acids Res., 1983,11,3393.

188


mononucleotide unit for use in phosphotriester oligonucleotide synthesis. If, at the conclusion of synthesis, the oligonucleotide unit is unblocked at the internucleotide links using ammonia, the 4-triazolylpyrimidinone unit is converted to cytosine; if syn-pyridine-2-aldoximateis used, it is converted to uracil. Thus (96) may be used as a ‘variable pyrimidine’

OBui

0

DMTrO 0

I I

Ph S-P=O Ph S

0

(951

I

OTBDMS

4 - C 1C6 H O-P=O

I

B

OCH 2CH2CN (96)

2 (or

-

While a large number of improvements in procedures for solid phase synthesis of oligonucleotides have been described, the techniques have not altered fundamentally from those described in previous reports.16oSolid-phase synthesis using a continuous-flow phosphotriester method on a kieselguhr-polyamide support has been described.lsl Other solid phases used as supports for synthesis include derivat ized h.p.1.c. -grade silica gel,ls2163 derivatized cross-linked poly9

L. Sung, J. Org. Chem., 1983, 47, 3623. J. B. Hobbs, in ‘Organophosphorus Chemistry’, ed. D. W. Hutchinson and J. A. Miller (Specialist Periodical Reports), The Royal Society of Chemistry, 1982, Vol. 13, p. 175; 1983, Val. 14, p. 172. la M. J. Gait, H. W. D. Matthes, M. Singh, B. S. Sproat, and R. C. Titmas, NucZeic Acids Res., 1982, 10, 6243. 162 V. Kohli, A. Balland, M. Winterzith, R. Sauerwald, A. Staub, and J. P. Lecocq, Nucleic Acids Res., 1982, 10, 7439. ls3 E. Ohtsuka, H. Takashima, and M. Ikehara, Tetrahedron Lett., 1982,23, 3081.

lS9 W. IRo


189

~ t y r e n e l ~ and ~ - l ~poly~tyrene-Teflon,~~~ ~ and porous glass.166,168 The chemical processes involved in these studies have been described previously and do not require reiteration. All used the ‘phosphate’ procedure, and most extended the chain in the 5’-direction from a polymer-bound 3’-terminus. In almost every case the dimethoxytrityl group was used to block the 5’-OH function of the unit used to lengthen the chain, and the 2- or 4-chlorophenyl group to protect the internucleotidic link. In some cases the chain was lengthened in the 3’-direction from a polymer-bound 5’-terminus, using monomer units of type (97).lesJs7 This has the advantage that no sulphonation of a polymer-bound hydroxy terminus can occur in the condensation stage. A 3 % solution of benzenesulphonic acid in DMF-dichloromethane has been found to be effective for the detritylation of oligodeoxyribonucleotidesattached to a solid support, and it is also reported that coupling using MS-nt may be performed at 60 “C far more rapidly than at room temperature, without a significant increase in the quantity of by-products formed, allowing coupling in an automated system to be speeded up to the point where it is competitive with the rate of synthesis by the ‘phosphite’ procedure.16 Ura

B

C B r 3CH 2O-!-O-+O-!/-O~OR3 I 4-Me

C-2-C1C6H30 3 OC6H4C 1- 2 1 ( 9 8 ) R = MThp, R2 = H , R3 = CH3CO(CH2),C0

(100) R1 = A c , R2 = OMThp, R3 = CH3CO(CH2)2C0 ( 1 0 2 ) R1 = A c , R2 = H , R3 = DMTr B

B

R ~ O DMTrO OC6 H4C 1- 2

(99) R2,

OC6H4C1-2

R3 as i n ( 9 8 ) (103)

( 1 0 1 ) R2,

R3 as i n ( 1 0 0 )

A. N. Sinyakav, A. I. Lomakin, V. F. Yamshchikov, and S. G. Popov, Bioorg. Khim., 1982, 8, 490 (Chem. Abstr., 1982, 97, 127 985). 165 R. Belagaje and C. K. Brush, Nucleic Acids Res., 1982, 10, 6295. 166 V. A. Efimov, S. V. Reverdatto, and 0. G. Chakhmakhcheva, Nucleic Acids Res., 1982, 10, 6675. 16’ A. Rosenthal, D. Cech, V. P. Veiko, T. S. Orezkaja, E. A. Kuprijanova, and Z. A. Shabarova, Tetrahedron Lett., 1983, 23, 1691. 16* H. Koster, A. Stumpe, and A. Wolter, Tetrahedron Lett., 1983, 24, 747. T. P. Patel, T. A. Millican, C. C. Bose, R. C. Titmas, G. A. Mack, and M. A. W. Eaton, Nucleic Acids Res., 1982,10, 5605. 164

190


In an elegant refinement of solid-phase oligonucleotide synthesis, standard solution phosphotriester methods are employed to synthesize (98), which is then treated with zinc to remove the tribromoethyl group, and coupled to a primary hydroxy group of cellulose or derivatized polystyrene using TPS-nt. The laevulinyl group is then removed from the 5’-position of the deoxynucleoside unit, and the chain extended in the 5’-direction by coupling with dimer (or larger) blocks of type (99). The use of hydrazine to remove the laevulinyl group between each coupling step eliminates the danger of depurination attending acidic detritylation. Finally, all base- and phosphate-protecting groups may be removed by washing the polymer-bound product with appropriate deblocking reagents before the methoxytetrahydropyranyl group is removed from the 2’-hydroxy group of the polymer-bound uridine terminus with acid and the unblocked oligodeoxyribonuckotide released by treatment with alkali or with ribonuclease A.170Essentially the same procedure has been used for solid-phase synthesis of an RNA fragment, starting with protected dimer (100) and coupling to protected blocks of type (101).171 In another variation of oligodeoxyribonucleotide synthesis, the terminal unit (102) .was synthesized and bound to polystyrene as described above, and following detritylation the chain was elongated by treatment with a hydroxybenzotriazole ester of type (103) in the presence of N-methylimida~ole.~~~ The ‘phosphite’ method of solid-phase oligonucleotide phosphotriester synthesis has received much attention. One simple practical method employing a derivatized silica gel support performs all the deblocking, coupling, and washing steps in conical centrifuge Following each step, the silica gel is removed from the suspension by centrifugation, and the supernatant decanted. 5’-0-Dimethoxytrityl ribonucleosides may be selectively benzoylated at the 2’-position using benzoyl chloride in pyridine at -45 “C, and subsequently converted to the 2’-O-benzoylated equivalent of (25). The resulting units may conveniently be used in the normal ‘phosphite’ synthetic and deblocking procedures for oligodeoxyribonucleotides with little modification, permitting the preparation of oligonucleotides containing both ribo- and deoxyribo-monomers, mixed as desired.174In two studies, the 5’-hydroxy group of a nucleosidic or oligonucleotidic fragment immobilized via its 3’-terminus has been activated in situ using methylphosphorodichloridite17s or methylphosphorobis(tetrazolidite)176 in large excess, and then treated with a base-protected 5’-0-dimethoxytrityl-2’deoxynucleoside. The danger of cross-linking the 5’-hydroxy termini is small, particularly if low loading on the silica support and a large excess of coupling 170

171

G. A. van der Marel, J. E. Marugg, E. de Vroom, G. Wille, M. Tromp, C. A. A. van Boeckel, and J. H. van Boom, Recl. Trav. Chim.Pays-Bas, 1982,101, 234. G. A. van der Marel, G. Wille, and J. H. van Boom, Red. Trav. Chim. Pays-Bas, 1982. 101, 241.

17a

173

J. E. Marugg, G. A. van der Marel, E. de Vroom, D. Bosch, and J. H. van Boom, R e d . Trav. Chim. Pays-Bas, 1982, 101, 411. P. L. de Haseth, R. A. Goldman, C . L. Cech, and M. H. Caruthers, Nucleic Acids Res.. 1983, 11, 773.

T. Kempe, F. Chow, W. I. Sundquist. T. J. Nardi. B. Paulson. and S. M. Peterson. Nucleic Acids Res., 1982, 10, 6695. 176 178

K. Jayaraman and H. McClaugherty, Tetrahedron Left., 1982, 23, 5377. T. M. Cao, S. E. Bingham, and M. T. Sung, Tetrahedron Lett., 1983,24, 1019.


I91

agent are used, and very high yields have been claimed for this procedure. The use of methyldichlorophosphine instead of methylphosphorodichloriditein the ‘phosphite’ synthetic procedure for oligonucleotides on a controlled pore glass support has permitted the synthesis of a number of oligodeoxynucleoside methy1pho~phonates.l~~ A technique for the rapid preparation of hexanucleotide triester blocks for use in polydeoxyribonucleotide synthesis, which is based on simple extractive purification of the comparatively hydrophobic desired products of each coupling step, has been described.17*Another stratagem utilizing hydrophobic properties to aid purification of the products of solution syntheses of oligodeoxyribonucleotides lies in constructing a large hydrophobic liquid phase carrier (octanedioic acid doubly esterified by phenolic groups on substituted trityl chloride molecules), upon which the phosphotriester oligonucleotide synthesis is performed, which is readily separated from all unreacted reagents and by-products of condensation by Sephadex gel filtration c h r ~ m a t o g r a p h y . ~ ~ ~ Short oligonucleotides containing phosphoramidate internucleotide links have been synthesized by condensing adenosine 5’-phosphorimidazolidate with 3’-amino-3’-deoxyribonucleosides.180The bis(3’ -+5’) cyclic dinucleotides cvpvp.’ and ‘ApUpl have been prepared by phosphotriester methods, and are found to be linear competitive inhibitors of initiation by DNA-dependent RNA polymerase from E. coli when poly(dA) and poly d(A-T), respectively, are used as templates.181 A number of tRNA fragments containing modified nucleosides have been prepared either by standard phosphodiester or phosphotriester methods using nucleotides containing modified bases or by direct modification of oligonucleotides; DpApG was prepared by hydrogenation of UpApG over platinum oxide, and m7GpUpC by methylation of GpUpC with dimethyl sulphate at pH 4.1e2 Phosphorylation and condensation reactions between appropriately protected d(TpT), 1,2-di-0-rnyristoyl-sn-glycerol,and bis( 1,2dimethyletheny1ene)pyrophosphate (104) have been used to introduce 1,2-di-0acyl-sn-3-glycerophosphoricacid at the 3’- and 5’-termini of d(TpT).les Me

Me

0

0

N. D. Sinha, V. Grossbruchhaus, and H. Koster, Tetrahedron Lett., 1983, 24, 877. G. R. Gough, M. J. Brunden, J. G. Nadeau, and P. T. Gilham, TetrahedronLett., 1982. 23, 3439. 170 J. Biernat, A. Walter, and H. Koster, Tetrahedron Lett., 1983, 24, 751. lR0 A. V. Azhaev, A. Azals, A. A. Kraevskii, N. V. Gnuchev, and B. P. Gottikh. Bioorg. Khim., 1982, 8, 1218 (Chem. Abstr., 1983, 98, 34893). lal C.-Y. J. Hsu and D. Dennis, Nucleic Acids Res., 1982,10,5637. laaE. Ohtsuka, J. Matsugi, H. Takashima, S. Aaki, T. Wakabayashi, T. Miyake, and M. Ikehara, Chem. Pharm. Bull., 1983, 31, 513. la3 F. Ramirez, S. B. Mandal, and J. F. Marecek, J. Am. G e m . SOC.,1982, 104, 5483. 177

17*

192


In order to gain information on the possible consequences of alkylation of the phosphate groups in nucleic acids, two decamers d[CpCpApApGp(Et)ApTpTpGpGp], each containing a single diastereoisomer of the chiral ethyl phosphotriester group, have been synthesized using phosphotriester methods, and oligo(dA) tails attached to each using dATP and terminal deoxynucleotidyl transferase. Both oligomers were tested as templates for DNA polymerase I from E. coli using d[(pT),pCpC] primer, and were found to depress the rate and extent of polymerization, compared with that found using an unmodified control template, but to different degrees. Ethyl phosphotriester lesions may therefore suppress the rate of replication of cellular DNA.184 A number of non-ionic oligonucleotide analogues containing methyl or ethyl groups at all the phosphotriester links, d [{Tp(Me) }aT(Ac)],d [{Tp(Et) },TI, d [{Gp(Et) },GI, and d [{Ap(Et) },A] have been prepared, and their binding to complementary polyribo- and polydeoxyribo-nucleotides investigated. The complexes with polydeoxyribonucleotides were found to be the more thermally stable, irrespective of the nature of the heterocyclic base or the size of the alkyl group.Ia5 Lack of space precludes mention of many uses being found for synthetic oligonucleotides, but the interested reader may care to consult reviews on the use of synthetic gene fragments in genetic engineeringlS6and in site-directed mutagenesis.187 A review on the preparation of oligonucleotides by metal ion-catalysed polymerization of activated nucleotides has appeared.lB8 In a study of the polymerization of 2-aminoadenosine 5’-phosphorimidazolidate and 2-aminoat pH 8 and 20 “C in the presence adenosine 5’-phosphoro-(2-methyl)imidazolidate of magnesium, only dimers and trimers, containing predominantly 2’-5’ links, were formed as major In contrast, guanosine 5’-phosphoro-(2methy1)imidazolidate undergoes template-directed condensation on poly(C) to give mainly 3’-5’-linked oligoguanylic acid in high yield.lso While the corresponding reactions cannot be performed for other cases where monomer and homopolymer might be expected to base-pair, due to the homopolymers forming triple helices, stable self-structure, etc., it has been found that in reactions using mixtures of nucleoside 5’-phosphoro-(2-methy1)imidazolidatesin lutidine buffer at pH 8, 0 “C, random copolymers containing cytosine as the major base component facilitate the incorporation of substantial amounts of a base other than guanine into oligomeric products if and only if the complementary base is present in the template. In other words, the reaction ‘models’ RNA polymerase, although the fidelity of incorporation cannot be determined unambiguously. The oligomeric products have mean chain lengths of 6-10 units, and contain a P. S. Miller, S. Chandrasegaran, D. L. Dow, S. M . Pulford, and L. S. Kan, Biochemistry, 1982,21, 5468. lE5 N. K. Danilyuk, V. A. Petrenko, P. I. Pozdnyakov, S. G . Popov, G. F. Sivolobova, and T. N. Shubina, Mol. Biol. (Moscow), 1982,16,116 (Chem. Abstr., 1983,98,54 380). 186 J. E. Davies and H. G. Gassen, Angew. Chem., Znt. Ed. Engl., 1983, 22, 13. 18’ M. Smith, Trends Biochem. Sci. (Pers. Ed.), 1982, 7 , 440; T. Harris, Nature (London), 1982, 299, 298. la* H. Sawai, Y&i Gosei Kagaku Kyokaishi, 1982, 40, 725 (Chem. Abstr.. 1982.97. 163 340). lS9 T. R. Webb and L. E. Orgel, Nucleic Acids Res., 1982, 10, 4413. lg0 T. Inoue and L. E. Orgel, Science, 1983,219, 859. lR4


193

high proportion of 3’ -+5’ links. The decamer d(T-G-G-C-C-A-A-G-C-Tp), which associates into self-complementary concatemer-type duplexes, has been converted to its 3’-terminal phosphorimidazolidate which is oligomerized efficiently at pH 8 in a buffer containing N-methylimidazole. Conditions in which the duplex is stable are essential for the polycondensation. Oligomers up to the heptamer, joined by 3’-5’ phosphodiester links, are formed.lal When d(pT)lo is annealed to poly(dA) and irradiated with light > 290 nm in buffer at pH 7 and 0 “C, high molecular weight oligomers corresponding to integral multiples of d(pT)loare formed.’ 92 The reaction involved, which does not occur in the absence of poly(dA), is thought to be photodimer formation between the terminal thymine bases on adjacent d(pT)lo units annealed to poly(dA). Photoreversal at 254 nm has been demonstrated. Such a reaction may have been of significance in ligating oligomers with thymine termini in ‘prebiotic’ conditions. Phosphotriester synthetic methods have been used to prepare a large number of analogues of ‘2-5A’ [(2’-5’)pppApApAl and ‘core trimer’ [(2’-5’)ApApA], containing 3’-deoxyadenosine (cordycepin) in place of adenosine and with cordycepin or another sugar-modified adenosine analogue at the 3’-terminus,lQ3 or containing a~a-adenosine,~~~ and core trimer and its tetramer analogue have been prepared with inosine replacing aden0sine.l OK Cordycepin analogues of ‘2-5A’ have also been prepared by oligomerization of N6-benzoyL3’-deoxyadenosine 5’-monophosphate using DCC, separation of the products (up to the hexamer) by ion-exchange chromatography, and phosphorylation to the 5’-triphosphate using carbonyldiimida~ole.~~~ The ‘2-5A’ analogue containing 1 ,N6-ethenoadenosinein place of adenosine has been prepared by treating (2’-5’)(pA), with chloroacetaldehyde, followed by 5’-pyrophosphorylation as above.lQ7These, and other analogues including higher homologues of ‘2-5A’ and ‘core trimer’, and analogues bearing a 5’-S-methylphosphorothioategrouplo* have been tested variously for their stability to cellular nucleases, and their ability to inhibit protein synthesis and cell growth, and to activate ‘2-5A’dependent endoribonuclease (also known, confusingly, as ribonuclease F and ribonuclease L).193JB4J96-200 The xylu-adenosine analogue of core trimer, in particular, is a stable and powerful inhibitor of cell growthla3and of the replication of HSV-1 and HSV-2.201Interestingly, ‘2-5A’ inhibits both cellular and M. G. Ivanovskaya and M. B. Gottikh, Bioorg. Khim., 1982,8, 940 (Chem. Abstr., 1982, 97, 163 392); Z. A. Shabarova, M. G . Ivanovskaya, and M. G. Isaguliants, FEBS Lett., 1983, 154, 288. lg2 R. J. Lewis and P. C. Hanawalt, Nature (London), 1982, 298, 393. Is3 D. A. Eppstein, Y. V. Marsh, B. B. Schryver, M. A. Larsen, J. W. Barnett, J. P. H. Verheyden, and E. J. Prisbe, J. Biol. Chem., 1982,257,13 390. lS4 M. Kwiatkowski, C. Gioeli, J. Chattopadhyaya, B. Oeberg, and A. F. Drake, Chem. Scr., 1982, 19, 49 (Chem. Abstr., 1982, 97, 56 171). l g 6 R. Charubala and W. Pfleiderer, Tetrahedron Lett., 1982, 23, 4789. lg6 H. Sawai, J. Imai, K. Lesiak, M. I. Johnston, and P. F. Torrence, J. B i d . Chern., 1983, 258, 1671. 19’ K. Lesiak and P. F. Torrence, FEBSLett., 1983,151,291. Is’

M. C. Haugh, P. J. Cayley, H. T. Serafinowska, D. G. Norman, C. B. Reese, and I. M. Kerr, Eur. J. Biochem., 1983,132, 77. l e a C. Lee and R. J. Suhadolnik, FEBS Lett., 1983,157,205. S . Rappaport, G. Arad, Y. Lapidot, and A. Panet, FEBSLert., 1982,149,47. 201 D. A. Eppstein, J. W. Barnett, Y. V. Marsh, G. Gosselin, and J.-L. Imbach, Nature (London), 1983,302, 723.

Is*

1 94


vaccinia viral mRNA(guanine-7)methyltransferases, the enzymes responsible for methylat ion during the ‘capping’ of mRNA, while its 3’-O-methyladenosinecontaining analogue selectively inhibits the viral enzyme.2o2Oxidation of (2’-5’)(pA), (n = 1 or 2) with sodium periodate, followed by condensation with n-hexylamine and reduction of the resulting material with sodium cyanoborohydride gives analogues (105) in which the 3’-terminal adenosine has been converted to the N-hexylmorpholine The 5’-triphosphate of (105 ; n = 3) is highly resistant to degradation by L-cell extracts, and a most potent inhibitor of protein synthesis and activator of ‘2-5A’-dependent endoribonucIease, showing that extensive modification at the 3’-terminus may not destroy the biological activity of ‘2-5A’, but even enhance it. A de

I

n-C H 6 13 (105) n = 2 or 3

Enzymatic Synthesis.-It has been demonstrated that, where the synthesis of longer double-stranded DNA segments is required, the amount of chemical synthesis involved may be reduced by more than 40 % by synthesizing chemically two 40-mers (say), each of which is part of the sequence of the two different strands but has an overlap sequence nine or ten bases long at the 3’-terminus complementary to that on the other strand, annealing them, and using the resultant part-duplex as a template-primer for Klenow fragment of DNA polymerase I to complete the duplex by copy synthesis.204 Poly(7-deazaguanylic acid) has been prepared by polymerization of 7-deazaguanosine 5’-diphosphate using polynucleotide phosphorylase from Micrococcus luteus, and its ability to form duplexes with complementary polynucleotides compared with that of poly(G). It is cleaved by ribonuclease T1 and also by nuclease S1, showing that unlike poly(G), it forms no selfstructure in aqueous solution.206 A copolymer containing alternating residues of 2’-deoxyadenosine and (E)-5(2-bromovinyl)-2’-deoxyuridinehas been synthesized from the corresponding 5’-triphosphates using DNA polymerase I from E. coli and a poly[d(A-T)]primer.2osThe product had lower thermal stability than poly[d(A-T)] but was 202

B. B. Goswamj, R. Crea, J. H. van Boom, and 0.K. Sharma, J. Biol. Chem., 1982,257, 6867.

203 204

J. Imai, M. I. Johnston, and P. F. Torrence, J. Biol. Chem., 1982, 257, 12 739. J. J. Rossi, R. Kierzek, T. Huang, P. A. Walker, and K. Itakura, J. Biol. Chem., 1982, 257, 9226.

206

F. Seela, Q.-H. Tran-Thi, and D. Franzen, Biochemistry, 1982, 21, 4338.

J. Sagi, A. Czuppon, M. KajtBr, A. Szabolcs, A. Szemzo, and L. Otvos, Nucleic Acids Res., 1982, 10, 6051.


195

comparatively resistant to nucleases, and showed higher activity as a template for DNA synthesis. Poly(2-aminopurine-9-~-~-deoxyribonucleot~de)~~~ and poly(2-aminodeoxyadenylic acid)207s208 have been prepared by polymerization of the corresponding nucleoside 5’-triphosphates using terminal deoxynucleotidyl transferase, and their spectroscopic and enzymatic properties investigated. Replacement of adenine in poly(dA) by 2-aminoadenine stabilizes the helical structures formed with poly(dT) and poly(U), while replacement by 2-aminopurine results in destabilization. Terminal deoxynucleotidyl transferase is much used to attach homopolymer tails to DNA restriction fragments prior to ligation and subsequent cloning, and the characteristics of this tailing reaction have been investigated using blunt-ended and 3’-overhang-ended DNA as substrates.20gThe latter was ‘tailed’ rapidly and efficiently, while the blunt-ended DNA was utilized only inefficiently, While most syntheses of oligoribonucleotides have used phosphotriester techniques, the enzymatic synthesis of a 21-mer has been reported.210Polynucleotide phosphorylase, in combination with ri bonucleases where necessary, was used to prepare six oligomers of three to five units length, which were then ligated using T4 RNA ligase. The yields in the ligase-catalysed reaction varied from 35% to nearly quantitative. In order to define the effect of acceptor oligoribonucleotide sequence on the reaction catalysed by T4 RNA ligase, an extensive study has been performed using trinucleoside bisphosphates of varying sequence as acceptors, and pNp (N = A,C,U,G) to model single-step synthesis, or pUpUpUpCp to model block synthesis, as donors.211With good donors such as pup, pCp, or the oligomer, the ligation step becomes rate-limiting and an excess of the 5’-adenylated donor is formed in solution. The use of h.p.1.c. on aminopropylsilyl ion-exchange and octadecylsilyl reverse-pbase columns is particularly useful for the isolation and analysis of products of T4 RNA ligase-catalysed reactions.2122’(3’)-O-~~-Alanyl hexainosinic acid has been prepared by condensing the orthoester of N-benzyloxycarbonylalanine with 5’-IMP, and coupling the product to (Ip),I using T4 RNA l i g a ~ e .T4 ~l~ DNA ligase has been bound to Sepharose 4B activated by treatment with 2,2,2trifluoroethanesulphonyl chloride or cyanogen bromide, and the immobilized enzymeused to ligate blunt-ended and sticky-endedDNA restriction T4 Polynucleotide kinase transfers thiophosphate rather slowly from ATPyS to the 5’-hydroxy terminus of d(C-T-T-T-C-C-A). The product can then be S-alkylated, permitting the placement of reactive groups suitable for affinity labelling purposes at the 5’-terminus of the oligonucleotide.216 An RNA ligase activity present in wheat germ and Chlamydumonas is able 207 209

210

K. H. Scheit and H.-R. Rackwitz, Nricleic Acids Res., 1982, 10, 4059. F. B. Howard and H. T. Miles, Biopolymers, 1983,22,597. A. M. Michelson and S. H. Orkin,J. Biol. Chem., 1982,257,14 773. M. Krug, P. L. de Haseth, and 0. C. Uhlenbeck, Biochemistry, 1982, 21, 4713. E. Romaniuk, L. W. McLaughlin, T. Neilson, and P. J. Romaniuk, Eiir. J. Biochem., 1982, 125, 639.

212 219 214

215

L. W. McLaughlin and E. Romaniuk, Anal. Biochem., 1982,124,37. A. T. Profy, K.-M. Lo, and D. A. Usher, Nucleic Acids Res., 1983, 11, 1617. L. Biilow and K. Mosbach, Biochem. Biophys. Res. Commun., 1982,107,458. S . I. Oshevski, FEBS Lett., 1982, 143, 119.

196


to circularize linear potato tuber spindle viroid RNA bearing a 5’-phosphate group at one end and a 2’,3’-monophosphate at the other, with the formation of a 2’-phosphomonoester, 3’-5’-phosphodiester at the point of ligation, as demonstrated by labelling the 5’-terminal phosphate using [y-32P]ATP,and analysing the products of nuclease digestion following ligation.21a A similar RNA ligase activity in HeLa cell extracts converts linear polyribonucleotides bearing 5’-hydroxy and 2’,3’-monophosphate termini to covalently closed circle~.~ This ~ ’ enzyme will also accept molecules bearing a 3’-terminal phosphate as substrates, in which case ligation is preceded by ATP-dependent conversion to the 2’,3’-monophosphate by a novel activity, RNA 3’4erminal phosphate cyclase. A remarkable recent discovery involves a 413-nucleotide-long non-coding intervening sequence (IVS) in immature ribosomal RNA (pre-rRNA) from Tetrahymena thermophila. In the presence of Mg2+ions and GMP cofactor, the IVS is precisely excised and the coding regions joined, without the presence of protein!218The IVS itself, to which the GMP cofactor has been attached at the 5’-end, then undergoes autocatalytic cyclization with loss of the 5’-terminal pentadecaribonucleotide. The sequence of events appears to be as follows : the 3’-OH of the GMP cofactor attacks a UpA sequence at the 5’-end of the IVS, cleaving it to form a uridine 3’-terminus and a new 5’-pGpA terminus. The 3’-OH of the uridine then attacks and cleaves a GpU sequence at the 3’-end of the IVS, completing the excision of the non-coding IVS by forming a UpU link and leaving the IVS with structure 5’-pGpA.. . .G-3‘. The 3‘-OH of the 3’-terminal guanosine then attacks a UpA sequence 15 nucleotides from the 5’-end of the excised IVS to form a GpA link, thus cyclizing the molecule with loss of the pGpA. . . .U 15-mer. Thus RNA can perform autocatalytic selfsplicing processes. These findings are bound to stimulate much further investigation, especially since evidence has been presented that the processes also occur in vivo.21aThe guanosineresidues must be bound and orientated highly specifically in order to attack the UpA links. It is noteworthy that while phosphodiester bonds are made and broken, the overall number remains the same throughout. 2’-5’-Oligoadenylate synthetases from rabbit reticulocyte lysates220and particularly from mouse L-cells221have been used to prepare a quite remarkable number of analogues of ‘2-5A’ from the corresponding nucleoside 5’-triphosphates. Evidently the enzymes are less substrate-specific than had previously been thought, or else a number of enzymes possessing this activity are present in the tissues. Y. Kikuchi, K. Tyc, W. Filipowicz, H. L. Sanger, and H. J. Gross, Nucleic Acids Res., 1982, 10, 7521. 217 W. Filipowicz, M. Konarska, H. J. Gross, and A. J. Shatkin, Nucleic Acids Res., 1983, 11, 1405. 218 A. J. Zaug, P. J. Grabowski, and T. R. Cech, Nature (London), 1983,301, 578; A. J. Zaug and T. R. Cech, Nucleic Acids Res., 1982, 10, 2823; R. Lewin, Science, 1982, 218, 872. 21s S. L. Brehm and T. R. Cech, Biochemistry, 1983,22, 2390. 220 R. J. Suhadolnik, Y. Devash, N. L. Reichenbach, M. B. Flick, and J. M. Wu, Biochem. Biophys. Res. Commun., 1983, 111, 205. 221 B. G. Hughes, P. C. Srivastava, D. D. Muse, and R. K. Robins, Biochemistry, 1983, 22. 2116; B. G. Hughes and R. K. Robins, ibid., p. 2127. 216

Nucleo tides and Nucleic Acids

197

5 Other Studies Af€inity Separation.- Affinity electrophoresis combines the principles of electrophoretic separation and biospecific ligand interaction, and nucleotides may be conveniently used in the technique. Beaded agarose gel is oxidized with periodate, and an amino-substituted ligand, such as the 5’-(4-aminophenyl)ester of uridine 3’,5’-bis(phosphate), condensed with the resulting aldehydic groups. After reduction to render the binding irreversible, the gel is melted and mixed with the polymerization mixture normally used for polyacrylamide gel electrophoresis, to give, after polymerization, a gel containing a homogeneous distribution of biospecific ligands. Otherwise the amino ligand may be bound to CNBractivated Sepharose beads, which are used to form a beaded layer in the polyacrylamide The specific affinity of a biomolecule for the immobilized ligand suppresses its mobility during electrophoresis, permitting separation of components which do not otherwise separate on gels. In addition the intercalator acriflavinemay be immobilized to form an affinity gel for double-stranded DNA fragments. If a normal acrylamide polymerization is performed in the presence of ethidium bromide, the drug seems to become covalently linked to the acrylamide matrix during the polymerization reaction via the methylenebisacrylamide spacer arms, and by performing this process in the presence of a particulate polyacrylamide matrix (Bio-Gel P4 beads), ethidium beads suitable for nucleic acid fractionation are The immobilization of DNA on CNBr-activated and on diazotization-activated macroporous supports has been compared with regard to the efficiency of coupling, the stability and accessibility of the coupled DNA, and the degree of base mismatching in subsequent hybridization, generated by the coupling procedure. Immobilization on 2-diazophenylthioether-derivativesof Sephacryl S500 was identified as the method of choice, giving high coupling efficiency and negligible mismatch effects.224 Oxidation of Sephadex G-50 or Enzacryl polyacetal using periodate affords aldehydic polymers with which the primary amino groups of the amino acid moieties in aminoacyl-tRNA form Schiff bases, and coupling is rendered irreversible by reduction with sodium cyanoborohydride. Hence, only the aminoacylated tRNA molecules in a mixture are retained, and the tRNA may subsequently be released by washing with ammonium bicarbonate buffer, thus affording a convenient method for the separation of isoacceptor tRNA species.225 ‘Capped’ RNA chains are bound specifically by 3-aminophenylboronate-substituted agarose, the binding being most effective above pH 8. The boronate binds specifically to the cis-diol of the 7-methylguanosineresidue in the cap, and the positive charge on the residue is necessary for efficient binding.226 When [3SS]thiophosphatewas added to a cell culture infected with simian virus SV40, and the viral DNA then extracted, the newly synthesized SV40 223

224 2z5

V. Horejsi, M. TichB, P. Tichjr, and A. Holjl, Anal. Biochem., 1982, 125, 358. A. T. Vacek, D. P. Bourque, and N. G. Hewlett, Anal. Biochem., 1982,124,414. H. Bunemann, P. Westhoff, and R. G. Herrmann, Nucleic Acids Res., 1982, 10, 7163; H. Bunemann, ibid., p. 7181. Q.-S. Wang and J. T.-F. Wong, Anal. Biochem., 1983, 131, 360. H.-E. Wilk, N. Kecskemethy, and K. P. Schafer, Nucleic Acids Res., 1982. 10. 7621.

198


DNA contained thiophosphate groups and could be selectively recovered on organomercurial columns. The inorganic thiophosphate must therefore enter the intracellular nucleotide pools, permitting the formation and isolation of thioderivatized DNA without the requirement of adding preformed thiophosphate n u c l e o t i d e ~ The . ~ ~ ~cave described previously lo*is, however, still relevant ! P1,P5-Di(adenosine-5’)pentaphosphatehas been used for the specific affinity elution of adenylate kinase from a number of proteins bound unspecifically to blue-Sepharose in a simple, rapid purification.228 Affinity Labelling.-When the [y-(4-azido)anilidates] of ATP and ITP are irradiated at 313 nm under argon, U.V. and lH n.m.r. data suggest that an intermediate is formed which reacts readily with nucleophiles, the rate of reaction being qualitatively correlated with nucle~philicity.~~~ If dilute hydrochloric acid is added, benzoquinone and ATP are isolable, and this, and other evidence, has prompted the suggestion that the photoaffinity label generated on irradiation is actually the y-quinonediimine derivative of ATP (106). Affinity labelling using this species would tend to be restricted to nucleophilic groups, and not show the low specificity of labelling by a nitrene. The [y-(4-azido)anilidate] of ATP has been used for the affinity labelling of leucyl-tRNA synthetases from Euglena g r a c i l i ~30. ~

As usual, most photoaffinity labelling studies employing azides have used base-substituted nucleotide analogues. 8-Azido-CAMPhas been used to probe CAMP-binding proteins in microtubule and 8-azido-ATP to label ATP-binding sites of sarcoplasmic and of the @-sub-unitof phosphorylase k i n a ~ in e ~a ~study ~ which also employed periodate-oxidized 8-azidoATP. 8-Azido-GTP has been used to label the GTP-binding site of the regulatory component of adenylate c y c l a ~ eand , ~ ~2-azido-ADP ~ to label a tight nucleotidebinding site on the @-sub-unitof chloroplast coupling factor CFl.235Other studies have utilized arylazido groups linked - if one disregards the possibility of transacylation - to the 3’-position of the sugar moiety. 3’-(4-Azidobenzoyl)-GTP 227

228

228

230 231 2a2

233 234

236

I. Y.-C. Sun and V. G. Allfrey, Proc. Natl. Acad. Sci. USA, 1982, 79, 4589. 0. Biirzu and S. Michelson, FEBS Lett., 1983,153,280. A. G. Badashkeyeva, T. S. Gall, E. V. Efimova, D. G . Knorre, A. V. Lebedev, and S. D. Mysina, FEBS Lett., 1983, 155, 263. R. Krauspe and 0. I. Lavrik, Eur. J , Biochem., 1983,132, 545. D. Soifer, K. Mack, and D. A. Chambers, Arch. Biochem. Biophys., 1982, 219, 388. K. P. Campbell and D. H. MacLennan, J. Biol. Chem., 1983, 258, 1391. M. M. King, G . M. Carlson, and B. E. Haley, J. Biol.Chem., 1982,257, 14 058. J. K. Northrup, M. D. Smigel, and A. G. Gilman, J. Biol. Chem., 1982,257, 11 416. J. J. Czarnecki, M. S. Abbott, and B. R. Selman, Proc. Natl. Acad. Sci. USA, 1982, 79. 7744.


199

and periodate-oxidized GTP have been used to label the exchangeable GTPbinding site of tubulin, the a- and P-sub-units being labelled in nearly equal amounts.236The chromium complex of 3’-0-[3-(4-azido-2-nitrophenyl)amino]propionyl-ATP has been‘foundto label specificallythe a-sub-unit of “a+ K+]A T P ~ S ~and , ~ ~in’ a photoaffinity cross-linking study, 3’-0-[3-(4-azido-2-nitrophenyl)amino]propionyl-8-azido-ATP has been used to form cross-links between the a- and P-sub-units of oligomycin-sensitive ATPase from beef heart mitoch~ndria.~ * Direct photoaffiity labelling using unmodified nucleotides has also been used widely. For instance, the catalytic site of sub-unit M1 of mouse ribonucleotide reductase is labelled by irradiation in the presence of CDP,23B and an allosteric site on the same unit using dATP.240Sub-unit B1 of ribonucleotide reductase from E. coli may be labelled using dATP or, more efficiently, dTTP.241 Both dATP and ATP have been used to label an ATPase/dATPase activity associated with a fraction from Drosuphila nuclei,242and cGMP to label a cytoplasmic cGMP-binding protein in embryos of the same organism.243 ‘2-5AY-dependentendoribonucleases in cell extracts have been labelled by direct photoaffinity labelling using (2’-5’)ppp(Ap)3Cp,244and tRNAp’ has been cross-linked to 16s RNA at the ribosomal P In this last study, the residues involved were identified as a cytidine residue on the 16s RNA and a 5-carbomethoxyuridine residue on tRNAp’, probably linked by cyclobutane dimer formation. Oxidation of ADP using periodate, followed by partial reduction with borohydride, affords a mixture of the fully reduced bis(hydroxymethy1)product and the semialdehydic reduction intermediate. By dint of comparison with model compounds using lH n.m.r. spectrometry, it has been shown that the first reduction step takes place at C-3’, to give (107) (which will prefer to cyclize to the hemia~etal).~*~ It is not clear why preferential reduction at C-3’ occurs; either the aldehydic group at this position is more reactive per se, or it is more accessible to borohydride. It seems likely that (107) and its analogues could prove to be useful new affinity labels. When periodate-oxidized ATP (oATP) is kept at room temperature and at neutral pH, the tripolyphosphate chain is lost, to form (108), which has been identified and characterized using IH n.m.r. spectroscopy. The rate of decomposition of oATP was found to increase with the pH value. In a study in which oATP was used as an affinity label for mitochondria1 ATPase, becoming

+

236 287

238

R. B. Maccioni and N. W. Seeds, Biochemistry, 1983,22, 1572. K. B. Munson, Biochemistry, 1983, 22, 2301. H.-J. Schafer, L. Mainka, G . Rathgeber, and G. Zimmer, Biuchem. Biophys. Res. Commun.. 1983,111, 732.

230

240 241

242 243

244 245

246

I. W. Caras, T. Jones, S. Eriksson, and D. W. Martin, jun., J. Biol. Chem., 1983,258.3064. I. W. Caras and D. W. Martin, jun., J. Biol. Chern., 1982,257,9508. S. Eriksson, J. Biol. Chem., 1983,258, 5674. M. Berrios, G . Blobel, and P. A. Fisher, J. Biol. Chem., 1983, 258, 4548. A. S. Olsen, B. M. Breckenridge, and M. M. Sanders, Anal. Biochem., 1982,126,306. G . Floyd-Smith, 0. Yoshie, and P. Lengyel, J. B i d . Chem., 1982, 257, 8584. J. B. Prince, B. H. Taylor, D. L. Thurlow, J. Ofengand, and R. A. Zimmermann, Pruc. Natl, Acad. Sci. USA, 1982, 79, 5450. L. P. Rosenthal, H. P. C. Hogenkamp, and J. W. Bodley, Carbohydrate Res., 1982,111,85.

200

Organophosphorus Chemistry A de

HOH2C

Ade

CHO

(107)

(108)

covalently bound to the a and p sub-units, it was observed that (108) inhibited the enzyme faster than OATP.~~’ It was also thought that following binding to the enzyme, most of the oATP lost its tripolyphosphate chain, an observation which accords exactly with the findings of another in which oADP was used for affinity labelling of NAD+-dependent isocitrate dehydrogenase, when comparison of the stoicheiometry of reaction using [14C]oADPand [32P]oADP showed loss of the diphosphate moiety. Several interesting points arise: if (108) is formed from oATP prior to binding to the enzyme, it will lack any specificity of binding conferred on oATP by the binding site for the tripolyphosphate chain. Moreover, (108) will be a good substrate for Michael addition, and may therefore bind to a number of different nucleophilic groups on the enzyme. This could explain the fast rate of inhibition by (108). The structure of the initial adduct formed between oATP and the enzyme is also of interest. Either the Schiff base (109) or the morpholine derivative (110) could be formed. The high reactivity of the 3’-aldehyde group noted above may favour initial formation of (log), but this could readily become converted to (110) by hydration of the imine followed by cyclization. Loss of triphosphate should occur readily from (log), since the (2-4’proton will have higher acidity conferred by any nonhydrated imine than by a hydrated aldehydic group. However, loss of triphosphate from (110) could occur by loss of water from the conjugate acid of (110), isomerization to the enamine, and elimination, and this sequence of events has been suggested from kinetic studies on compounds of this type.249Irrespective of the path followed, hydration of the product of elimination should eventually mean that (1 11) is formed in accord with the observation that no reduction of the enzyme-oADP adduct could be The same product (1 11) would be formed by direct binding of (108), formed by prior decomposition, to the amine ! It is clear that periodate oxidized nucleotides must be used circumspectly for affinity labelling. The purity of the material must be checked before use, and radiolabelling in the polyphosphate chain should be avoided, since spurious results may be obtained. The complications should be avoidable, however, by using a reagent such as (107). Of the less widely used analogues of ATP, 6-[(2,4-dinitrophenyl)thio]-9-P-~ribofuranosylpurine 5’-triphosphate has been used for labelling an ATPase activity in rat liver nuclear envelope and 6-[(3-carboxy-4-nitrophenyl)thio]-9-P-~-ribofuranosylpurine 5’-triphosphate has been used to differentiate different classes of binding site in m a + K + ] - A T P ~ S ~ . ~ ~ ’

+

247 248

249

250

251

P. N. Lowe and R. B. Beechey, Biochemistry, 1982, 21, 4073. M. M. King and R. F. Colman, Biochemistry, 1983, 22, 1656. M. Uziel, Arch. Biochem. Biophys., 1975, 166, 201. C. Kondor-Koch, N. Riedel, R. Valentin, H. Fasold, and H. Fischer, Eur. J . Biochem., 1982, 127, 285. H. Koepsell, F. W. Hulla, and G. Fritzsch, J. Biol. Chem., 1982,257, 10 733.


20 I Ade

Enz

Ade Ade

I

Enz

Acylation of the 3-(3-amino-3-carboxypropyl)uridine residue of tRNAPhe using the N-hydroxysuccinimide ester of N-(4-azido-2-nitrophenyl)glycine affords a functionalized tRNA molecule, fully functional for aminoacylation and for ribosomal interaction, which has been cross-linked to the ribosomal P site in the presence of p01y(U).~~~ A related method of functionalizing tRNA involves statistical alkylation of the N-7 atoms of exposed guanosine residues using 4-(N-2-chloroethyl-N-methylamino)benzylamine followed by arylation of the aliphatic primary amino groups thus introduced using 2,4-dinitro-5-fluorophenyl a ~ i d e The . ~ ~resulting ~ azido-tRNAPhespecies gave different patterns of ribosomal affinity labelling in the presence and absence of poly(U). Treatment of tRNAPhewith liquid hydrogen sulphide and pyridine results in the conversion of exposed cytidine residues to 4-thiouridine (see below) which becomes photoreactive upon irradiation at 335 nm, and thiolated N-acetylphenylalanyltRNAPhe becomes specifically cross-linked to protein S10 of the 30s ribosomal sub-unit on irradiation in the presence of poly(U) and 70s ribosomes.264 Post Synthetic Modification.-Various methods have been used to modify tRNA in order to relate its structure to its function in the reactions of protein synthesis. Excision of the Y nucleotide from yeast tRNAPhe using the method reported last year,l8O followed by resealing of the anticodon loop with T4 RNA ligase gives modified tRNAPhe, with six nucleotides in the anticodon loop instead of seven, which is virtually non-chargeable with phenylalanine, although the half-molecules used to prepare the modified tRNA were chargeable.255A 252

253 254

255

I. Schwartz and J. Ofengand, Biochim. Biophys. Acta, 1982, 697, 330. S. N. Vladimirov, D. M. Graifer, and G . G . Karpova, FEBSLett., 1982, 144, 3 3 2 . N. Riehl, P. Remy, J.-P. Ebel, and B. Ehresmann, Eur. J. Biochem., 1982,128,427. K. Nishikawa and S. M. Hecht, J . Biol. Chem., 1982,257, 10 536.


202

particular spatial or conformational arrangement of the anticodon loop may thus be critical for charging to occur. Nicking of yeast tRNAPheat the Y-base residue with hydrochloric acid and aniline, followed by treatment with ribonuclease A, results in excision of the sequence GmpApApY, being the anticodon sequence plus the Y base, and this has been replaced with sequences CpUpApNp (N = A,C,U,G) using the agency of T4 RNA ligase, to give tRNA species with an anticodon complementary to the amber ‘stop’ codon UAG.256The modified tRNA molecules acted as amber suppressors in a mammalian protein-synthesizing cell-free system, the efficiency of suppression being greatest with a purine base (N = A,G) on the 3’-side of the anticodon. In another study the anticodon of the tRNAfMetfrom E. coli was excised with RNase A, and the two resulting halfmolecules either joined directly, or joined with CpUpAp or UpUpAp in place of the original anticodon, as before.257None of the three modified tRNA species exhibited methionine acceptor activity. Following treatment with nuclease S1 to remove the 3’-terminal tetranucleotide, tRNAfMet,from E. coli has also been ligated to the 2’,3’-ethoxymethylidene-terminatedtetranucleotides pNpCpCpA(em) (N = A,C,U,G) to determine the effect of altering the ‘discriminator’ base on the 5’-side of C ~ C P AAfter . ~ ~removal ~ of the blocking group with acid, all four tRNA species could be charged with methionine by methionyl-tRNA synthetase, albeit with different values of V,,,. Chemically misacylated tRNAPhe has been prepared by ligating 3’-aminoacylated pCpA to tRNAphe lacking its . ~ ~binding ~ to the ribosomal P-site, pCpA terminus using T4 RNA l i g a ~ e On the amino acids of the species misacylated with N-acetyl-L-tyrosineand N-acetylP-phenylalanine could be transferred to L-phenylalanyl-tRNAPhein the A site, but N-acetyl-D-phenylalanineand -D-tyrosine were transferred poorly.

4 A

“ i (112)

N f (

I

N

i ‘ ,d

(113)

Treatment of single-stranded nucleic acids with chloroacetaldehyde results in the formation of hydrated etheno derivatives of cytosine and adenine bases (112) and (113), which lose water slowly under physiological conditions to give the fluorescent bases 3,N4-ethenocytosine (EC) and 1,Wethenoadenine (&A), respectively.260DNA has been rendered fluorescent by this treatment, and the 256

257 258

259 260

A. G. Bruce, J. F. Atkins, N. Wills, 0. Uhlenbeck, and R. F. Gesteland, Proc. Natl. Acad. Sci. U S A , 1982,79,7127. E. Ohtsuka, T. Doi, R. Fukumoto, J. Matsugi, and M. Ikehara, Nucleic Acids Res., 1983, 11, 3863. H. Uemura, M. Imai, E. Ohtsuka, M. Ikehara, and D. Soll, Nucleic Acids Res., 1982, 10. 6531. T. G. Heckler, Y. Zama, T. Naka, and S. M. Hecht, J. Biol. Chem., 1983,258, 4492. J. T. Kusmierek and B. Singer, Biochemistry, 1982, 21, 5717.


203

changes observed in fluorescence on binding recA protein used to investigate protein-polynucleotide binding interactions.261Upon transcription of poly(rC) and poly(dC), modified to contain varying quantities of (1 12) and EC,with DNAdependent RNA polymerases from E. coli and calf thymus, misincorporation was observed, more so in the presence of Mn2+ than of Mg2+ ions, with adenine misincorporated predominantly opposite (1 12) and uracil opposite ECresidues.262 Using similarly modified poly(dC) as a template for replication by DNA polymerase I from E. coli, (1 12) did not mispair, but thymine was misincorporated frequently opposite EC residues (and also opposite 3-methylcytosine residues in another modified Errors in transcription of the carcinogenmodified polynucleotides thus appear more frequent than errors in replication. The misincorporation of 2-aminopurine deoxyribofuranoside 5’-triphosphate instead of dATP opposite thymine sites on template DNA by T4 DNA polymerase also increases markedly when Mn2+ ions replace Mg2+ ions in the incubation.264The presence of Mn2+ ions seems to increase the frequency of excision of the correctly incorporated dAMP residues, while increasing the residence time of the 2-aminopurine nucleotide mispaired in the polymerase template complex, and thus its chance of incorporation. On treatment of cells with methylating mutagens, such as N-methyl-Nnitrosourea (MNU), the deoxyribonucleosides in the cellular precursor pool are more susceptible to methylation than are the residues within the DNA. Using an adaptation of Sanger’s ‘plus and minus’ gel sequencing technique, it has been shown that N1-methyl- and N3-methyl-dATP (and also the y-methyl ester of dATP), which are products of the methylation of dATP by MNU, can be incorporated into DNA opposite thymine bases by T4 DNA polymerase, and N1-methyl-dATP is similarly incorporated opposite thymine by DNA polymerase I.266DNA Polymerase a and DNA polymerase I (E.coli) will incorporate 06methyl-dGTP in the presence of poly(deoxyribonuc1eotide) templates containing thymine bases, and 04-methyl-dTTP in the presence of templates containing guanine bases, albeit far less efficiently than the proper complementary nucleotides are incorporated.266These observations, together with a demonstration of an increase in revertants in a bacteriophage T7 mutant which incorporated 06methyl-dGTP into newly synthesized DNA,267indicate that mutagenesis may occur via the incorporation of nucleotides modified by mutagens into DNA as well as by direct modification of the nuclear material. The structures of the products of interaction of several mutagens with DNA have been determined by spectroscopic methods. Both 4-acetoxy-7-methoxy2H-1,4-benzoxazin-3(4H)-one (1 14)268 and 6-methyldipyrido[1,2-a : 3’,2’-d]261 262 263

264

265 266 267

M. S. Silver and A. R. Fersht, Biochemistry, 1982,21, 6066; ibid., 1983,22,2860. J. T. Kdsmierek and B. Singer, Biochemistry, 1982, 21, 5723. B. Singer, J. T. Kusmierek, and H. Fraenkel-Conrat, Proc. Natl. Acad. Sci. USA, 1983,80, 969. M. F. Goodman, S. Keener, S. Guidotti, and E. W. Branscomb, J . Biol. Chern., 1983, 258, 3469. M. D. Topal, C. A. Hutchinson, 111, and M. S. Baker, Nature (London), 1982,298, 863. J. A. Hall and R. Saffhill, Nucleic Acids Res., 1983, 11, 4185. L. A. Dodson, R. S. Foote, S. Mitra, and W. E. Masker, Proc. Natl. Acad. Sci. USA, 1982,79, 7440. T. Ishizaki, Y . Hashimoto, K. Shudo, and T. Okamoto, Tetrahedron Lett., 1982,23, 4055.


204 Me0

I

OAc (114 1

I

H

Me (115)

imidazole (115)268 become bound at C-8 of guanine, the former by displacement of the acetoxy group and the latter via the amino group. N5-Methyl-N6-formyl2,5,6-triamino-4-hydoxypyrimidine (116) has been identified as a major adduct in rat liver DNA following exposure to N,N-dimethylnitrosamine or 1,Zdimethylhydrazine, and is obtained on alkaline hydrolysis of 7-methylg~anine.~~~ While N7-methylationof guanine residues in poly[d(G-C)] facilitates conversion of the duplex from the low-salt (B) form to the high-salt (Z) form, possibly because the positive charges introduced reduce phosphate repulsion between the two polynucleotide chains during the conformational changes involved, aflatoxin B 1, which also binds at N-7, suppresses the B -+ Z transition.271It is thought that the bound aflatoxin may form hydrogen bonds to the sugar-phosphate chain, stabilizing the right-handed (B) helix. Discussion of many of the interesting recent findings concerning left-handed (Z) helical DNA is beyond the scope of this Report, but a review article272may be commended. Upon irradiation of d(TpA), but not of d(ApT), at 254 nm in water at pH 7, a photo-adduct is formed between the two bases.273The same photo-product has been demonstrated in irradiated poly[d(A-T)] and in DNA. While its structure has not yet been fully elucidated, spectroscopic evidence suggests that the photo-adduct is formed by photo-addition of the 5,6-double bond of thymine across a double bond in the six-membered ring of adenine. On treatment of the photo-adduct with hydrochloric acid, a fluorescent hydrolysis product, thought to be l-methyl-l-deazapurin-2-one, is formed. While this adduct is not a major photo-product, its occurrence and capacity for repair are of considerableinterest ; no photo-adduct in DNA involving the adenine base has previously been

270

Y.Hashimoto, T. Shudo, and T. Okamoto, J. Am. Chem. SOC.,1982,104,7636. D.T.Beranek, C. C. Weis, F. E. Evans, C. 3. Chetsanga, and F. F. Kadlubar, Biochem.

273

Biophys. Res. Commun., 1983,110,625. A. Nardheim, W. M. Hao, G. N. Wogan, and A. Rich, Science, 1983,219,1434. S. Neidle, Nature (London), 1983,302, 574. S. N. Bose, R. J. H. Davies, S. K. Sethi, and J. A. McCloskey, Science, 1983,220,723.

269


205

described. Irradiation of d(TpC), d(TpT), d(CpT), and d(CpC) with U.V. light leads to the formation of fluorescent photo-products which are labile in alkali with a 3'-phosphate group being formed on hydrolysis.274The photo-products formed from d(TpC) and d(TpT) have also been identified in u.v.-irradiated DNA. The photo-product from d(TpT) is thought to have the structure (117), and thus to be a hydrated precursor of the 6-4'[pyrimidine-2'-one]pyrimidine class of photo-products previously known to occur in u.v.-irradiated DNA. The significance of the formation of these products for mutagenesis is unknown. H

H

0

l %

0

hH H

H

(117)

"K"" 0

OH

Sequencing and Cleavage Studies.-When DNA is irradiated at 0 "C in buffer, pH 10.5, in the presence of methylamine, and subsequently heated at 70 "C, the thymine bases are lost and 1-methylthymine is isolable, and the 3'-5' phosphodiester link is cleaved The reaction is highly selective for thymine, although some reaction occurs at guanine residues.276In a model experiment using 2'-deoxythymidine, (1 18) was isolated, and mechanistic studies suggest that the amine attacks the excited thymidine anion at C-2.275 Used with 5'-["P]phosphate-labelled DNA fragments, the thymine-specific cleavage has been utilized to allow direct determination of the positions of thymine residues in DNA by gel sequencing.276 In a systematic photochemical study of the rate of phosphate release from mononucleotides, and of the generation of new phosphornonoester end groups in oligoribonucleotides up to hexamers upon irradiation at 254 nm, the reaction cross sections were found to be largely independent of the nature of the base residues present, and of oligonucleotide This suggests that the photolysis reactions observed are consequent upon absorption of photons by the sugar phosphate groups, rather than by the base rings, and also that energy transfer from excited bases does not contribute to the cleavage reactions. Previous values of quantum yields for chain cleavage of RNA and DNA, which have tended to assume that cleavage followed absorption of photons by the base 274 275 276 277

W. A. Franklin, K. M.Lo, and W. A. Haseltine, J. Biol. Chem., 1982,257, 13 535. I. Saito, H. Sugiyama, and T. Matsuura, J. Am. Chem. Soc., 1983, 105,956. A. Simancsits and 1. Torok, Nucleic Acids Res., 1982, 10, 7959. 2.Jericevic, I. Kucan, and R. W. Chambers, Biochemistry. 1982, 21, 6563.

206


rings, may have been severely underestimated. A study of the hydrolysis of apurinic and apyrimidinic sites in DNA catalysed by polyamines such as spermine, spermidine, etc., has been performed.278 The rate of hydrolysis increases with pH, and reduction at the sites with borohydride practically eliminates cleavage. The mechanism of cleavage thus probably involves P-elimination, and it is thought that the polyamines may be involved in fracturing DNA at apurinic sites during repair. Gel sequencing has again found many uses other than that of simply giving sequence information. For instance, the characteristic patterns of alkylation of tRNA by MNU, by ethylnitrosourea (ENU) and by dimethylsulphate (DMS) have been defined.279In buffer at pH 8, MNU and ENU react mainly with phosphate residues of end-labelled tRNA, and give similar patterns when the products of alkylation are treated with alkali to hydrolyse the phosphotriesters formed and separated on sequencing gels, while DMS at pH 7.2 reacts more specifically with bases, particularly guanine, giving a ‘guanine’ cleavage pattern on cleavage at the affected sites, using aniline, and gel separation. The accessibility of the phosphodiester bonds in DNA and RNA to modification by ENU, or of the bases to modification by alkylating agents which results in labilization of the adjacent phosphodiester links after removal of the bases affected, may be monitored using sequencing gels and used to obtain information on the secondary and tertiary structures of the nucleic acids, and of the ‘masking’ of reactive sites which results when they are bound to other molecules. Thus, the tertiary structure of eukaryotic ribosomal 5s RNA has been probed using ENU;280 DMS and diethyl pyrocarbonate have been used to compare the accessibility of G, C , and A bases of tRNAPhe in the free state, in the tRNAPhe-GTP-EF-Tu complex, and in the ribosomal A and P sites;281diethyl pyrocarbonate has been used to investigate the accessibility of A bases of 4.5s RNA both in the free state and in spinach chloroplast ribosomes;282and ENU and 4-(N-2-chloroethyl-N-methy1amino)benzylamine(which alkylates G bases at N-7) have been used to study the interactions of tRNA species with cognate and non-cognate aminoacyl-tRNA ~ y n t h e t a s e s .When ~ ~ ~ DNA is methylated using DMS, the N3-methylcytosine formed in single-stranded regions is more susceptible to attack by hydrazine than is unmodified cytosine, thus permitting preferential chain cleavage at the methylated site. This has been used to map interactions between DNA polymerase I from E. coli and three promoter sites on DNA.2s4 The cleavage of accessible sites in end-labelled nucleic acids by nucleases may also be monitored using sequencing gels, and cobra venom nuclease V (which specifically cleaves double-stranded RNA), nuclease S1 (which specifically 278 279 280

281 282

p83 284

R. Male, V. M. Fosse, and K. Kleppe, Nucleic Acids Res., 1982, 10, 6305. J. Barciszewski, P. Romby, J. P. Ebel, and R. Giege, FEBS Lett., 1982, 150, 459. J. McDougall and R. N. Nazar, J. Biol. Chern., 1983, 258, 5256. S. Douthwaite, R. A. Garrett, and R. Wagner, Eur. J . Biochem., 1983, 131, 261. I. Kumagai, M. Bartsch, A. R. Subramanian, and V. A. Erdmann, Nucleic Acids Res.. 1983, 11, 961. V. V. Vlassov, D. Kern, P. Romby, R. Giege, and J.-P. Ebel, Eur. J. Biochem., 1983, 132, 537. K. Kirkegaard, H. BUC,A. Spassky, and J. C . Wang, Proc. Natl. Acad. Sci. USA. 1983.80, 2544.


207

cleaves single-stranded regions), and other ribonucleases have been used to probe the structures of tRNA species285and their interaction with aminoacyl.~~~ tRNA synthetases,286 and the structure of 5s RNA from S a c c h a r ~ m y c e sThe sequence specificity of binding of actinomycin D and netropsin to DNA has been deduced from the resultant protection of the sequences from cleavage by deoxyribonuclease I. In other studies sterically exposed bases have been modified chemically and classical sequencing methods (ribonuclease digests, finger printing, ‘wandering spot’ analysis) used to determine the sites of modification as pointers to secondary and tertiary structure. For instance, 5s RNA in 50s ribosomal sub-units of E. coli has been treated with monoperphthalic acid to convert exposed adenine bases to their N-1 unpaired cytosine residues of tRNAVa’ from mouse cells have been thiated using liquid H2S and pyridine to give 4-thiouracil bases, a process which apparently does not affect the secondary and tertiary structure( !);290 unpaired cytosine residues of mouse ribosomal 5s RNA have been thiated similarly,291and unpaired guanine residues identified by reaction with kethoxal ;292 and methoxyamine and bisulphite, which react with exposed cytosine and uracil bases, respectively, have been used to probe helical content of a number of ribosomal RNA species.293On treatment of guanine-, adenine-, and cytosine-containingribonucleotidesand deoxyribonucleotides with formaldehyde followed by bisulphite, at pH 2.4-9.5, N-sulphomethylation takes place via initial formation of the N - r n e t h y l ~ l .At ~ ~pH ~ 7 and 4 “C, this reaction is virtually specific for guanine bases in single-stranded regions of DNA, to give (119), and thus offers potential as a new conformational probe. In an assay of the rates of cleavage of susceptible sites on DNA by restriction endonucleases, the DNA is partially digested by an enzyme of this type, the termini thus generated labelled using [Y-~~PIATP and T4 polynucleotide kinase, the digestion then completed by the same enzyme and the products separated by gel electrophoresis. Autoradiography and densitometry then allow the amounts of cleavageat each susceptiblesite in the partial digests to be The ability of adenine nucleotides to aid catalysis of the hydrogen peroxidedependent formation of hydroxyl radicals by ferrous ions has been investigated, P. E. Auron, L. D. Weber, and A. Rich, Biochemistry, 1982,21,4700. J. Gangloff, R. Jaozara, and G. Dirheimer, Eur. J. Biochem., 1983, 132, 629. 287 R. A. Garrett and S. 0. Olesen, Biochemistry, 1982,21,4823. M. J. Lane, J. C. Dabrawiak, and J. N. Vournakis, Proc. Natl. Acad. Sci. USA, 1983. 80, 3260. 28B M. Silberklang, U. L. Rajbhandary, A. Luck, and V. A. Erdmann, Nucleic Acids Res., 1983, 11, 605. K. Miura, T. Iwana, S. Tsuda, T. Ueda, F. Harada, and N. Kato, Chem. Phnrm. Bull.. 1982, 30, 4126. 201 K. Miura, S. Tsuda, T. Twano, T. Ueda. F. Harada, and N. Kato, Biochim. Biophys. Actn. 1983,739, 181. *02 K. Miura, S. Tsuda, T. Ueda, F. Harada, and N. Kato, Biochim. Biophys. Acm, 1983. 739, 281. “03 P. Cammarana, P. Londei, R. Biagini, M. DeRosa, and A. Gambacorta. Eur. J . Biochem.. 1982, 128, 297. 294 H. Hayatsu, Y. Yamashita, S. Yui, Y . Yamagata, K. Tomita, and K . Negishi, Nucleir Acids Res., 1982, 10, 6281. 205 K. L. Berkner and W. R. Folk, Anal. Biochem., 1983,129,446. 285

286

208


(120)

using the spin trap 5,S-dimethyl-1-pyrroline 1-oxide. While AMP is ineffective, ADP and ATP increase the rate of formation of hydroxyl radicals some 20- to 50-fold, presumably by chelation of ferrous ion by the polyphosphate chain.2g6 Complexes of ferrous ion with EDTA catalyse cleavage of the DNA chain, probably via the formation of hydroxyl radicals, and thus linkage of Fe".EDTA to an intercalating drug, as in methidium propyl-EDTA .Fe" (120), affords an artificial agent for degrading DNA chains. It has been found that (120) cleaves double-helical DNA with low, if not entirely neutral, sequence specificity, a property which may prove useful for cleaving chromatin.2g7The inhibition of cleavage of DNA by (120) due to the protection of specific sequences by bound ligands, as determined by sequencing gel analysis, has permitted the preferred sites of binding on DNA of distamycin, netropsin, actinomycin,2g8chromomycin, mithramycin, and 01ivomycin~~~ to be characterized. The attachment of EDTA.FeI' to a sequence-specific drug such as distamycin permits the synthesis of a molecule cleaving DNA specifically at, or close to, distamycin binding Bleomycin, phleomycin, t a l l y ~ o m y c i n ,and ~ ~ ~chartreusin302 are antibiotics which effect cleavage of DNA strands, and gel sequencing methods have been used to determine their preferred sites of binding302and cleavage.3o1The products 9g6 297

R. A. Floyd and C. A. Lewis, Biochemistry, 1983, 22, 2645. I. L. Cartwright, R. P. Hertzberg, P. B. Dervan, and S. C. R. Elgin, Proc. Nut/. Acad. Sci. USA, 1983, 80, 3213.

298

299

30n

301

M. W. Van Dyke, R. P. Hertzberg, and P. B. Dervan, Proc. Nntl. Acnd, Sci. U S A , 1982, 79, 5470 M. W. Van Dyke and P. B. Dervan, Biochemistry, 1983,22,2373. P. G. Schultz, J. S. Taylor, and P. B. Dervan, J . Am. Chem. SOC.,1982, 104, 6861. J. Kross, W. D. Henner, S. M. Hecht, and W. A. Haseltine, Biochemistry, 1982, 21,4310.

M. Uramoto, T. Kusano, T. Nishio, K . Isono, K. Shishido, and T. Ando, FEBS Lerr.. 1983,153, 325.

209


RO;--Oy 0

II

-

O y au r

0

yyur 0

a

*0' 0

0

I

I 0-P-OR

O=P-OR'

OH

I

bH

0

0

I I

I O=P-OR' I

O = P -OR

OH

OH

0

0

II

B

O=P-OR'

I

II

O=P

OH

-OR

I OH

and mechanism of the cleavage process by agents of this type have been widely studied. The degradation of poly(dA.dU), separately and specifically tritiated at the 1'-, 2'-(ribo-~onfiguration),3'-, and 4'-positions of the dUMP units, by bleomycin in the presence of Fe'* and oxygen, has been investigated.303Both uracil and (E)-3-(uracil-l '-y1)-Zpropenal are formed during the process. The findings are consistent with a scheme in which a 4'-radical species (121) initially 30s

J. C.Wu, J. W. Kozarich, and J. Stubbe, J. B i d . Chem., 1983,258,4694.

210


formed is trapped, either by oxygen or by a mono-oxygen species, to give (122) or (123), respectively. While (122) is thought to break down according to a scheme reported last year,160in which the uracil propenal is formed in the course of a stereospecific elimination, (123) is thought to decompose with loss of uracil to afford (124), which subsequently loses the 3’-phosphomonoester by P-elimination. The dual breakdown pathway is required by the finding that the [3’-3H]uridineresidues only lose tritium as 3 H 2 0when uracil is lost as the free base, and this could occur by exchange in (124). An alternative breakdown mechanism via (125) might account for these observations. The 1,lO-phenanthroline-Cu’ complex cleaves DNA to give an array of fragments similar to those obtained using micrococcal n u ~ l e a s eThe . ~ ~oxidation ~ of DNA by this system in the presence of hydrogen peroxide generates both 3’- and 5’-phosphoryl termini, and using labelled poly[d(A-T)], both adenine and thymine are found to be released.305All the deoxyribose carbon atoms seem to remain attached to the remnants of the phosphodiester backbone, and no ketonic, aldehydic, acidic, or ester products were detected. A dual breakdown pathway has been suggested in which initial one-electron oxidation of the C-1’ oxygen atom by hydroxyl radical is followed by loss of a further electron, and then a proton, to give (125) and (126), which decompose further with loss of base and the 5’-phosphoryl, and 3’-phosphoryl termini respectively to give a substituted furfuryl alcohol in each case. In contrast, in a study using d(CpG), 1 ,lo-phenanthroline, copper(I1) sulphate, and 3-mercaptopropionic acid aerated at 0 “C in phosphate buffer, cytosine, guanine, dGMP, (127) and (128) were identified among the The formation of the free bases, dGMP, and (128), is most easily rationalized via initial attack of oxygen free radicals at C-I’ leading to hydroxylation at that position, base loss, and further decomposition. However, it is by no means certain that 1,lO-phenanthroline would interact with the self-complementary dinucleoside phosphate in the same way as with DNA, and no u.v.-transparent products could have been detected in this last study. Further work is clearly needed. When poly[d(A-T)] is treated with the non-protein chromophore of neocarzinostatin, and then digested with nuclease, the predominant adduct formed contains the chromophore linked to the C-5’ position of the 2’-deoxyadenosine residue of the sequence d(TpApT). At pH 8.6 hydrolysis occurs to give the chromophore, 3’-dTMP, and another product which affords 2’-deoxyadenosine 5’-aldehyde and 5’-dTMP on treatment with snake venom phosphodiesterase. Evidently oxidation at C-5’ occurs, possibly with formation of a phosphorylacetal such as (129).307y-Irradiation of DNA in aqueous solution also leads to dose-dependent strand breakage, regardless of sequence, with the formation of 5’-phosphoryl termini.308In a study using 5‘-end-labelled poly(dG), both d(pGp) and the glycolic acid ester (130) were 304

305

306 307 308

B. Jessee, G. Gargiulo, F. Razvi, and A. Worcel, Nircleic Acids Res., 1982, 10, 5823; I. L. Cartwright and S. C. R. Elgin, ibid., p. 5835. L. M. Pope, K. A. Reich, D. R. Graham, and D. S. Sigman, J. Biol. Chem., 1982, 257. 12 121. S. Uesugi, T. Shida, M. Ikehara, Y. Kobayashi, and Y. Kyogoku, J. Am. Chem. Soc., 1982, 104, 5494. L. F. Povirk and I. H. Goldberg, Nucleic Acids Res., 1982,10,6255. W. D. Henner, S. M. Grunberg, and W. A. Haseltine, J. Biol. Chem., 1982, 257, 11 750.


211

0

II

NHCHO

0-x

0

Gu a

0

I

O=P-OH

I

0- ( dThd-5 (129)

X

=

0

'

I -OCH 2COOH I

)

0 sP

Chromophore

bH (130)

identified as producfs, the latter by comparison with the authentic compound (lacking the 5'-phosphate) which was prepared by phosphotriester methods.30e Compound (130) could arise via initial abstraction of a hydrogen radical at C-4' followed by addition of oxygen [CL(121),(122)] as in mechanisms suggested elsewhere. Metal Complexes.-Lead(@ ions catalyse sugar-phosphate strand scission between residues 17 (dihydrouridine) and 18 (guanine) of yeast tRNAPhe. Comparison by difference Fourier analysis of the X-ray structures obtained before and after soaking tRNAPhecrystals in Pb" solution at pH 7.4 (when strand scission occurs) with those obtained at pH 5 (when the cleavage reaction is very slow, and the sugar-phosphate backbone intact) affords a picture of the reactants and products of the cleavage reaction.310It appears that cleavage takes place via a lead-bound hydroxy group which facilitates deprotonation of the 2'-hydroxy function on dihydrouridine, catalysing attack on the internucleotidic link [(131) 3 (132)l. The process is reminiscent of the role of His-12 in ribonuclease A, although models suggest that in this case an 'adjacent' attack may be involved. These results not only suggest a mechanism for the toxicity of lead, but may be relevant to the requirement of self-splicing RNA for the presence of metal ions. 308

W. D. Henner, L. 0. Rodriguez, S. M. Hecht. and W. A. Haseltine. J. Biol. Chem., 1983. 258, 711.

310

R. S. Brown, B. E. Hingerty, J. C. Dewan, and A. Klug, Nature (London), 1983,303, 543.


212

0

\ /\Hf

0

0.0

\Pb/

O=P-0

'O-(Guo-5'

'.

)18

H2Ura = 5 , 6 - d i h y d r o u r a c i l

If ferrous ions are present during assays of DNA and RNA polymerases in which radioactive newly synthesized polynucleotides are precipitated on to filter paper discs in trichloroaceticacid, spuriouslyhigh results are obtained, apparently due to acid-insoluble complexes of Fe" with substrate nucleotides precipitating on the paper.311 Clearly ferrous ions should be avoided in assays of this type. The complex Al. ATP- is a potent inhibitor of hexokinase, and neutron activation analysis of many commercial samples of ATP has shown that AlrIr is ubiquitous, and the most common metal contaminant!312It is best removed by passing the ATP preparation over a cellulose polyphosphate column at pH 5. Chelates of ATP with divalent metal ions have been separated from nonchelated ATP using reverse-phase h . p , I . ~ . ~ l ~ The influence of Cu2+,Zn2+,and Ni2+ions in promoting dephosphorylation of ATP, UTP, CTP, and dTTP has been studied in the pH range All the ions catalyse hydrolysis, the order of effectiveness being Cu2+> Zn2+ > Ni2+, with the effect being greater for ATP, in which the metal ion can interact strongly with the base, than for the pyrimidine nucleotides, where it does not do so significantly. The most reactive metal-ATP species is thought to be dimeric. Potentiometric pH titrations have been used to determine the relative stability of mixed ligand complexes of type M .NTP .L2- (M = Mn2+,Co2+,Cu2+,Zn2+, or Cd2+;N = A or U; L = imidazole or ammonia) as models of metal-nucleotideprotein complexes.316The complexes containing UTP are more stable than the corresponding complexes containing ATP, since co-ordination of the metal ion to N-7of adenine denies access to the other nitrogen ligand. Calculation of apparent stability constants shows that only the imidazole-containing complexes are formed in significant concentration at pH 7, since competition by protons drastically reduces the availability of ammonia (or primary amines) as accessible ligands . 311 312

313 314

315

N. L. Sat0 and T. Yamada, Anal. Biochem., 1982, 127, 300. J. V. Schlass, G . Smith, A. Aulabaugh, and W. W. Cleland, Anal. Biochem.. 1982, 120. 176. J. H. Jahngen and E. F. Rossomando, Anal. Biochem., 1983, 130,406. H. Sigel and F. Hofstetter, Eur. J. Biochem., 1983, 132, 569. N. Saha and H. Sigel, J. Am. Chem. SOC., 1982,104,4100.


21 3

Reviews on the recent chemistry of cis-diamminodichloroplatinum(cis-DDP) summarize the work on its interaction with DNA.3U cis-DDP binds to d(A-G-G-C-C-T) with a stoicheiometry of one platinum atom per hexamer, and comparison of plots of the lH n.m.r. shifts of the non-exchangeable base protons with pH for the platinated and unplatinated hexamers show that the cis-DDP is chelated to the N-7 nitrogen atoms of the adjacent guanine residues.317Although the unplatinated hexamer forms a duplex, being self-complementary,the platinated hexamer does not. Virtually identical results have been obtained on binding cis-diamminodiaquoplatinum nitrate to d(T-G-G-C-C-A).318The distortion of the secondary structure in DNA caused by the binding of cis-DDP results in the formation of single-stranded regions which are cleaved by nuclease S1, and greater levels of digestion of DNA by the nuclease are observed following the binding of cis-DDP than of its trans-isomer.31* 6 Analytical Techniques and Physical Methods

The Karplus parameters used for analysing 3Jpocc values for nucleotides in terms of the conformational properties of the C-0 bond have been re-examined, and an apparent discrepancy, between the parameters derived from studies on 3’,5’-nucleotides and those subsequently derived to accommodate larger values of sbpoccin 2’ -+5’-linked oligonucleotides, explained in terms of substituent electronegativity at C-1’ caused by the base nitrogen atom. A new set of Karplus parameters for use in analysing 3 J p o c c magnitudes in 3’- and 5’-nucleotides has been A 31Pn.m.r. study of the conformation of 2‘-deoxythymidine 3’,5’-cyclopyrophosphatehas been performed, and used (together with lH n.m.r. data) to predict that the compound exists as an equilibrium mixture of two conformers, each containing a crown pyrophosphate ring.321 Analysis of the principal values of the chemical shift tensor derived from the solid-phase 31Pn.m.r. spectrum of 5’-AMP adsorbed on Zn2+-exchanged bentonite clay shows that the zinc ion is co-ordinated directly to an oxygen atom of the phosphate.322Multinuclear n.m.r. studies, including 31P n.m.r., have been used to investigate the nature and co-ordination pattern of the complexes formed by ATP with aluminium(II1) ions323and with vanadyl ionss2*at different pH values, At least four different complexes could be distinguished with A13+ions, and three with V 0 2 + ions. The perturbation of the 31Pn.m.r. spectrum of ATP, bound in the high-affinity ATP-binding site of nitrated S . J. Lippard, Science, 1982, 218, 1075; A. T. M . Marcelis and J. Reedijk, Red. Truv. Chim. Pays-Bus, 1983,102,121. 317 J. P. Caradonna, S . J. Lippard, M. J. Gait, and M. Singh, J. Am. Chem. SOC.,1982, 104, 5793. 318 J.-P. Girault, J . 4 . Chottard, E. R. Guittet, J.-Y. Lallemand, T. Huynh-Dinh, and J. Igolen, Biochem. Biophys. Res. Commun., 1982,109, 1157. 31* W. M. Scavell and V. J. Cappani, Biochem. Biophys. Res. Commun., 1982,107, 1138. 320 D. B. Davies and H. Sadikot, Org. Magn. Reson., 1982, 20, 180. 321 Yu. N. Vorab’ev, A. G. Badashkeeva, and A. V. Lebedev, Zh. Strukt. Khim., 1982, 23, 29 (Chem. Abstr., 1982, 97, 39 300). 322 N. J. Clayden and J. S. Waugh, J. Chem. SOC.,Chem. Commun., 1983,292. 323 S . J. Karlik, G. A. Elgavish, and G . L. Eichhorn, J . Am. Chem. SOC., 1983,105, 602. 324 H. Sakurai, T. Goda, and S . Shimomura, Biochem. Biophys. Res. Commun., 1982.108,474. 316

214


G-actin, by added paramagnetic Mn2+ions, has been used to deduce that the manganese ion is bound within 10 A of the ATP-binding In another study, the perturbation by Mn2+ions of the longitudinal relaxation rates of the 31P nuclei of the substitution-inert P,y-bidentate Co(NH,),ATP complex bound to m a + K+]-ATPase was used to measure the Mn2+-P distance for all three phosphorus atoms, and gave values consistent with the formation of a secondsphere co-ordination complex between Mn2+ and the phosphate groups.326 When paramagnetic Co2+is bound to the P-sub-unit of DNA-dependent RNA polymerase from E. coli, in place of the usual Zn2+ion, the perturbation of the relaxation rates for the 31Pnuclei permits the distances between the bound Cog+ and the phosphorus atoms to be measured. The cobalt ion seems to be co-ordinated directly to the base moiety of ATP.327 A review on the determination of the backbone geometry of single-stranded nucleic acids in aqueous solution has appeared.328A method for assigning n.m.r. signals of lH and 31P nuclei in the oligonucleotide backbone by 2-D n.m.r. plots using homonuclear (lH-lH) and heteronuclear (1H-31P) spin-spin coupling has been described.329A study of the temperature dependence of the n.m.r. spectra of several tRNA species has been described.330In the presence of Mg2+,most signals are invariant over the range 22-66 "C, but merge indicating a random coil conformation above 70 "C. However, some peaks do shift and broaden over the intermediate temperature range suggesting the occurrence of multiple conformations in the anticodon loop. Conformational transitions in this region were also observed on mixing yeast tRNAPheand E. coli tRNA?", which possess complementary anticodons and form a dimer. The salt-dependence of the structure of poly[d(A-T)], poly(dA. dT), and poly[d(G-C)] in solution have been examined by 31P n.m.r. spectroscopy using several salts over a wide range of on cent ration.^^^ Poly(dA. dT) shows no unusual effects on salt addition, appearing to have a regular B-form backbone, poly[d(G-C)] shows a slow co-operative transition from B to Z conformation as MgC12 and NaCl concentrations are raised, and poly[d(A-T)] shows a distinct dinucleotide repeat unit, with the d(ApT) and d(TpA) segments possessing different conformations, which appears to undergo transition to a different dinucleotide repeat unit conformation with changing salt concentration. The dependence of the B -+ Z conformational transition occurring in the 5-methyl-2'-deoxycytidylic acid copolymer poly[d(G-m6C)]upon salt concentration has also been monitored by slP n.m.r. spectroscopy.332 The effects of intermolecular DNA interactions on the motional dynamics of double-stranded DNA segments of defined length have been investigated using

+

325 326

327

328

32B 330 331 33a

M. Brauer and B. D. Sykes, Biochemistry, 1982, 21, 5934. C. Klevickis and C. M. Grisham, Biochemistry, 1982, 21, 6979. D. Chatterji and F. Y.-H. Wu, Biochemistry, 1982, 21, 4657. C. Altona, Recl. Trav. Chim. Pay-Bas, 1982, 101, 413. A. Pardi, R. Walker, H. Rapoport, G. Wider, and K. Wuthrich, J. Am. Chem. Soc., 1983, 105, 1652. D. G. Gorenstein and E. M. Goldfield, Biochemistry, 1982,21, 5839. C.-W. Chen and J. S. Cohen, Biopolymers, 1983, 22, 879. C. Chen, J. S. Cohen, and M. Behe, Biochemistry, 1983, 22, 2136.


21 5

13C and 31Pn.m.r. At high concentration, DNA undergoes a spontaneous transition to a liquid crystalline state, although the average phosphodiester conformation, that of B-form DNA, does not change with the transition. The internal motions occurring in DNA are thought to be mainly coupled periodic bending deformations and partially uncoupled local motions within the sugar ring. Discrepancies in the apparent information available from lSC and 31P n.m.r. spectra of nucleosome cores has led to the expressed opinion that 31Pn.m.r. measurements yield at best a very incomplete representation of DNA dynamics,333but others have not been discouraged from using the technique to try to deduce the molecular motions occurring in supercoiled and circular DNA.33431P n.m.r. spectroscopy has also been used to compare DNA backbone structures in fd and Pf 1 bacteriophage^,^^^ and to follow the changes in the conformation of DNA consequent upon binding meso-tetra(4-N-methylpyridy1)porphineand its Ni" and Zn" derivatives.33*The parent compound and its nickel complex appear to intercalate, while the zinc complex does not. Yeast tRNA, and 5s RNA from several species, have been spin-labelled at the 3'-terminus by oxidation with periodate, condensation with 4-amino-2,2,6,6tetramethylpiperidin-l-oxyl, and reduction of the resulting product with borohydride. Analysis of the line shape variation of the e.s.r. spectra of the labelled molecules as a function of temperature reveals thermal unfolding transition~.~~' A method for the rapid sequencing of unprotected or 5'-tritylated oligodeoxyribonucleotides up to at least ten units long using negative ion fast atom bombardment mass spectrometry (FAB-m.s.) has been The method generates simultaneously one series of sequence ions with a 5'-phosphate terminus and another with a 3'-phosphate terminus. Ions with the same numbers of nucleotide units show a consistent difference in peak intensities, with the 5'-phosphate sequence ions having the greater intensity, permitting ready identification of the two series, and sequence information is simply obtained from the mass differencebetween sequence ions of the same series. One sequencing run can take as little as one hour, rendering it the most rapid method available for small oligodeoxyribonucleotides. Investigation of progress in oligonucleotide synthesis by the solid-phase phosphotriester method by pyrolysis mass spectrometry of the protected oligonucleotides has been A method for the quantitation of zeatin nucleotide (133) in Datura crown gall tissue which uses direct chemical ionization mass spectrometry of the penta(trimethylsily1) derivative of (133), and of its pentadeuterio derivative, has been detailed.340

334

336

337 338

339 340

R. L. Rill, P. R. Hilliard, jun., and G. C. Levy, J. Biol. Chem., 1983, 258, 250. P. Bendel, 0. Laub, and T. L. James, J. Am. Chem. SOC.,1982,104, 6748. T. A. Cross, P. Tsang, and S. J. Opella, Biochemistry, 1983, 22, 721. D. L. Banville, L. G. Marzilli, and W. D. Wilson, Biochem. Biophys. Res. Commun., 1983. 113, 148. G . A. Luoma, F. G. Herring, and A. G. Marshall, Biochemistry, 1982,21, 6591. L. Grotjahn, R. Frank, and H. Blocker, Nucleic Acids Res., 1982, 10, 4671; Int. J, Mass Spectrom. Ion. Phys., 1983,46,439. L. Alder, A. Rosenthal, D. Cech, and V. P. Veiko, 2. Chem., 1982,22,266 (Chem. Abstr., 1983, 98, 34 888). R. E. Summons, L. M. S. Palni, and D. S. Letham, FEBS Lett., 1983, 151, 122.

216


HHcH20H

HN-CH,

Me

I

R i b - 5 ’ -P

Oligodeoxyribonucleotides bearing hydroxy-group termini at both 3’- and 5’ends migrate anomalously in 23 % polyacrylamide gels containing 7~ urea, generally rather faster than when a 3’- or 5’-phosphate is present. This observation has a useful application: gel analysis of the products of digestion by a DNA exonuclease of substrates of known structure {e.g., dA-(~dA),-[~~PlpdA or [5’-32P](pdA),}in comparison with the substrates, and also following 5’-phosphorylation of the products using polynucleotide kinase and re-separation on gels, permits the mode of action of the exonuclease to be determined.341Branched DNA molecules, such as those containing replication forks, and intermediates in recombination events, migrate more slowly on agarose gel electrophoresis than does linear DNA of the same mass, with the degree of retardation being enhanced by higher agarose voltage and higher concentration. This property has been used to effect separation of branched and linear DNA in a 2-D gel electrophoretic technique.342 The use of 30% or 60% formamide solutions for performing ion-exchange h.p.1.c. of oligodeoxyribonucleotide sequences generated in solid-phase synthesis affords improved separation and higher purity of the products.343The higher concentration is used when the oligonucleotide of interest is highly selfcomplementary, or rich in 2’-deoxyguanylate residues. Ultrasonic relaxation techniques have been used to estimate the energy barrier to syn-anti conformational interconversion in cytidine 2’,3’-monophosphate, in the presence and absence of ethidium Raman spectroscopic measurements on a number of dinucleoside monophosphate crystals of precisely known sugar-phosphate structure have been compared with those of B- and A-form DNA, to give information on the comparative rigidity of the backbone in the nucleic The same technique, applied to poly(dA-dT) and poly[d(A-T)] at different temperatures, suggests that some of the furanose 341 342

343 344

345

S. P. Becerra, S. D. Detera, and S. H. Wilson, Anal. Biochem., 1983, 129, 200. L. Bell and B. Byers, Anal. Biochem., 1983, 130, 527. C. R. Newton, A. R. Greene, G . R. Heathcliffe, T. C. Atkinson, D. Holland, A. F. Markham, and M. D. Edge, Anal. Biochem., 1983, 129, 22. F. Jordan, P. Hemmes, S. Nishikawa, and M. Mashima, J. Am. Chem. SOC.,1983, 105, 2055. G. A. Thomas and W. L. Peticolas, J. Am. Chem. SOC.,1983,105,986.


217

rings alter their puckering modes at low temperatures, without change in base Optical spectra titrations of the binding of ethidium bromide to the self-complementary dinucleotides d(pCpG), d(pGpC), d(pTpA), and d(pApT) have been performed, and the association constants evaluated.347 Electrostatic phosphate-dye interactions are thought to contribute a large part of the binding energy, which varies with dinucleotide geometry.

346 347

G. A. Thomas and W. L. Peticolas, J. Am. Chem. Soc., 1983,105, 993. S. Doglia, A. GrMund, and A. Ehrenberg. Eur. J. Biochern., 1983. 133. 179.

YIides and Related Compounds BY B. J. WALKER

1 Introduction

In spite of the thirty years which have elapsed since Wittig’s original papers the reaction is being used more than ever in olefin synthesis and in this Chapter these papers have been the subject of considerable selection. For a number of reasons phosphorus-based syntheses of tri-substituted alkenes have created difficulties and it is encouraging to note a number of useful reports in this area. There has been a great resurgence of interest in the mechanism of the Wittig reaction and these studies have reached the stage of producing a number of quite different detailed descriptions which are individually quite convincing, but in total still confusing. No doubt all will be revealed in the next few years. There has been a small reorganization in this year’s Chapter in that reactions of phosphine oxide-stabilized carbanions will all be discussed in Chapter 4. Finally, boron has now joined the group of elements which stabilize anions capable of undergoing the Wittig reacti0n.l 2 Methylenephosphoranes The chemistry of fluorine-containing phosphorus ylides has been reviewed.? Preparation and Structure.-X-Ray crystal structures of benzoylmethylenetriphenylphosphorane (1) and arsorane (2) suggest that the phosphorus ylidic bond has more double bond character, which is in agreement with the greater nucleophilic reactivity of (2).3P-Chloroalkylidenephosphorane(3) and (or-chloroalky1)phosphine (4) isomers undergo substituent-dependent interconversion by intramolecular 1,Zchlorine shift.4 a-Lithiomethylenetriphenylphosphorane(9,generated by base-treatment of methylenephosphorane at low temperature, is a useful new reagent.sapbIt acts as a more reactive alternative to methylene ylide (e.g., it reacts with hindered ketones and epoxides) and reactions with aldehydes provide a new route to allylic alcohols. (However, see ref, 5b.) ‘L

A. Pelter, B. Singaram, and J. W. Wilson, Tetrahedron Lett., 1983, 24, 635. V. V. Tyuleneva, E. M. Rokhlin, and I. L. Knunyants, Rum. Chem. Rev., 1982, 51, I . M. Shao, X. Jin, Y. Tang, Q. Huang, and Y . Huang, Tetrahedron Lett., 1982,23, 5343. R. Appel, M. Huppertz, and A. Westerhaus, Chem. Ber., 1983, 116, 114. (a) E. J. Corey and J. King, J . Am. Chem. Soc., 1982, 104, 4724; (b) M. Schlosser, H. B. Tuong, J. Respondek, and B. Schaub, Chimia, 1983, 37, 10.

21 8

219

Ylides and Related Compounds

(1)

x

= P

(2) X = As

+

Ph3P=CHLi

2 RCHO

-

HO

RL

R

(5)

Extending his elegant work on multiphosphorus-ylidesystems, SchmidbaurH"+bl' has prepared (8) and (9) by phosphinylation of the ylidic-anion (7),6" pure (8) and (9) can be obtained and both compounds form alkali metal-ylide complexes. H ph2P'

-

H

CBPPh2-Ph2P/c~>pPh2 i

I

CH3

Li+

ii

II

'CH~

Ph 2 fH 2 "\CH

Ph 2P

+

I

PPh2

Ph2 r!CH2COOEt

l-0

Me

(30)

A kinetic study of the reaction of acyclic, (28), and cyclic, (29) and (30), phosphonates with p-substituted benzaldehydes using ethoxide as the base has been carried out.22The results show the reactions to be third order, indicate a build up of negative charge in the transition state of the rate determining step (p = +2), and show an acceleration in the case of five-membered cyclic phosphonates of about 20x over the acyclic analogues. An analogous study of phosphinates and phosphine gives similar results and shows that phosphinates form alkenes approximately 35 x faster than phosphine oxides in spite of similar pK, values for the or-protons in each compound. ’1

H2C=C

/R1 ‘CH-PPh

i

H2C=

/R1

T

+

‘CH=CHR2

(31)

Reagents: i, R2CHO; ii. A

Scheme 5

Pure (2)-1,3-disubstituted 1,3-dienes can be obtained by Wittig reaction of the suitably substituted allylic phosphorane (3 1) followed by thermolysis which causes dimerization of only the (E)-isomer (Scheme 5).24A variety of methods, including 22

23 a4

R. 0. Larsen and G. Aksnes, Phosphorus Sulfur, 1983, 15, 219. R. 0. Larsen and G. Aksnes, Phosphorus Sulfur, 1983, 15, 229. J. Mulzer, G. Briintrup, U. Kuhe, and G. Hartz, Chem. Ber., 1982, 115, 3453.

225


the Wittig reaction, have been used to prepare tetraenes and p e n t a e n e ~ .The ~~ reaction of penta-2,4-dienylidenetriphenylphosphoranewith (E)-penta-2,4-dienal (32) as the only characterized product, gave (E,E,E)-deca-l,3,5,7,9-~entaene with no evidence for formation of the expected (E,Z,E)-isomer.

Benzyl- and methyltriarylphosphonium salts bound to 2% and 8 % crosslinked, and to 20 % cross-linked macroporous, polystyrene undergo Wittig reactions in good yield with both aldehydes and ketones.2sThe Wittig reaction has been carried out under gas-liquid phase-transfer catalytic using solid potassium carbonate as the base. An advantage of the procedure is that the alkene product separates from the phosphine oxide. Unprotected phenolic aldehydes can be converted into alkenes by Wittig reactions provided two moles of base are used.28

0CHO

Ph2P=CRAr

+

Ar&cocl

COC 1

(33)

COOEt Ph 3P/ L C O O E t H (35)

(36)

Benzylidene ylides react regioselectively with the formyl group of 4-formylbenzoyl chloride to give (33).29 However, the same selectivity is not observed in C. W. Spangler and D. A. Little, J. Chem. SOC.,Perkin Trans. I , 1982, 2379. M. Bernard and W. J. Ford, J. Org. Chem., 1983,48, 326. 27 E. Angeletti, P. Tundo, and P. Venturello, J. Chem. Sac., Chem. Commun., 1983, 269. 2 8 Y. Le Bigot, M. Delmas, and A. Gaset, Tetrahedron Lett., 1983, 24, 193; L. Crombie and S. V. Jamieson, J. Chem. SOC.,Perkin Trans. I , 1982, 1467. zQ F. Watjen, 0. Dahl, and 0. Buchardt, Tetrahedron Lett., 1982, 23, 4741.

26

226


reactions with non-stabilized or highly stabilized ylides. The reaction of ethoxycarbonylmethylenetriphenylphosphorane with mucochloric and mucobromic acids gave ethyl (2E,4Z)-4,5-dihalogeno-2,4-pentadienoates(34) and not the expected (22,46)-2,3-dihalogeno-5-ethoxycarbonyl-2,4-pentadienoicacid.30 In the case of the dibromo compound (26)-5-bromo-2-penten-4-ynoate (35) is also formed. The phosphonium ylide (36) appears to undergo a retru-Michael reaction when heated since an attempted Wittig reaction with p-chlorobenzaldehyde gave ethyl p-chlorocinnamate as the major Ph p J(/

COOE t

H (37)

R' Reagent: i, NaH

Scheme 6

The reaction of (3-carbethoxy-2-oxopropylidene)triphenylphosphorane (37) with a,p-unsaturated aldehydes in the presence of base provides a new synthesis of cyclohexenones in moderate yield,32 presumably via an intramolecular Wittig reaction of the initial Michael addition product (38) (Scheme 6). Olefination of aldehydes with methyl 5-(triphenylphosphoranylidene) levalinate (39) proceeds in excellent yield33 and so provides a method of homologation to 6-ene-y-keto esters in one step. Several tetravinyl derivatives (40)of tetrathiafulvalene have been prepared by Wittig reactions with tetraformyltetrathiafulvalene.34 0

30

31 38

33 34

0

A. H. Al-Hakim and A. H. Hines, Tetrahedron Lett., 1982, 23, 5295. A. J. H. Labusschagne and D. F. Schneider, Tetrahedron Lett., 1982,23,4135. K. M. Pietrusiewicz, J. Monkiewicz, and R. Bodalski, J. Org. Chem., 1983,48, 788. R. C. Ronald and C. J. Wheeler, J. Org. Chem., 1983,48, 138. A. Gorgues, P. Batail, and A. Le Coq, J. Chem. SOC.,Chem. Commun., 1983,405.

227


Reactions of Ketones with Methy1enephosphoranes.-Intramolecular Wittig reactions have been used to prepare a variety of cyclic compounds including . ~ a~ similar way both Wittig3' and bicyclic alkenes (41)35 and cyclic i m i n e ~ In phosphonate3* reactions can be used to synthesize many strained bicyclic alkenes (42), but fail with the most strained examples, e.g., (43). Intramolecular Wittig

(41) n = 1-4

R = Me, n = 1 35

36 37 38

J. K. Crandall, H. S . Magaha, M. A. Henderson, R. K. Widener, and G . A. Tharp, J . Org. Chem., 1982,47, 5372. P. H. Lambert, M. Vaultier, and R. Corrie, J. Chem. SOC.,Chem. Commun., 1982, 1224. H. J. Bestmann and G . Schade, Tetrahedron Lett., 1982,23, 3543. H. 0. House, J. L. Haack, W. C . McDaniel, and D. Van Derveer, J . Org. Chem., 1983. 48, 1643.

228


reactions of ylides, generated by nucleophilic ring-opening of the cyclopropylphosphonium salts (44), have been used to prepare a large variety of heterocycles, e.g., (45).39Cyclic 1 ,Zdiketones (46) can be converted into bicyclic 4-alkylidene2-buten-4-olides (49) by reaction with (2,2-diethoxyvinylidene)triphenylphosphorane (47), probably via the enolate salt (48) and intramolecular Wittig reaction.40 Enolates of smaller ring diketones undergo alkylation to give the vinyl ethers (50). 0

-

-

:Is 40

0

3,

+ZOOR ROOC

0

PPh

W. Flitsch and P. Russkamp, Liebigs Ann. Chern., 1983, 521 ; W. Flitsch. K . Pandl, and P. Russkamp, ibid., 1983, 529. R. W. Saalfrank, P. Schierling, and P. Schatzlein, Chern. Ber., 1983, 116. 1463.

229


Through the Wittig reaction the phosphorane (51) acts as a convenient homologating agent for aldehydes and ketones since the alkenes (52) undergo Wittig fragmentation (as shown in Scheme 7) on treatment with fluoride reactions with various other silylalkylidenephosphoranes have been rep~rted."~

Ph3P=CHOCH 2

CH SiMe3-R 2

1R 2C=CHOCH2CH2SiMe3

(51P

K

(52)

R 1 R 2CH2CH0 + CH,j=CH2

+

Me3SiF

Reagents: i, R1R2CO: ii, HF, MeCN

Scheme 7

Miscellaneous Reactions of Methy1enephosphoranes.-The synthesis of threemembered rings by means of phosphorus ylides has been reviewed43and there have been several new reports of this type of reaction. Optically active or,P-unsaturated esters have been converted into cyclopropanes highly stereoselectively by reaction with isopropylidenetriphenylphosphorane as the key step in syntheses of both (lR,3R)-chrysanthemic acid methyl ester (53)44 and the (1R) cis-gem dibromovinyl analogue (54).45 The addition of reactive phosphonium ylides to functionalized 1,3-butadienylphosphonates provides a new synthesis of 2-cyclopenten-1-ylphosphonates(55).4s

(53)

(54) 0

Ph3P=CR

1 3

R"

Ph (55)

41 4a 43 44 45 46

K. Schonauer and E. Zbiral, Tetrahedron Lett., 1983, 24, 573. L. Birkofer and J. Kittler, Chern. Ber., 1982, 115, 3737. H. J. Bestmann, G. Schmid, and L. Kisielowski, Isr. J. Chem., 1982,22,45. J. Mulzer and M. Kappert, Angew. Chem., Znt. Ed. Engl., 1983,22, 63. M. J. De Vos and A. Krief, Tetrahedron Lett., 1983, 24, 103. T. Minami, T. Yamanouchi, S. Takenaka, and I. Hirao, Tetrahedron Lett., 1983, 24, 767.

230


The carbonyl group of thietan-Zones undergoes Wittig reactions with stabilized ylides to give isomeric mixtures of 2-methylenethietans (54).47 However although 00-dimethyl dithiooxalate also gives Wittig products (58), the analogous dimethyl tetrathiooxalate gives 1,3-dithioles(57) on reaction with phosphoranes.**

""=d-R2Nd-+ Ph3P=CHR1

RL

0

MexxI +

Ph3P=CR

k S

( 5 6 ) R1=

COOEt , CN, o r COMe

1 2 R

MeX

(57)

The addition reaction of phosphonium ylides to carbon disulphide has been further investigated and the exact nature of the 1 : 1 adducts formed shown to depend on the structure of the ylide.*@The Wittig reaction of monosubstituted phthalic anhydrides with ethoxycarbonylmethylenetriphenylphosphorane to give 3-ethoxycarbonylmethy1idenephthalides (59) has been investigated with a view to determining the factors controlling which carbonyl group reacts.60 CHCOOE t

p7 48 4Q

S. Al-Zaidi and R. J. Stoodley, J. Chem. SOC.,Chem. Commun., 1982,995. K. Hartke, A. Kumar, and J. Koster, Liebigs Ann. Chem., 1983, 267. U. Kunze, R. Merkel, and W. Winter, Chem. Ber., 1982, 115, 3653. A. Allahdad and D. W. Knight, J. Chem. SOC.,Perkin Trans. 1 , 1982, 1855.

23 1


A new method of fluoro-olefin synthesis involves initial reaction of the ylidesalt (60) with perfluoroacyl fluorides to give vinylphosphonium salts (61), rather than the acylation products.61Alkaline hydrolysis of (61) gives (E)-fluoroalkenes (Scheme 8). The reaction of non-stabilized ylides with chlorodifluoro-

[ I ] -+

Bu3P-CF-PBu3+ +

+

Bu3P-CF--PBu3

X-

0-C-F

,Bu3P

++RIC-

+

Bu3P0

X-

(60) RF

1

(61)

ii

F

Reagents: i. R,COF: ii, NaOH, HBO

Scheme 8

methane provides an alternative to the Wittig reaction for the synthesis of 1,I-difluoro-1-alkenes (62).62As well as giving better yields than carbonylolefmation, the method generates phosphonium salt and triphenylphosphine, both of which can be readily recycled.

2 Ph3P=CR1R2

+

HCF2Cl -Ph3&XR1R2

c1-

+

F2C=CR1R2

+

Ph3P

(62)

The reaction of cinnamylidenetriphenylphosphorane (63, R1= H) with ketenes provides a synthesis of 1,2,4-~entatrienes(64), although the corresponding dimer is also formed.63An analogous reaction of the 1-phenyl substituted phosphorane (63, R1= C,H6) gives the betaine (65) through addition of ketene at both a- and y-positions (Scheme 9). Continuing his study of the addition of vinylidene ylides to heteroallenes, Bestmann has shown that the intermediate (66), formed from [bis(ethylthio)vinylidene]triphenylphosphorane, undergoes 5-exo-trig~yclization.~~ The product (67) loses phosphine to give (68) (Scheme 10).

6L 6a

6s 64

D. J. Burton and D. G. Cox, J. Am. Chem. SOC.,1983, 105, 650. G. A. Wheaton and D. J. Burton, J. Org. Chem., 1983, 48, 917. L. Capuano, C. Wamprecht, and A. Willmes, Chem. Ber., 1982, 115, 3904. H. J. Bestmann and K. Roth, Angew. Chem., Int. Ed. Engl., 1982,21, 621.

232


CHMe Reagent: i, R2&=C=0

Scheme 9

+

Reagents: i, RIN=C=X;

ii, R2N=C=Y

Scheme 10

Sodium amalgam-reduction of the salt (69) (obtained from the reaction of acyl-stabilized ylides with trifluoromethane sulphonic anhydride) provides a new synthesis of acetylenes55(Scheme 11). A new synthesis of ethynyltriphenylphosphonium salts (70) is provided by the reaction of acylmethylenetriphenylphosphoranes with dibromotriphenylphosphorane and base.56 66 68

H. J. Bestmann, K. Kumar, and W. Shaper, Angew. Chem., Int. Ed. Engl.. 1983,22, 167. H. J. Bestmann and L. Kisielowski, Chem. Eer., 1983, 116, 1320.

233


0so2CF Ph3P=CR1COR2-

\

(69)

R1C=CR2

+

Ph3P + 2 CF SO Na 3 3

Reagents: i, (CF,SO,),O; ii, 2%Na-Hg, THF

Scheme 11

Although alkylation and acylation of the ylide (71) generally proceed normally, benzoylation also gives substituted pyridazines and pyrazoles through further reaction of the ylide formed initially.57 Benzylidenetriphenylphosphoranes react with benzenediazonium-2-carboxylatesto give adducts (72), which on thermolysis give mixtures of (73) and (74).583-Oxoindazolin-2-yi-(methoxycarbony1)methylenetriphenylphosphoranes (75) are the products from the reaction of methoxycarbonylmethylenetriphenylphosphoranewith the diazonium salts of isatic acids, rather than the expected arylazomethylenetriphenylpho~phoranes.~

R1COCH=PPh3

+

Ph2PBr2-

+

Et N 3

R1C&Ph3

B r - + Ph3P0 + H N E t 3 B r -

(70) Ph

H

H

PPh

Ar

+

(72)

67 68

'@

0

NCOAr 0

E. E. Schweizer and K. J. Lee, J . Org. Chem., 1982, 47, 2768. A. Compagnini, A. L. Vulla, U . Chiacchio, A. Corsaro, and G. Purrello, J. Heterocycl. Chern., 1982,19, 641. A. Alemagna, P. 0. Buttero, E. Licandro, S. Maiorana, and C. Guastini, J . Chem. Suc., Chem. Commun., 1983, 337.


234

Rq H

N-C

\

COOMe

0

Reactions of 2,3-di(methoxycarbonyl)-2H-azirine with keto-stabilized and ester-st abilized ylides give, respectively, substituted pyrroles and iminophosphoranes (76).60 A similar reaction of the ketene-stabilized ylide (77) with 3.3-dimethyl-2-phenyl-1-azirine forms the oxaphospholene (78).s1

+

Ph 3P0

MeOOC

I

H R Ph P=kCOOEt 3

M e OOC

COOMe

R

The formation of the phosphine (79) on base-treatment of methyltrimesitylphosphonium bromide is the only reported example of an uncatalysed Stevens rearrangement of a phosphonium ylide.62However, Schmidbaur has now shown that this is incorrect and the product is in fact the phosphine (81), probably Attempts to prepare the carbodiphosformed via the tautomeric ylide phorane (82) led to a related reacLion to give the cyclic carbodiphosphorane (83). 6o

6a

63

G. L'abbe, P. V. Stappen, and J-P. Dekerk, J. Chem. SOC.,Chem. Commun., 1982, 784. A. Kascheres, A. C. Joussef, and H. C. Duarte, Tetrahedron Lett., 1983,24, 1837. F. Heydenreich, A. Malbach, G. Wilke, H. Dresskamp, E. G. Haffmann, G . Schroth. and W. Stempfle, Isr. J . Chem., 1972, 10, 293. H. Schmidbaur and S . Schnatterer, Chem. Ber., 1983, 116, 1947.

Ylides and Related Compourrds

235

Mes PCH2Mes

2

(79)

+

r

Base

Mes3PCH3

Mes3P=CH2

L

Mes

=

H3C

MesZP’/ c \ ‘Phles2

I

I

CH3

CH3

(82)

M e s 2P

+

-CH2-

PMes + 2

21-

(83)

Reaction of suitably substituted phosphonium ylides with (R)-or (S)-di-0benzoyltartaric acid, followed by recrystallization, provides a simple route to optically pure phosphonium Betaines (86) are obtained by treatment of niethylenetrimethylphosphoranewith dialkyl(fluoren-9-yl)chlorosilane,possibly via the silafulvene (85).65 However, a similar reaction of the sterically hindered isopropylidenephosphorane allows isolation of the phosphonium salt (84, R2 = Me). 1 -Bromobenzyloxycarbonylmethylenetrip henylphosphorane (87) is reported to undergo decomposition on reaction with ethanol to give benzyl bromoacetate.66 The mechanism suggested is one of several possibilities but insufficient details are given for any conclusions to be drawn. 64 e6

H J. Bestmann, J. Lienert, and E. Heid, Chem. Ber., 1982, 115, 3875. I. V. Borisova, N. N. Zemlyansky, V. K. Belsky, N. D. Kolosova, A. N. Sobolev, Y. N. Luzikov, Y. A. Ustynynk, and I. P. Beletskaya, J. Chem. SOC.,Chem. Commun.. 1982, 1090.

N.F. Ozborne, J. Chem. SOC.,Perkin Trans. I , 1982, 1435.


236 2

R P=CR 3 2

I

I Rl2SiCl

~

I

R~PCHR~

RIZSiCl

Me3P=CH2

]

[

+

R12Si

R1 2 S i CH2PMe3

Various ylide complexes, e.g., (88), have been prepared by the reaction of manganese carbonyl complexes with methylenetrimethylph~sphorane.~~ The related cationic complex (89) undergoes rearrangement to the isomer (90) on treatment with base.6 -

/COOCH2Ph

0 R Q

Ph3P=C ‘Br

Me3P=CHc’

(87)

II

1

M e P+

Mk

\ ‘co co

@ I

1

+

OC F -,eC ,, OC

NaOMe

PMe

/ \SiMe3 H

3 Reactions of Phosphonate Anions

Phosphonate carbanions have been generated by treatment of the corresponding cr-silylphosphonate with fluoride 67 68 6o

W. Malisch, H. Blan, and U. Schubert, Chem. Ber., 1983, 116, 690. S.Voran and W. Malisch, Angew. Chem., Znt. Ed. Engl., 1983, 22, 151. T. Kawashima, T. Ishii, and N. Inamoto, Tetrahedron Lett., 1983, 24, 739.


237

Olefination using phosphonates continues to be a popular method, for example in the preparation of 3-vinylindole~~~ and cyclohexylidenexanthenes (91)'l from the appropriate carbonyl compounds. Moderate to good yields of a,@-unsaturatedesters and ketones have been obtained from the crown ethercatalysed reactions of aldehydes with ester- and keto-phosphonates in highly concentrated aqueous potassium carbonate Olefination of pulegone oxides, with retention of the epoxy group, gives predominantly (E)-alkene from (92) and (2)-alkene from (93).73 The carbanion derived from diethyl(l,3-

(91)

dithian-2-y1)phosphonatehas been used in a method of ring-expansion to prepare caprolactones (Scheme 12).74A general synthesis of (E)-1-fluorovinylphosphonates and hence 1-fluoroalkylphosphonates is available from the

-

OH

-

I

I

1

k

k

I

R iii

I

k Reagents: i, (EtO),!-C:]

Li';

ii, PPTS, CH,CI,, R.T.;

S

iii, AgNOS, CdCOs, MeCN, THF,Ha0

Scheme 12 S. Brooks, M. Sainsbury, and D. K. Weerasinge, Tetrahedron, 1982,38, 3019. M. A. Christie, R. L. Webb, and A. M. Tickner, J. Org. Chem., 1982,41, 2802. J. Villieras and M. Rambaud, Synrhesis, 1983, 300. 7s G. Van der Locht, H. Marschall, and P. Weyerstahl, Liebigs Ann. Chem., 1982, 1150. ',i T.-J. Lee, W. H. Holtz, and R. L. Smith, J. Org. Chem., 1982,47,4750. To

71


238

F (94)

Reagents: i, BuLi; ii, R1R2C0

Scheme 13

bisphosphonate (94) (Scheme 1 3).75 The bisphosphonate ( 9 9 , obtained from the addition of cyclohexylamine to the corresponding alkylphosphonate, undergoes olefination with aldehydes to give a-aminoalkylphosphonic acid precursors (96) (Scheme 14).76 0

0

II

II

( E t O ) 2 P y C H P ( OEt )

-

II

(

Cy NH (951

CHR

0

i, ii

II

"I'Kc" CyN

to)

Cy = c y c l o h e x y l

(96)

Reagents: i, LDA; ii, RCHO

Scheme 14

A new method for generating aldehydic enol ethers and enamines, which has some advantages over the large number of methods already available has been developed." Although based on phosphonate olefination of ketones, the method involves use of dimethyl diazomethylphosphonate to generate a diazoalkene in the presence of alcohols or secondary amines (Scheme 15). Dimethyl diazomethyl0

II

(MeO)2PCHN2

+

R2C0

*

ii

i [R2C=CN2]

1

* - .

R2C=CHOR1

iii

R2C=CHNR

1 2

Reagents: i, KOBut; ii, RlOH; iii, R1,NH

Scheme 15

76

7e

77

G. M. Blackburn and M. J. Parratt, J. Chem. SOC., Chem. Commun., 1982, 1270. M. A. Whitesell and E. P. Kyba, Tetrahedron Lett., 1983, 24, 1679. J. C. Gilbert and U. Weerasaoriya, J . Org. Chem., 1983, 48, 448.


239

phosphonate carbanion has also been used to construct a dihydrofuran ring across the 3”-4” positions of 9-dihydroerythromycin and hence as an entry into C-3”-modified erythromycins (Scheme 16).7e 1

\

OMe

- \

1

0

II -

Reagent: i, (MeO)zPCHNz

Scheme 16

Phosphonate carbanions (97), generated by the addition of various carbanions to vinylphosphonates, provide routes to functionalized alkenes.’# Thermolysis of the dienes (98) prepared in this way offers a route to 1,Cdisubstituted benzenes via electrocyclization of the intermediate trienes (99) (Scheme 17). The reaction of phosphonate carbanion (100) with alkyl or aryl benzenethiosulphonates provides a general synthesis of the useful dialkyl alkyl- and aryl-thiomethylphosphonates (101).80

’*

J. R. Hauske, M. Guadliana, and K. Desai, J. Org. Chem., 1982, 47, 5019. T. Minami, K. Nishimura, I. Hirao, H. Suganuma, and T. Agawa, J. Org. Chern., 1982, 47, 2360. J. G. Smith, M. S. Finck, B. D. Kontoleon, M. A. Trecoske, L. A. Giardano, and L. A. Renzulli, J . Org. Chem., 1983,48, 1110.

240


--

0

II

o Li+ II-

i

/SMe (Et0)2PCXCH CH \S(O)Me

I i

iii

[MesyJ] - [Mes 1 CH-CH=CHR

(99)

Y" R

X 0

II-

Reagents: i, MeSCHSMe; ii, RCH=CHCHO; iii, A

Scheme 17

New routes to substituted arylphosphonates (102) and (103) are available from the reactions of phosphonate carbanions with vinamidinium salts and P-dimethylamino enones, respectively. An extensive study of olefination reactions of phosphonate carbanions in heterogeneous media using weak bases, e.g., carbonate and bicarbonate, has been carried out .82 (For phosphine oxide-based olefin synthesis see Chapter 4.) 0

0

II

(Me0)2PCH2Li (100) as

+

RSS02Ph

II

(Me0)2PCH2SR

(101)

G. D. Ewen, M. A. K. El-Deek, D. J. H. Smith, and S. Trippett, J. Chem. Res. (S),1983, 14. J. Villieras, M. Rambaud, and B. Kirschleger, Phosphorus Sulfur, 1983, 14, 385.


24 i

R3

c104 R2

R3 "Me2

0

R1

4 Selected Applications in Synthesis Carbohydrates.-Wittig reactions of pyrimidinylmethylenephosphoranes (104) with protected D-ribose have been used to synthesize homo-C-nucleosides (105).83The alkenes formed initially can be quantitatively cyclized to (105) by treatment with amine bases. Acyclic products (106) can also be isolated from Wittig reactions of 2,3-di-O-isopropylidene-~-ribose in dichloromethane and cyclized c1

c1

1

$2

0x0

k2 Tr =

'

CPh3

N. Katagiri, K. Takashima, T. Kato, S. Sato, and C. Tamura, J. G e m . SOC.,Perkin Trans. I , 1983, 201.

242


stereospecifically using phenylselenyl chloride to give 1-substituted-l-deoxyribose derivatives, e.g., (107).84However, the alkene intermediate obtained from the reaction of the aldose (108) with diphenyl triphenylphosphoranylidenemethylphosphonate undergoes spontaneous cyclization and so provides a one-step synthesis of aldose sugar 1-phosphonates, e.g., (109).85 COOEt

RovoH RO

Ph P=CHCOOEt

I

\

*

I

t

I

PhSeCl

YOOE t

0

1 I

CH2P ( OPh ) 0

TroH2c~L~'H

+ Ph3P=CHP(II OPh )

Carotenoids and Related Compounds.-The synthesis of the last two unsynthesized geometrical isomers of vitamin A ( 7 4 3 , g-cis, 11-cis, and all cis) has been accomplished.8s2,2'-Dinorcanthaxanthin (1 13)87and canthaxanthin (114)88have been synthesized in high yield by Wittig reaction of the dialdehyde (1 12) with the ylides (110) and (1 1l), respectively. 86 87

P. D. Kane and J. Mann, J. Chem. Soc., Chem. Commun., 1983, 224. R. W. McClard, Tetrahedron Lett., 1983, 24, 2631. A. E. Asato, A. Kini, M. Denny, and R. S. H. Liu,J. Am. Chem. SOC.,1983, 105, 2923. M. Rosenberger and P. J. McDougal, J. Org. Chem., 1982, 47, 2134. M. Rosenberger, P. J. McDougal, and J. Bahr, J. Org. Chem., 1982,47, 2130.


I

= 2

(111) n

243

Phosphorus-based olefin synthesis continues to be the method of choice for the preparation of retinals and related compounds. Reports include the synthesis of retinal Schiff bases (1 15),89 the photoaffinity-labelledretinal (1 16),g0 retinoic esters (1 17),91and the acyclic analogue (1 18).92 However, earlier reports of the

4iQ c104

NK

0

A,,

0

80

@O

s1 gg

-

(115)

R

= 1 or 2

4

CHO

M. Sheves and T. Baasav, Tetrahedron Lett., 1983, 24, 1745. R. Sen, J. D. Carriker, V. Balogh-Nair, and K. Nakanishi, J. Am. Chern. SOC.,1982, 104, 3214. K. Natsias and H. Hopf, Tetrahedron Lett., 1982, 23, 3673. R. K. Crouch, J. Am. Chem. SOC.,1982, 104,4946.


244

6OOMe NaOMe, THF, -5

(1191

OC

(120 1

synthesis of all trans-(13-trifluoromethy1)retinal have been shown to be incorrect.O8 The phosphonate (119) used in the synthesis, and assumed to be trans, is now shown to be cis; hence the retinal obtained from (1 19) is really 13-cis (120). Even when the trans-phosphonate was used it isomerizcd under the reaction conditions to cis and hence still did not provide a synthesis of the all transproduct.

s9 H

PhOCH2COHN

H

COOMe

0 I

bOOCH2Ph

E, Aaato, D. Moad, M. Danny, 1982,104,49790

A.

T. T. Bopp, and R. S, HaLiu,J . Am.

Chcm. Soc.,

Ylides and Related Compound8

245

p-Lactam Antibiotics.-Intramolecular Wittig reactions continue to be used in penam and cepham synthesis, e.g., (121).04 However, problems can arise. The phosphorane (122) forms the ceph-2-em (123) rather than the expected ceph-3emo6and, unlike the corresponding cis-isomers, the phosphoranes (124) do not give penams (125), but rather thiazoles and oxazolines, presumably due to the instability of the initially formed penams.Oe COOR2

I

c00r2

Ph 3P

(122 1

R COHN,.

SCOMe

R'COHN.,

R2 J

s,

pYpph3 COOR~

(124 1

Leukotrlenes and Related Compounds.-Reviews of methods of s y n t h ~ i s ~ ~ , ~ ~ and biological activitye8of leukotrienes have appeared. Wittig reactions of the ylides (126) and (127) have been used in the Synthesis of dimethyleicosatrienoicacids.O0The eicosatetraenoicacids (130) and (13l), which are metabolites of LTB,, have been synthesized using Wittig reactiond of ylides (128) and (129), respectively.100Arachidonic acid metabolites (132) and (133) have been prepared by cis-olefination with ylides (134) and (135).lo0'

O4 O4 Oe O1 go

C, L. Branch and M. J, Peareon, J. Chem. Soc., Perkln Trans, 1 , 1982, 2123. T. Kametani, N. Kanaya, ToMochizuki, and T,Honda, TetrahedronLett,, 1983,24, 1511. J. R.Irving, E. Perrone, and ReJ. Stoodley, TetrahedronLett,, 1983,24,2501. J, Akroyd and F,Scheinmann, Chem. Soc. Rev., 1982,11, 321, R. H. Orsen and P,F. Lambeth, Tetrahedron, 1983, 39, 1687. C. D. Perchonock, J. A. Finkelstein, I. Ukinekas, J, 0. Gbabon, H,M. Sarau, and L. B.

Cielinnki, TetrahedronLett,, 1983, 24, 2457.

R. Zambani and J. Rokath, TetrahedronLett,, 1982, 23, 4751, S, Manna, J, R. Falck, N. Chacos, and J. Capdevila, Tetrahedron Lett,, 1983, 24, 33.

loo


246

Ph3P

’

XR (126) R = COOH

( 128) R2= COOMe

(127) R = C5Hll

1 2 (129) R = CH20R

HO

(130) R = COOH (131) R = CH20H

OR Y X

(132) X = H , OH or X = 0 ; Y = Me (133) X = H , H ; Y = OH

d

Ph gP

-0-N

Ph 3P

A short synthesis of the important leukotriene synthon (136) has been reported.lo2Good, reliable methods of synthesis for leukotrienes and related compounds have now been developed, although the work still requires a high level of practical skill on the part of the chemist. The Wittig reaction has been lo2

L. S. Mills and P. C. North, Tetrahedron Lett., 1983, 24, 409.


247

OR

used to synthesize the 5s- and 5R-isomers of HETE (137)lo3and tetrahydro7E,9Z-leukotriene A methyl ester (138).lo4 LTAl methyl ester itself has been prepared using a similar reaction of the epoxyaldehyde (140) with the phosphonate (139)(Scheme 18) as the key step.lo6The first total synthesis of 5-desoxyleukotriene D (141) uses a Wittig reaction of non-3-enylidenetriphenylphosphorane to form the carbon chain.lo6 OHC

OR'

I COOR2

1

2

(137) R = R = H

O Ph3P=CHC10H21

lo3

>.

C

C

COOMe

R. Zambi and J. Rokach, Tetrahedron Lett., 1983, 24, 999. Crea, W. Petters, and W. Konig,Tetrahedron Lett., 1983, 24, 2135. F. Ellis, and P. C. North, Tetrahedron Lett., 1982, 23, 4161. E. J. Corey and D. J. Hoover, Tetrahedron Lett., 1982, 23, 3463.

lo4 B. Spur, A. lo6J. C. Buck,

lo6

H

+


248

Reagents: i, NaH, THF. 15-crown-5, 0 OC, l h

Scheme 18 600H S C HCHCONHCH~ ~ COOH

I

NH2

Pheromones.-Further use has been made of Bestmann’s ‘unitized construction principle’ to synthesize a variety of 1’5- and 1,dalkadiene pheromones.107 Standard Wittig methods have been used to synthesize (32,62,92)-1,3,6,9nonadecatetraene (142) (Scheme 19) (now identified as a sex pheromone of the winter moth 0. brumata),loesex attractants (143) of Laslocampidae species,1oe and the trail pheromone (144) of Pharaoh’s ant.llo A variety of 2,4-dienoic ester insect juvenile hormone analogues (145) with terminal cyclohexene, cyclohexane, or pinene rings have been prepared by phosphonate olefination.lll The queen H,J. Bestmann, KaH.Koschatzky, and 0. Vostrowsky, Liebigs Ann. Chem., 1982, 1478. H. J. Bostmann, T. Brosche, K, H,Koschatzky, K, Michaelis, H.PIatz, K.Roth, J. Suss,

lo’ lorn

0. Vostrowsky, and W. Knauf, Tetrahedron Lett., 1982,23,4007. J. Bestmann, K. H. Koschatzky, H. Platz, J. Suss, 0. Vostrowsky, W, Kncruf, G.

loo H.

Burghardt, and I. Schneider, Lieblgs Ann, Chem,, 1982, 1359, DmW. Knight and B. Ojhara, J. Chcm. Soc,, Perkln Trans, I , 1983, 955. *li L,Borowiscki, A. Kazubski, and E,Reca, LfebfgsAnn. Chrm., 1982, 1766; L,Borowiscki and E,Reca, fbid,, 1982, 1775.


249

E

I Id

cv =m

n

+

8

t

250


recognition pheromone (146) of the red imported fire ant Solenopsis invicta has been synthesized as a roughly equal mixture of isomers;l12however, the (2)-is completely isomerized to the (E)-form by treatment with iodine in benzene.

0 +

0

Ph3P=CH(CH2)2Me

-

CH=CH ( CH2 )2Me

CHO

-

Attempt.s to synthesize (2E,42)-2,4,1l-dodecatrien-l-a1 (147), a linolenic acid degradation product, using the Wittig reaction, led to isomerization of the terminal double bond.113 This isomerization apparently takes place during synthesis of the phosphonium salt (148). OHC

( CH2 )5CH=CH2

(148) R =

@(CH2)6, MeCH=CH( C H 2 I 5 ,

or

MeCH2CH=CH(CH2)4

A new general route to methyl ketones has been developed from unsaturated acyl ~1ides.l'~ The method involves addition of a nucleophile to give an ylidic carbanion, which can be alkylated to provide the required substitution and finally hydrolysed to give the methyl ketone. The method is illustrated by a synthesis of the sex pheromone (149) of the California red scale (Scheme 20). A modification of this method by reduction of the intermediate phosphorane (150) with aluminium amalgam to give a P-keto ester, followed by alkylation and decarboxylation, provides a new synthesis of ketones.l15This is illustrated by a synthesis of (151), the defence substance of L. longipes (Scheme 21). The doubly stabilized ylides (152) can also be converted into the carboxylic acid (153), derived from the acyl group in high yield by oxidation with excess alkaline sodium hypochlorite, presumably by a mechanism analogous to the haloform reaction (Scheme 22).l16 112

J. R. Rocca, J. H. Tumlinson, B. M. Glancey, and C. S. Lofgren, Tetrahedron Lett., 1983. 24, 1889.

F. Bohlmann and W. Rotard, Liebigs Ann. Chem., 1982, 1216. M. P. Cooke, jun. and D. L. Burman, J. Org. Chem., 1982,47,4955. 115 M. P. Cooke, jun., J. Org. Chem., 1982, 41, 4963. llS

114

116

M. P. Cooke, jun., J . Org. Chem., 1983, 48, 744.

25 I

).'/idesarid Related Compounds

T H op-

i , ii,

Ph 3P

Ph 3P

/ (149)

; iii, AcOH; iv, NaOH; v, EtOH,

Reagents: i, CH2=CHCH,Li, ii, BrCH, (CH,),OTHP H,O. 70 OC: vi. Ac20, py: vii. Ph,P=CH2

Scheme 20

0

0

ii, iii

1

Reagents: i, AI-Hg: ii, Mel; iii, BafOH),

Scheme 21

0

252


RTooH + C12CHCOOH + Ph3P0

(153)

Roagents: i, NaOCI. THF: ii. NaOH

Scheme 22

Prostaglandins,-The synthesis and biological properties of prostacyclin and its analogues has been reviewed.ll7 The now standard Wittig methods have been used to construct side-chains in syntheses of various prostaglandins and related compounds including sixmembered ring analogues of 6ct-carba-PGI,,lle 12-azacarboprostacyclins,e,g., (154),110 and the cyclic sulphonamido analogue (155).lmoA new route to the

O2

OH

prostaglandin side-chain synthon (157), which retains optical purity, involves acylation of t-butoxycarbonylmethyleneylide (156) followed by decarboxylation (Scheme 23).lQL W,Bartmann and a, Beck, Angew. Chern., Int, Ed. Engl., 1982, 21, 7.51. u8 f, C. Sih, J , Org. Chem., 1982, 47, 431 1, llp C.-L. J, Wang, Terrahcdron Left., 1983, 24, 477. lUu D. N, Jonas and K. W. Lumbard, Tetrahedron Left,, 1983, 24, 1647, la1 F. Buzzetti, N, Barbugian, and C, A. Oandolfl, Terrahcdron Lerr,, 1983, 24, 2505. 11'

25 3

Yiides and Related Compounds

-

ii

i

Ph3P=CHCOOR1 ( R 1 = But)

Ph3P= CHCO&R2R3

Ph3P=CCO;HR2R3-

I

COOR'

(1561

(157)

Reagents: i , RnRs6HCOCl: it, p-MeC,H4SOsH, PhH, 80 "6: Scheme 23

The ylide (1 58) and dimethyl 4=(methoxycarbonyl)-2=(oxobutyl)phosphonate have been used to construct the side chains in the Arst reported synthesis of the major metabolite (159)of PC3Da.1aaWittig reactions with polyether ylida, e.g., (160),have been used to construct the side chains in the synthesis of a variety of furan-based secoprostacyclins.1a8

PH

Miscellaneous Applications.-The Wittig reaction of (E)-6,1O-dimethyl-5,9undecadien-2-ylidenetriphenylphosphorane with ethyl fruns-(2-~arboxaldehyde)cyclopropanecarboxylateyields a 1 : 1 mixture of (E)- and (Z)-alkene~.1~~ The former isomer was converted into an analogue (161)of a proposed intermediate in squalene biosynthesis, (10R,11R)-(+)-Squalene-l0,ll-epoxide(164),identical to a constituent of the red algae Laurencfu okumurj, was isolated from the isomeric mixture produced from a Wittig reaction of the ylide (162)with the aldehyde (163)Y

E. J. Corey and K. Shimoji, J. Am, Cham. Soc., 1983, €05,1662. Saunders, D. C. Tipney, and P. Robins, Tetrahedron Lett., 1982,23,4147, R. M.Sandifer, M.D.Thompron, It,0. Gaughan, and C, D.Poulter, J, Am, Clrem. Soc.,

laa J.

1982,104,7376,

H.Kigoshi, M.Ojjka, Y, Shizuri, H,Miwa, and KnYamada, TefrahrdronLett., 1982.23.

5413.

254


0

m

u

n

TY (D W ri

/

1 t u X II

n

I+ (D

I+ v

am c

a


255

Some phosphonates, e.g., (165), derived from tetramic acids have been prepared and shown to undergo normal olefination with ketones in work ultimately aimed at the synthesis of tetramic acid-containing natural products.lasA general method for the synthesis of 3-enoyl and 3-dienoyl tetramic acids, involving olefination with the phosphonate (166), has been R1

1

HN$qpi( 0

OR

0

0

(167) m

0

0

= 1 or 2

Syntheses of a variety of naturally occurring polyene and polyenyne amides have been reported.12* Pepper alkaloids have been obtained using the Wittig reactioda9and phosphonate, e.g., (1 67),lS0routes.

OMe

Ph ,P

0

\

R1O

/

0

OR2

-

eM&

0

/

R1 0

/

0

0r2

R. K. Boeckmann and A. J. Thomas, J. Org. Chem., 1982,47,2823. P. Deshong, N. E. Lowmaster, and 0. Baralt, J. Org. Chem., 1983, 48, 1149. la* F. Bohlmann, M. Gamer, M. Kruger, and E. Nordhoff, Tetrahedron. 1983. 39. 123. l t O B. G. Pring, J. Chem. SOC.,Perkin Trans. I , 1982, 1493. 130 S. Linke, J. Kurz, and H.-J. Zeiler, Liebigs Ann. Chem., 1982, 1142. las la'

256


Fused ring systems have been synthesized using both inter- and intra-molecular Wittig reactions. Various polyaromatic compounds, e.g., (1 69), have been prepared in one step by the reaction of the diylide (168) with the appropriate o-quinone.lal An intramolecular reaction of ylide (170) has been used to synthesize the dihydronaphthacene (171) as an early step in the synthesis of 3-demethoxyaranciamycinone,an anthracyclinone analogue.la2

(172 1

(173) X

(174) X

-

-

CH2 or 8

0, S , or (CH2)2

‘

S/CH=PPh3 CHzPPh (176)

(175)

X = 0 or S

A series of preliminary reports of the synthesis of annulene dioxides, e.g., (172) and (173), using Wittig reactions of diylides (174) has appeared,183 Bis-Wittig reactions, in this case of the diylide (175), have also been used to prepare furano- and thieno-[3,4-d]thiepins, e.g., (1 76).lB4

OR

OR ( 1 7 8 ) X = CHO, R

-

H

D. N,Nicolaides and K. E, Litinas, J . Chern, Res. (S),1983, 57, Krohn and E,Broser, Lleblgs Ann. Chem., 1982, 1907. IRA H. Ogawa, C. Fukuda, T. Imoto, 1. Miyamoto, Y. Taniguchi, Y . Koga, and Y . Nogami, Terrahedron Lett., 1983, 24, 1045; H. Ogawa, C. Fukuda, T. Omoto, I. Miyamoto, H. Kato, and Y. Taniguchi, Angew. Chem4, Int. Ed. Engl., 1983,22,417; H. Ogawa, N . Sadabari, T. Imoto, I. Kiyamoto, H. Kato, and Y. Taniguchi, ibbld., 1983,22, 417. Ia4 D,N. Nicolaides, E. C. Tsakalidou, and C. T. Hatziantoniou, J , Heterocycl. Chem,, 1982. Ia1

lag K.

19, 1243.

YIfdes and Related Compounds

257

The antibiotic aurocitrin (178) has been synthesized using a Wittig reaction of the dienylidene ylide (177),lsa A series of PO-olefinations have been used to construct the polyene system (179), which, after suitable modification, was cyclized to (180) in a trial of a new approach to the synthesis of the polyether antibiotic X-14547A.las

0

II

(Me0)2PCH2COOR ( 1 8 11

+

e

Base

R

O

O

C

A

0-

0

L C, Ronald, J. M,Lansinger, T,S. Little, and C. J, Wheeler, J. Org. Chcm.. 1982, 47, 2541. la0 W. R. Roush and 5. M,Psseekie, Tetrahedron Lett., 1982, 23,4879. la6 R.


258

'p \

Ylides and Related Cornpoutids

2 59

A new synthesis of verrucarin J uses a PO-olefination reaction of the phosphonate (181) with malealdehydic acid as a key step to give verrucarin J seco acid (182) which can be cyclized to verrucarin J.I3' The all (E)-triene (1 83) has been synthesized en route to a total synthesis of omp pact in.^^* Various eupomatenoids, e.g., (184), have been prepared by a simple procedure involving a one-pot quarternization and intramolecular Wittig reaction as the key step (Scheme 24).139In a series of papers investigating the synthesis of the endiandric acids both Wittig and phosphonate oldinations have been used.140 0

II-

( EtO)2PCHCOCHMe2

(185)

The phosphonate anion (185)requires a much shorter reaction time and milder conditions than the ylide (186) to convert dinorcholenaldehyde into 3P-acetoxycholesta-5,22(E)-diene-24-0ne.~*~ A Wittig reaction of trans-2-methylcyclopropylmethylenetriphenylphosphorane with aldehyde (187) has been used to synthesize the four possible sterol isomers (188)142 of papakusterol and by comparison establish the stereochemistry of the natural material as (E).

yHo+ -

-.+

H

R

( 1\87)

13'

13* 13B 14*

141 142

W. R. Roush and T. A. Blizzard, J. Org. Chem., 1983, 48, 758. M. Hirama and M. Uei, J. Am. Chem. Suc., 1982, 104,4251. B. A. McKittrick and R. Stevenson, J. Chem. SOC.,Perkin Trans. 1 , 1983, 475. K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, and J. Uenishi, J. Am. Chem. Suc., 1982, 104, 5555 and 5557; K. C. Nicolaou, R. E. Zipkin, and N. A. Petasis, ibid., p. 5558; K. C. Nicolaou, N. A. Petasis, and R. E. Zipkin, ibid., p. 5560. P. H. Le, M. W. Preus, and T. C. McMorris, J. Org. Chem., 1982,47, 2163. C. Bonini, R. B. Kinnel. M. Li. P. J. Scheuer. and C. Djerassi. Tetrahedron Lett.. 1983. 24, 277.

9 Cyclic and Polymeric Phosphazenes* BY J, C, VAN DE GRAMPEL AND B. DE RUITER

I Introduction This review covers the literature on cyclic and polymeric phosphazenes over the period mid 1979-mid 1983, When touching on some trends it can be concluded that applied research is going to occupy an increasingly important position, which is reflected by the large number of patents and patent applications. The discovery of metal-halogen exchange reactions has opened a new field of research, the limits of which have not yet been reached. Aziridinyl derivatives of cyclophosphazenes and related sulphur-containing ring systems have drawn attention as potential anticancer agents. The growing interest to side-group alteration is focused on the use of polyphosphazenes as carriers for chemically and biomedically (re)active species I

2 Cyclic Phosphazenes

Introduction,-Few reviews have appeared dealing with more or less general aspects of cyclophosphazene chemistry. The role of cyclophosphazenes as model compounds for reactions of their polymeric analogues has been discussed;' some fundamental subjects in the area of phosphorus-nitrogen chemistry such as aminolysis, alcoholysis, hydrolysis, and tautomerization phenomena have also been discussed.*An extensive review has appeared dealing with reactions of phosphazenes with alkoxides and aryloxides.a A book has been published covering the subject of sulphur-phosphorusnitrogen ring system^.^ The chemistry of some specific examples of these rings, NPC19(NSOCI)Pand (NPCla)aNSOCI,has been reviewed in detail.b Formation of the Ring Skeleton.-The increasing interest in polyphosphazenes has intensified the investigations concerning the preparation of their most *Dedicated to tho memory of Jacob M. E. Ooldschmidt, He R. Allcocb, Acc. Chcm. Res,, 1979, 12, 351. R. A. Shaw, Pure Appl. Chem., 1980, 1063. V. V. Kireov, V. I. Astrina, and E. A. Chernyshev, Usp. Khlm., 1980,50,2270 (Russ. Chem. Ruv., 1981, 50, 1186). H. 0. Heal, 'The Inorganic Hoterocyclic Chemistry of Sulfur. Nitrogen, and Phosphorus', Academic Press, London, 1980. J. C. van do Grampel, Rev. Inorg. Chem., 1981,3, 1.

260

Cyclic and Polymeric Phosphazenes

261

important precursor (NPCla)s, The most important of these preparations follow well known routes and will not be considered here. Many minor alterations of the PClJNH4C1 procedure have been patented; particular attention has been paid to choice of catalystaand purification procedure.' Redistribution of CI and NHa ligands between the starting materials leads to tl complex mixture of products if (1) is allowed to react with MepPCIs,8 c1-

Ph PHN\ + PPh2

I

21 hi2

+ Me 2PC 1

NH2

(1)

Monomers (2) can be used as precursors for cyclic or polymeric dialkylphosphazenes; for X = Br cyclic oligophosphazenes (n = 3-5) are generally formed.s

-

IR1 Me3SI-N-P-X

'9

X = Br, OCH2CF3, NMe2

(NPR1R2)n

R1,R2

-

Me, Et, Ph

n > 3

(2)

Sulphur-containing cyclophosphazenes have been prepared using a novel approach, viz. reactions of simple PI1*compounds with S4N4;lo(3) was prepared from S4N4and (RpP)p (R = Me, Ph) or RBP (R = OPh), (4) from S4N4and c1 R\ N\'/N

-

I

k N / S

lo

Ph P '

11

hP,!

I'N)!

Ph

Ph

p

c q

I'NgI

c1

c1

Me, Ph, OPh (3)

'

O\,/C1 ' N %N

N 0'\N

1

R

I

0 R

(4)

(5)

c.g., I. Kinoshita, Y.Ogata, and M, Suzue, Ger. Offen., 2 851 911 (Chcm, Absrr., 1980. 92,61 204); Jpn. P. 79 151 593 (Chcm, Absrr,, 1980, 92,113 147); 80 15 956 (Chcm. Absrr,. 1980, 92, 261 240); J. W.Hudson and T,F. Dominick, Swiss P., 620 173 (Chcm. Absrr., 1981, 94, 86 574); K. Horie, Y. Moritrr, Y, Mikamori, M. Suzuki, and S. Yano, Ger. Offen.,3 112 192 (Chcm, Absrr., 1982,96, 183 677) u.g,, I, Kinoshita, Y oOgata, K. Nishiuchi, S, Masuda, M. Suzue, and T. Hasegawa, Jpn. Pa,80 23 041 (Chem, Abstr,, 1980,92, 199 047); I. Kinoshita, S, Masuda, and T,Hasegawa. Jpn, Po,80 15 439 (Chum. Abstr,, 1980,93,46 827); Otsuka Pharmaceutical Co, Ltd,, Jpn, P., 80 136 106 (Chum, Abstr,, 1981, 94, 142 069); L. W. Anderson, US P,,4 259 305 (Chcm. Absrr,, 1981, 94, 194 454); CmH. Kolich, US Pa,4 241 034 (Chum. Absrr., 1981, 94, 86 580); J, W,Fieldhouse and D, F. Graves, Eur. P. Appl., 46 584 (Chcm. Absrr., 1982, 96, 218 398). K,D , Oallicano, R. T. Oakley, and N,L. Paddock, J , Inorg. Nucl, Chcm., 1980,42,923, R,H,Neilson and P,Wisian-Neilson, J. Mucromol. Scl., Chcm., 1981, 16, 425, (a) N,Burford, T. Chivers, A. W. Cordes, W. G, Laidlaw, M, C,Noble, R,T. Oakley, and P. N. Swepston, J. Am. Chcm. Soc,, 1982, 104, 1282; (b) T. Chivers, M. N. S. Rao, and S. F. Richardson, J. Chcm. Soc., Chcm. Commun., 1982,982.

262


CIPPh2. A synthesis of ( 5 ) using sulphamide, PC15, and (Me,Si),NH that gave good yield has also been reported.ll Carbon-containing phosphazene rings have been constructed from the usual building blocks of organic cyano- and/or amino/imino compounds and a Pv-Cl derivative.12 Aspects. Kinetic data of reactions of Reactions with Amines.-Fundamental (NPCI,), and with t-butylamine in THF and acetonitrile are in agreement with an sN2 (P) mechanism for the first substitution step. The higher rate for the tetramer is due to a lower value of AH*.13 For the dimethylamine case, kinetic evidence has been presented to show that the trans-preference for the (nongeminal) second amination step of (NPCI,), in ethereal solvents is caused by an entropy effect; this is ascribed to a neighbouring-group interaction in a key R 2N- -H.

I

I

-c1

NR2

intermediate in the process of trans-substitution that facilitates elimination of HCI (substituent solvating effect).14 Equilibrium studies show that cisltruns isomerizations of dimethylamino derivativesof (NPCI2),by amine-hydrochlorides proceed either by means of nucleophilic attack of CI-, or are initiated by C1 elimination.16 The rates of reaction of amines with N,P,CI,R (R = primary or secondary amino) are hardly influenced by the size of R.lS If R is a primary amino ligand. the incoming amino group can also take a geminal position, due to initial

Reagents: i. base; ii, RNH,

deprotonation of the amino ligand already present.17 Aziridine, a secondary amine previously claimed to react exclusively geminally, has now been shown to give both geminal and non-geminal disubstituted products.18 D. Suzuki, H. Akagi, and K. Matsumura, Synthesis, 1983, 369. e.g., K. J. L. Paciorek, T. I. Ito, and R. H. Kratzer, J. Fluorine Chem., 1980,15, 327 (Chem. Abstr., 1980, 93, 132 558); P. P. Kornuta, L. S. Kuz'menko, and L. N. Markovskii, Zh. Obshch. Khim., 1979, 49, 2201 (Chem. Abstr., 1980, 92, 58893); A. P. Boiko and V. P. Kukhar, Zh. Obshch. Khim., 1981, 51, 517 (Chem. Abstr., 1981, 95, 7 234). la S. S. Krishnamurthy and P. M. Sundaram, J. Chem. SOC.,Dalton Trans., 1982, 67. l4 J. M. E. Goldschmidt and R. Goldstein, J. Chem. SOC.,Dalton Trans., 1981, 1283. l6 N. Friedman, J. M. E. Goldschmidt, U. Sadeh, and M. Segev, J. Chem. SOC.,Daltori Trans., 1981, 103. l6 J. M. E. Goldschmidt and E. Licht, J. Chem. Soc., Dalton Trans., 1981, 107. l7 Z. Gabay and J. M. E. Goldschmidt, J. Chem. SOC.,Dalton Trans., 1981, 1456. A. A. van der Huizen, A. P. Jekel, J. Rusch, and J. C. van de Grampel, Red. Tmv. Chirn. Pays-Bas, 1981,100,343.

l1 l2

263


Electron-donating ligands linked to the phosphazene ring promote a changeover from a second-order substitution mechanism to a first-order one;Ie this observation is probably connected with the solvent effects reported for amination reactions with N3P3C14R4(R = secondary amino)2oand N3P3C15(N=PPh3).21 Spirocyclic Compounds. Reactions of ring systems containing NPCl, units with difunctional reagents HX-(CH,),-YH (X,Y = NH, 0, NMe; n = 2 4 ) lead to spirocyclic d e r i v a t i ~ e s . If ~ ~X* or ~ ~Y = NH only mono(spirocyc1ic) derivatives

/

TP-k /\

N\ -P=N

p ,

;CH2)n

Y

\

can be obtained in substantial yield; attempts to substitute more chlorine ligands lead to extensive resin formation, presumably due to an initial proton abstraction from the mono(spir0) compound.22For H,N-(CH,),-NH, a bridged compound RNH-(CH,),-NHR (R = N3P3CI,) is formed in addition to the mono(spiro) Similar bridged products have been isolated from reactions with o- and p-phenylenediamine.26 Bicyclic Compounds. Reactions between (NPCl,), and primary amines (1 : 4) preferentially lead to t r a n ~ - ( 6 )If. ~(~6 ) is permitted to react with an excess of dimethylamine in acetonitrile or chloroform, the expected product trans-2,6N4P4(NHR)2(NMe2)6 is accompanied by the bicyclic compound (7). A mechanism C 1 HNR

R

/\

@\

N N

Cl

c1

R = Me, Et, P r n 9 Bun, B z ,

(6)

R lo 2o

21 22

23

24

2b z6

N N

I

(7)

# P r i , B u t , Ph

K. V. Katti and S. S. Krishnamurthy, Phosphorus Sulfur, 1983, 14, 157. D. J. Lingley, HA.Yu, and R. A. Shaw, Inorg. Nucl. Chem. Lett., 1980, 16, 219. S. S. Krishnamurthy, P. Ramabrahmam, A. R. Vasudeva Murthy, R. A. Shaw, and M . Woods, Inorg. Nucl. Chem. Lett., 1980, 16, 215. S. S. Krishnamurthy, K. Ramachandran, A. R. Vasudeva Murthy, R. A. Shaw, and M . Woods, J. Chem. SOC.,Dalton Trans., 1980, 840. V. Chandrasekhar, S. S. Krishnamurthy, A. R. Vasudeva Murthy, R. A. Shaw, and M . Woods, Znorg. Nucl. Chem. Lett., 1981, 17, 181; B. de Ruiter, G. Kuipers, J. H. Bijlaart. and J. C. van de Grampel, 2. Naturforsch., Teil B, 1982,37, 1425. G. Guerch, J.-F. Labarre, R. Lahana, R. Roques, and F. Sournies, J. Mol. Struct., 1983. 99, 275. S. S. Kuznetsova and R. P. Smirnov, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1978,21, 346 (Chem. Abstr., 1978, 89, 109 422). S. S. Krishnamurthy, K. Ramachandran, and M. Woods, Phosphorus Sulfur, 1981,9,323.

264


for its formation has been proposed, in which deprotonation of one of the NHR ligands of (6) is the initiating step, followed by intramolecular nucleophilic Similar bicyclic derivatives have been prepared earlier from reactions of N4P4C18with an excess of various primary amines, or even dibenzylamine; in the latter case, the formation of the bicyclic product requires an intervening dealkylation stepY Sulphur-containing Rings. In the products of reactions of (8) (X -- C1, F) and (9) (X = Ph) with primary amines, the amino ligands are linked exclusively to P, 0

0

I,N\I

x/l

c1

c1

y\x N\ p H N

c1’

‘c1

If possible, geminal as well as non-geminal disubstituted derivatives are formed.ag Reactions of (9) (X = C1, Ph) with secondary amines follow a non-geminal pathway, with preferential attack from the ‘oxygen side’ of the ring plane;aOtalfor (9) (X = C1) the third chlorine atom to be substituted (with inversion) is the sulphur-bonded oneY Reactions of (8) with dimethylamine are less straightforward, involving both solvent-dependence and isomerization reactions,

R = Ph, CC13

R*- CC13, Ph, Et, C1, H R2= CN, M e , C1, H

(10) (11)

Carbon-containlng Rings. Both in (10) and (11) C1’ is the first chlorine ligand that is substituted by amino residues;aa(10) (R = C1) is readily converted into the tetrakis(I -aziridinyl) derivativeOs4 S. S, Krishnamurthy, K, Ramachandran, A. C. Sau, R. A. Shaw, A. R,Vasudeva Murthy, and M,Woods, Inorg. Chcm,, 1979, 18, 2010. S. S, Krishnamurthy, P, M. Sundaram, and M,Woods, Inorg. Chem,, 1982,21, 406. C, Cnossen-Voswijk and J. C,van de Grampel, Z,Nuturfbrsch., Tell 8, 1979, 34, 850: C. Cnossen.Voswijk, I, C. van de Grampel, and C,Kruk, Ibld., 1980,3S, 1559, ao B. de Ruiter and J , C , van de Grampel, Org. Magn. Rcson., 1981, 1S, 143. B. de Ruiter, H,HeBaalmann, and J. C. van do Orampel, J , Chem Soc., Dalfon Trans,, uT

1982,2337,

a3

84

B. de Ruiter and J, C. van de Grampel, J . Chcm, Soc., Dalfon Trans,, 1982, 1773, P. P, Kornuta, N. V. Kolotilo, and V. No Kalinin, Zh, Obshch, Khlm., 1979, 49, 1777 (Chon, Abstr., 1980, 92, 6 616); P. P. Kornuta, L. S. Kuz’msnko, and V. N, Kalinin, Zh. Obshch. Khlm., 1980, SO, 1313 (Chrm, Abstr., 1980,93, 204 4981, E. Fluck and M,Pachali, Chcm.-Zfg,, 1982,106, 270 (Chem. Absfr., 1982,97, 198 273),


265

Miscellaneous. Reactions of cyclophosphazenes (NPCla), (n > 3) with n-butylamine (and other nucleophiles) have been suggested to be accompanied by ring-ring interconversion reactions.a6 Only powerful nucleophilic reagents are able to replace more than one F of every PFPgroup in (NPF,), and e; the low reactivity is due to the poor leavinggroup capacity of F-.aa Reactions of (NPBr,), with ethylamine proceed similar to analogous reactions of (NPCla)a, but resin formation is more Reactions with Alcohols.-Reactions of (NPClJa" and (NPCla)48@ with NaOPh have now been thoroughly investigated. Substitution reactions of the rings as well as the polymer (NPCla)" with alkyl- and aryloxides are accelerated drastically by addition of (Bu;N)+X- (X = C1, Br) to the reaction mixtures.4o Monospirocyclic derivatives of (NPC1a)a have been prepared from reactions with some dihydroxybinaphthyls; the conjugation within the naphthyl moieties in the

I

II

products has been investigated by U.V. spectroscopy. salts of various steroids give 'monosubstituted derivatives of (NPClJa, the remaining ligands being readily replaceable by other organic groups,4a Protected a-D-gIucose can be linked to phosphazenes, and then be deprotected and chemically modified,4a Olefinic side groups can be attached to the phosphazene rings by reaction of (NPXJa (X = C1, F) with enolate anions of various carbonyl corn pound^;^^^^^ bonding to the ring takes place via the oxygen atom. The series of vinyloxy derivatives has received particular a t t e n t i ~ n Fluorinated .~~ olefinic side groups G. I. Mitropol'skaya, V. V. Kireev, V. V. Korshak, and A, A, Goryaev, Zh, Obshch, Khlm,, 1982,52,2486(Churn, Absrr,, 1983,98,107 408). T.L.Evans and H. R. Allcock, Inorg. Chum., 1979,18,2342, S,5. Krishnamurthy, M,NoS,Rao, and M. Woods, J, Inorg, Nucl. Chum., 1979,41,1093. W. Sulkowski, A, A, Volodin, K. Brandt, V, V. Kireev, and V, V. Korshak, Zh, Obshch. Khlrn., 1981,51, 1221 (Chum, Abstr., 1981,95, 169 303). K.S,Dhathathreyan, S. 5. Krishnamurthy, and M. Woods, J. Churn. Soc., Dalton Trans., 1982,2151, 40 P,E.Austin, C3, H. Riding, and H.R. Allcock, Macromolecules, 1983,16,719, IC,Brandt and Z, Jedlifiaki, J, Or#, Chrrn., 1980,45,1672;K. Brandt, fbld, 1981,46,1918; K. Brandt and W,Kaaperczak, Sprcrrochlrn. Acts, Purr A , 1982,38,961, 4m H.R. Allcock, T.J. Fuller, and K,Matsumura, J, Org. Chum., 1981,46, 13, H,R. Allcock and A. C3, Scopelianos, Macromokcuk~,1983, 16,715. 44 PIJ. Harris, M.A. Schwalke, V. Liu, and B. L. Fisher, Inorg. Chum., 1983,22, 1812, C, W, Allen, K.Ramachandran, R. PoBright, and J. C. Shaw, Inorg, Chlm. Acta, 1982,64, L109;K,Ramachandran and C. W,Allen, Inorg, Chum,, 1983,22, 1445.

266


can be introduced by modifying the analgous -OCH,CF, derivatives via the following reaction sequence :46 BuLi

Rx

Li

( R = H , D, Me, SnPh3)

Reactions of (8) (X = Cl, Ph) with NaOR (R = Me, Ph) afford mono- and disubstituted products with the oxide ligand(s) attached to P.47Compound (10) (R = Ph) reacts with NaOR (R = Me, Et, Pr, Ph) to afford products with the oxide ligands bonded to P and/or C. They readily rearrange to products with phosphazane character R

I

" " y N , y O R

N\

___)

phYNYo

//N

ROOp\OR

Similar rearrangements have been observed for alkoxy (in particular methoxy) derivatives of (NPCl,), and The composition of the products depends on the technique used for the rearrangements (solution or melt). The mechanism involves autocatalysis, whereas intermolecular OR exchanges occur.49In some instances, cyclophosphazenes with partial phosphazane character have been isolated.50 4.49950

Hydrolysis and Related Phenomena.-ln connection with their prospective biomedical applications, the hydrolysis of fully aminated derivatives of (NPCI,), has been scrutinized. In general, primary amino derivatives hydrolyse much faster than do secondary amino ones to give ring-opened products, the pentakis(amino)-monohydroxy derivative being an intermediate in the P I - O C ~ S S . ~The ~ 1-imidazolyl derivative N3P31m6reacts more rapidly than any other primary amino derivative investigated, probably due to an initial protonation of the dico-ordinated nitrogen atom of the ligand~.~, The complex hydrolytic behaviour of [NP(NH2)J3 and to several linear P-N derivatives has been investigated in detail.53 46

47

H. R. Allcock, P. R. Suszko,and T. L. Evans, Organometallics, 1982, 1, 1443. D. M. Kok, A. M. G. Kok-Hettinga, and J. C. van de Grampel, Znorg. Chim. Acta, 1982, 59, 105.

48 49

6o

51 52

53

P. P. Kornuta, N. V. Kolotilo, and L. N. Markovskii, Zh. Obshch. Khim., 1982, 52. 590 (Chem. Abstr., 1982, 97, 23 896). W. T. Ferrar, F. V. DiStefano, and H. R. Allcock, Macromolecules, 1980,13, 1345. K. S. Dhathathreyan, S. S. Krishnamurthy, A. R. Vasudeva Murthy, R. A. Shaw, and M. Woods, J . Chem. SOC.,Dalton Trans., 1981, 1928. H. R. Allcock, T. J. Fuller, and K. Matsumura, Inorg. Chem., 1982,21, 5 15. H. R. Allcock and T. J. Fuller, J. Am. Chem. SOC.,1981,103,2250. W. Toepelmann, H. Kroschwitz, D. Schroeter, D. Patzig, and H. A. Lehmann, Z . Chern.. 1979, 19, 273.


267

Reactions of (NPC12)3with various carboxylic acids in the presence of Et,N lead to the stable salt [(NPC12)2NPC10]-[Et3NH]+.54 Controlled hydrolysis of the sulphur-containingring cis-NPC12(NSOC1), [cis-@) (X = Cl)] in the presence of [Me4N]+C1-or [Ph4As]+C1- gives the analogous salts [(NSOCl),NPCIO][R4M]+.55Carbon-containing rings, such as derivatives of (lo), are most susceptible to hydrolysi~.~~ Hydroxycyclotriphosphazenes generally exist in their tautomeric oxocyclophosphazadiene form. Temperature-dependent 31P n.m.r. phenomena, observed for these tautomers, have been explained in terms of a proton exchange between the ring nitrogen atoms, and related with the relative basicities of these

Reactions with Organometallic Reagents.-Metal-HaZogen Exchange. Cyclophosphazenes, directly linked to metals (Li, Mg, Cu) are believed to play an important role in reactions between cyclophosphazenes and organometallic reagents. Thus, (NPC12)3reacts with R-MgX to afford not only the substitution product N3P3C15R, but also the bi(cyc1ophosphazene) (12), formed via a c1

l-2

R R

c1 ii

P

C 12\ N k E 1 2

P

C 12'

P N4C

l2

Reagents: i, RMgX (R = Me, Et, Prn, or Ph); ii, N,P,Cl,R

metallophosphazene intermediate.58In the presence of [Bu,PCuI], the same reaction leads to the analogous copper-linked phosphazene (13),59 which is a versatile reagent for the preparation of derivatives that are otherwise difficult to obtain. With organic halides it affords geminal bis(alky1) derivatives,BO and with i-propanol the hydride (NPC12),NP(H)R1is This hydride can be converted into (NPCl,),NPXR1 with the halogens(includingiodine!).61With MeLi the hydridophosphazene is converted into the corresponding lithiophosphazene (14), that in its turn can be used to link various groups to the phosphazene ring.g2 Thus, a-(cyclophosphazeny1)-substituted ketones have been prepared;44 the analogously prepared prop-2-ynyl derivatives undergo interesting rearrangements into the corresponding propa-l,2-dienyl and prop-1-ynyl compounds.g2 64 66

F. DiGregorio, W. Marconi, and L. Caglioti, J. Org. Chem., 1981,46,4569. F. van Bolhuis, B. de Ruiter, and J. C. van de Grampel, J. Chem. SOC.,Chem. Commun.. 1981, 1065.

67

m 50 6o

62

E. Fischer, H. Weber, and M. Michalik, 2. Chem., 1981, 21, 137. K. S. Dhathathreyan, S. S. Krishnamurthy, A. R. Vasudeva Murthy, R. A. Shaw, and M. Woods, J. Chem. SOC.,Dalton Trans., 1982, 1549. H. R. Allcock, J. L. Desorcie, and P. J. Harris, J. Am. Chem. SOC..1983. 105, 2814; H. R . Allcock, M. S. Connolly, and P. J. Harris, ibid., 1982,104,2482. H. R. Allcock and P. J. Harris, J . Am. Chem. SOC.,1979, 101, 6221. H. R. Allcock, P. J. Harris, and M. S. Connolly, Inorg. Chem., 1981, 20, 11. H. R. Allcock and P. J. Harris, Znorg. Chem., 1981, 20, 2844. H. R. Allcock, P. J. Harris, and R. A. Nissan, J. Am. Chem. SOC.,1981, 103, 2256.


268

\ ii

R1

I

iii

r

v vi

I

r l R i t ,CH2CCH3 vi

ll

I

-

lv

OMe

0

1 I R, ,CH-CCH N/% N

II

I 3 vi

I

Reagents: i, Me,CHOH; X, (X = CI, Br, or I); iii, RaX (Rs= primary alkyl or allyl; X :--:I or Br); iv, MeLi; v, BrCH&(OMe)=CH,; vi, HoO/HC

R

I

R

-

alkyl, a l l y l

Roagonts: i, BrCH8C-CH; ii, AlaOs (cat.); iii, MeLi (cat,)

Lithiophosphazenescan also be prepared from (NPPh,),NPMeH. It has been converted into a large number of derivatives,ba in particular transition-metal ~0rnp1e~es.~~ Alkyl/Aryl-Halogen Substltutlon. Reactions of (N PC1p)a with MeLi are supposed to procad via methyl-halogen substitution and not via metal-halogen exchange, thus giving rise to extensive ring cleavage.eaAn important factor responsible for the low yields of reactions of (NPX& (X = C4, F)with alkyl-lithium compounds

e4 66

J, Hosgol and A. Schmidpotor, 2.Naturforsch., TcllB, 1979,34915; 2,Anorg. Allg. Chcm., 1979, 458, 168. A. Schmidpotor, K,Blanck, H. Hoss, and H,Riffol, Angcw, Chsm,, 1980, 92, 655; K. C, Darh, A. Schmidpoter, and H.Schmidbaur, 2, Nafurforsch,,Tell B, 1980, 35, 1286, P. J. Harris and C, L. Fadoloy, Inorg. Chcm,, 1983, 22, 561.


269

is a cross-linking process, initiated by the abstraction of a a-hydrogen (by RLi) from substituents R.O0 MeLi is indeed able to deprotonate the model compound N8PsMeo,and the anionic species, thus formed, can be converted into cyclophosphazenes bearing the ligand -CHnR1(R1 = Me&, PhCO, Br).07 Reactions of alkenyl-lithium compounds with (NPF& also give rise to crosslinking by anionic attack at the olefinic side chain, but this can be suppressed by introducing an electron-donating ligand at the a-position, e.g., by using Li(RO)C=-CH, (R = Me, Et). The observed geminal substitution order for these systems can be ascribed to the a-electron-donating properties of the (RO)CIIPCH, ligand; non-geminal substitution is generally promoted by the presence of x-electron-donating ligands.e8 Another way of avoiding cross-linking of organophosphazenes during their formation is using organolithium reagents without a-hydrogens. Thus Bu'Li gives excellent yields of a mono- and a (non-geminal) disubstituted derivative of (NPFp)a; the high regio- and stereoselectivity of these reactions is due to steric effccts.dgAryl-lithium (and -Grignard) reagents are also very suitable for reactions with (NPF&; LiCoH4-p-R(R = C1, F, Me, OMe, NMe,) all show a non-geminal substitution order,7oSimilarly f~rroccnyl-~~ and 24 1-methylpyrr~lyl)~~ derivatives of fluorocyclophosphazenes have been prepared. Derivatives with more than two organyl substitutents are seldom found. Miscellaneous Substitution Reactions.-A reaction cycle has been described for the synthesis of non-geminal bromofluorocyclotriphosphazenes N aPaFo-,Br , (n = 2, 3)78, e.g.:

Reagonte: i, MenNH;ii, SbF,; iii, KSOaF; iv, HBr

Reactions between (NPXfi)a (X = C1, F) with MeaSiN-PR8 (R = Me, Ph or Ra = Me,Ph, etc.) afford mono- and non-geminal bis- and tris[(phosphoranylidene)amino]cyclotriphosphazenes ;trans-isomersare preferentially formed? Complexes of (NPXJ, (X= C1, F)with direct P-Fe bonds have bean prepared by reactions with complex ions such aa [Fes(CO)a]s- and [Fe(CO)n(C6H6)]-.To uu C. W. Allen, I n k Eng, Chem., Prod. Rcs, Dev., 1981,20,77. uT K. D,Oallicano, R, T. Oakley, N. L. Paddock, and R. D. Sharma, Can, J, Chcm,. 1981. 59,2654. 68 C, W, Allen and R. P, Bright, Inorg, Chcm., 1983,22,1291, OD K. Ramachandran and C. W. Allen, J. Amo Chem. Soc,, 1982,104,2396, 7o C. W eAllen, 0. EmBrunet, and M. E. Perlman, Inorg. C h h Ada, 1980, 41, 265; C. W. Allen and P,LoToch, Znorg. Chcm., 1981,20,8. T1 P. R,Suizko, R. R. Whittle, and H. R. Allcock, J. Chem. SOC~, Chcm. Commun., 1982,960, Tn Re D. Sharma, S. J. Rettig, NoL. Paddock, and J, Trotter, Can. J. Chcm.$ 1982, 60,535, Ta P. Clare and D. BeSawerby, Inorg. Synrh., 1978,l8, 194, T4 D.Dahmann, HoRoee, and W. Walz, 2. Naturforsch., Tell B, 1980,3S, 964, P. R. Suezko, R. R,Whittle, and HaR, Allcock, J. C h m Soc., Chcm. Commun., 1982,649.


270

co \/

cp

/F

'

Fe

F-PEN

P' l'CO

N

\ F-P-N

/\ / OC

F

Cp

(15)

Ruthenium- and mixed ironlruthenium complexes have been prepared in a similar way, e.g., (15).76 Carboranyl derivatives of (NPCI,), can be prepared in various ways. Derivatives bearing a closo-o-carboranyl ligand have been prepared using Li-o-

i\

N

\\ C1-P-N

\ \

R = Me, Ph

C1

c1

CB1,HloCR (R = Me, Ph).77o-Carboranyl ligands attached to the phosphazene ring via a methylene spacer group can be introduced by reaction of the corresponding prop-Zynyl derivatives with decaborane. With base the o-carboranyl moieties can be converted into anionic nido-carboranyl derivatives, that can be

-

II Reagents : i, B,,H,,(MeCN),; ii, piperidine; iii, NaH

I

linked to transition metals.'* m-Carboranyl derivatives have been prepared using Li-m-CBloH,,CH or HS-rn-CBloHloCH,7R

Theory and Spectra.-Theory. H.M.O. calculations, using the theoretical Fukui and Dewar models of cyclophosphazenes, show good agreement with each other 76

'7 78

'9

H. R. Allcock, L. J. Wagner, and M. L. Levin, J. Am. Chem. SOC.,1983, 105, 1321. H. R. Allcock, A. G . Scopelianos, J. P. O'Brien, and M. Y. Bernheim, J. Am. Chem. SOC., 1981,103, 350. H. R. Allcock, A. G. Scopelianos, R. R. Whittle, and N. L. Tollefsan, J . Am. Chem. SOC., 1983, 105, 1316. V. V. Korshak, A. I. Solomatina, N. I. Bekasova, M. A. Andreeva, E. G . Bulycheva, S. V. Vinogradova, V. N. Kalinin, and L. I. Zakharin, Vysokomof. Soedin., Ser. A , 1980. 22, 1988 (Chem. Abstr., 1981, 94, 66 133).

Cjvclic and Polymeric Phosphazenes

271

and with experimental data.8o For (NPC12), (n = 3, 4, polymer) the normal co-ordinates have been calculated from their vibrational spectra, and assignments of the normal modes of vibration have been made.81A more tentative approach has been used for the analysis of i.r. and Raman spectra of N,P,X,F,-, ( X = C1, Br; n = 2--4).82 Nuclear Magnetic Resonance Spectroscopy. The amount and nature of interaction between phosphazene rings and their aromatic ligands has been the subject of some investigations. 13C n.m.r. shifts of N,P,CI,-,Ph, have been explained in terms of a combination of inductive and mesomeric interactions between N-P and phenyl ring;83 p.e.s. measurements of N,P,F,-,Ph, indicate that mesomeric interactions must be very 13Cn.m.r. data of derivatives of (9) (X = Ph) indicate that the interaction between P-N-S and phenyl ring is of an essentially inductive nature.30 On the other hand, U.V. and diffraction techniques show substantial mesomeric interaction between the P-N ring and the 2-(l-methylpyrrolyl) ligands in N4P4F,(C4H,NMe).72The dx-px interactions between P-N ring and fluoroalkoxy side chains have been investigated with lH and 19F n.m.r.8s 31P n.m.r. chemical shifts of alkylsubstituted cyclotriphosphazenes can be resolved in additive contributions of the ligands.8s 13Cn.m.r. measurements of amino derivatives of (8) and (9) (X = C1, Ph) show a dependence of 2J(PC) of conformational effects.87According to temperature-dependent lH and 31Pn.m .r. measurements the proton in the [N,P,Me,H]+-ion migrates between the ring-N atoms.88 The symmetric disposition of cyclophosphazenes renders them useful as models for 15Nn.m.r. spectroscopy. In studies concerning this subject compounds have beenused witheitherendocyclicorexocyclic 15Nincorporation, e.g., (l5NPR2), The (R = F, C1, Br, SEt)8gand N,P3Cl4R2 (R = 15NH2,15NHMe, 15NMe2).90 trends in the values of chemical shifts and coupling constants can be rationalized in terms of substituent effects. Nuclear Quadrupole Resonance Spectroscopy. The temperature dependence of the 35Cln.q.r. signals for some geminal amino derivatives of (NPC12)3has been C. Mihart, M. Mracec, and Z. Simon, An. Univ. Timisoarn, [Ser.] Stiinte Fiz.-Chim., 1980, 18, 71 (Chem. Abstr., 1982, 96, 121 861); Rev. Roum. Chim., 1983, 28, 3 (Chem. Abstr., 1983, 99, 38 628.) P. C. Painter, J. Zarian, and M. M. Coleman, Appl. Spectrosc., 1982, 36. 265, 272, and 277 (Chem. Abstr., 1982,96, 225 666, 225 667, and 225 668); J. P. Huvenne, G. Vergoten, and P. Legrand, J. Mol. Struct., 1980, 63, 47. r)2 P. Clare and D. B. Sowerby. Spectrochim. Acta, Part A , 1981, 37, 883. S. S. Krishnamurthy, P. Ramabrahmam, and M. Woods, Org. Magn. Reson., 1981, 15, 205. n4 C. W. Allen and J. C . Green, Inorg. Chem., 1980, 19, 1719. H3 V. N. Prons, N . B. Zaitsev, V. P. Sass, and A. L. Klebanskii, Zh. Obshch. Khim., 1980, 50, 17 (Chem. Abstr., 1980, 92, 214 432). d6 P. J. Harris, Inorg. Chim. Acta, 1983, 71, 233. B. de Ruiter and J. C. van de Grampel, Phosphorus Sulfur, 1982, 14,99. A 8 V. Ramamoorthy, T. N. Ranganathan, G . S. Rao. and P. T. Manoharan, J. Chem. Res.. 1982, (S) 316, ( M )3074. B. Thomas and G. Grossmann, J. Magn. Reson., 1979,36, 333; B. Thomas, G . Seifert, and G. Grossmann, 2. Chem., 1980, 20, 217. B. Thomas, A. John, and G . Grossmann, Z. Anorg. Allg. Chem., 1982, 489, 1 3 1 . do

*’

272


investigated.P1Temperature- and pressure-dependent V I n.q.r. measurements have been performed with the ring systems (NPCIa),(NSOCI)a,, (n = 0, 1,2); the results can be related with X-ray structural data (conformations, bond lengths).eg and rlBr n.q.r. measurements of bromine-containing cyclotriphosphazenes show the larger sensitivity of this technique (compared with W1 n.q.r.) for physical and chemical changes.0a The temperature dependence of Br n.q.r. signals of (NPBrP),has b a n scrutinized, and the signals of (NPBr,), have been assigned to the respective Br Miscellaneous. Electronic effects within carbon-containing cyclophosphazenes (both NaPCp and NaPCa systems) have been investigated using various techniques such as electronic spectroscopy and dipole measurements,e6a6Cln.q,r. spectroand vibrational analysis,n7 scopy and CND0/2

Pbyolologically Active Compounds,--I-Rziridlnyl Derfvatlves. The antitumoral properties of a number of 1-aziridinyl (Az) derivatives of cyclophosphazenes and related ring systems, in particular of (NPAzp)a (Apholate or MYKO 63) AZ

I N

AzO['

N\

BN

APHOLATE

%~\AZ

N \*#N

Az

or MYKO 6 3

t"

AZ

A2

OR

AZ

0

-N

I

9

'Az SOAz

'CH2

and (NPAza)aNSOAz (SOAz), have been reviewed,e8 and therefore only the recent developments will be mentioned here. On the one hand, investigations are focused on a deepening of the knowledge of known active compounds. Thus, in vitro,OOJOO in vfvo,lolJoa and phase I K,R. Sridharan, J. Ramakriehna, K. Ramachandran, and 5. S. Krirhnamurthy, J, Mol. O0

Srrucr,, 1980, 69, 105. A. Connolly, P. Harkins, A, L. Porte, SOC.,Dalron Trans., 1980, 1012,

R. A. Shaw, and J.

C , van do Orampel, J. Chrm.

K. Sh, Ahmad and A. L. Ports, Jo MoL Srrucr,, 1980, 58, 459, K,R, Sridharan and J. Ramakrirhna, Polyhrdron, 1983, 2,427. E. A, Romanenko, S. V. Ikranova, and Yu. P. Egorov, Teor. Eksp, Khlm,, 1980, 16, 308 (Chrm, Absrr., 1980,93, 203 492), O0 E, A. Romanenko, Teor, a s p . Khlm., 1981, 17, 549 (Chem. Abstr,, 1981, 95, 167991); J. Mol. Srrucr,, 1982, 83, 337, OT E. A. Romanenko, S. V. IkBanOVa, Yu. P. Egorov, P. Pa Kornuta, and T. N, Karheva, Tuor. E k ~ pKhlm., . 1982,18, 710 (Chem, Absrr,, 1983,98, 89 512). O@ JPF. Labarre, Top. Curr. Chem,, 1982, 102, 1. O0 A, A. van der Huhen, J. C. van do Orampel, W, Akkerman, P,Lelioveld, A. A, van der Mser-Kalverkamp,and H,B. Lambertr, Inorg. Chlm. Acra, 1983,78,239, loo H,B, Lamberts, A. van der Meer=Kalverkamp,J, C. van do Orampel, A. A, van der Huizen, A, P,Jekel, and N. H.Mulder, Oncology, 1983,40,301. lol K,Kitazato, 5. Takodo, and N. Unomi, J. Pharmacoblo=Dyn,, 1982,5,803 (Chem, Abstr.. O0 O4 O6

1982, 97, 46 546).

T. S. Safonova and V. A. Chernov, Slnt. fzuch. Nov. Orechestvennykh Protfvolelkoznykh Prrp., Teslzy KO&, 1979, 32 (Chsm, Abstr., 1980, 92, 121 549),


273

clinicalma-lOBstudies have been carried out; phase I studies with SOAz have shown that, although it has many advantageous properties, a cumulative myelotoxicity prevents its application in conventional cancer chemotherapy. The mode of cytostatic action of MYKO 63 and SOAz has been investigated using various techniques (e.g., vibrational and Raman spectroscopy,mamolecular structure determinations,lo7and quantum-chemical calculationsZo8), but a satisfactory explanation has not yet been found. On the other hand, the development of new potential drugs is an important aim of research, A large number of derivatives N8P8AzxRyCl,( x y f z = 6; R = various organic groups, in particular amino groups) has been preparedZoB and tested in vitro.BBA distinct relationship exists between cytostatic activity of a certain compound and the electron-donating capacity of R. Derivatives of (NPCln)8with the 'open aziridine' HpNCHoCHpX(X = CI, Br) have also been prepared; some show anticancer activityOZlo

-+

Miscellaneous Applications.-Polyesters can be prepared from their monomers by interaction with (NPCln)s/LiClin pyridine.lZ1Alkenes have bean polymerized in the clathrate tunnel system of (16), resulting in polymers with enhanced stereoregularity.Z1n Derivatives of cyclic phosphazenes have further been used as thermal stabilizers of various as corrosion inhibitors,Z14antifriction agents,11s ioa

S. Nasca, D. Jemkova, P. Coninx, E. Oarbe, Yo Carpentier, and A, Cattan, Cancrr Treatment Rep., 1982,66, 2039, S. Rodenhuia, A, H, J, Scaf, N. H. Mulder, D. Th,Sleijfer, M, H.Beneken genaamd Kolmer, D. R, A. Ugea, and J. C. van de Grampel, Cancer Chemothsr. Pharmacol., 1983, 10, 174. l o b S. Rodenhuia, N. H,Mulder, D. Th, Sleijfer, H. Schraffordt Koopa, and J, C. van do Orampel, Cancer Chcmothcr. Pharmacol., 1983,10,178. toe M,Manfait, A, J. P,Alix, JPF, Labarre, and F. Sourniea, J. Raman Sprctrosc,, 1982,12, 212. I01 (a) T.S. Cameron, J.-FoLabarre, and M. Graffeuil, Acra Crysrallogr., 1982,M 8 , 2000; (b) J. Oaly, R. Enjalbert, A. A. van der Huizen, J, C. van do Orampel, and J.-F. Labarre, ibfd., 1981,B37, 2205, 108 a. Ouerch, J.=F. Faucher, M. Oraffeuil, 0. Levy, and LF. Labarru, THEOCHEM, 1982, 5, 317. 108 A. A. van der Huizsn, A. PoJekel, J. K.Bolhuis, D. Keekatra, W. H,Ousema,and J, C. van de Orampel, Inorg. Chim. Acta, 1982,66185, 110 C. W,Allen, J. A, McKay, J, J. McCormack, €4, A. Newman, and M,P, Hacker, Inorg, Chfm, Acta, 1982,67, L17. 111 F. Higarhi, K,Kubota, M. Sekizuka, and M. Higarhi, J s Polym, Sci,, Polym, Chum, Ed,, 1981,19,2681;H.R. Kricheldorf, Q.-Z. Zang, and 0. Schwarz, Polymer, 1982,23,1821. i i a J, Finter and O, Wegner, Makromol. Chrm., 1979, 180, 1093; HaR, Allcock, W, T, Ferrar, and M.L,Lsvin, Macromolrcules, 1982,15,697. i i a R. Vllceanu, T. Suhateanu, and R. Ilie, Rom, P.,63 380 (Chem. Abstr., 1980,92,7 792); K. Sugawara, Y.Sato, T. Sugino, and K. Atruta, Jpn, Kokai Tokkyo Koho, 80 16 011 (Chrm. Abstr., 1980,92,199 344); C, C. Wu and A, Y. Garner, US Pa,4 191 715 (Chum. Abstr., 1980, 93, 27 700); B, E. Adama, ElJ. Quinn, and W, R, Rodgera, Br, U.K. P. Appl., 2 046 627 ( C h m Abstr,, 1981,94,210 466); So F. Zapuakalova, OmS, Nikitina, S. 0. Fedorov, On S. Ool'din, and Lo M. Sukhova, Khim. I Tekhnol. E~rmmloorgan, Poluproduktov. 1 Polfmsrov Volgograd, 1981, 24, 27 (Chrm. Abstr,, 1982, 97, 216319, 56 917), 114 K,J. L. Paciorek, T. I. Ito, J. H.Nakahara, and R. H,Kratzer, J. Fluorinr Chrm,, 1980, 16, 431 and 441;E. Schmidt, OmSchmidt, and L,Ludmann=Salanky,Stud, Univ. BabesBofyal, [Sir.] Chrm., 1982,27,9 (Chrm. Abm., 1983,98,148 019). 118 A, S, Letin, I. I. Ura, S, F. Zapuakalova, S. G1 Fedorov, 0 , So Ool'dtn, Khim. Tekhnol. Topl. Masel, 1980,24 (Chrm. Abstr., 1981,94, 17 994). 104

274


fertilizers,l18and anti-mildew Some derivatives are able to extract heavy metals from aqueous solutionll* and to modify s i l i ~ a - g e l . ~ ~ ~

3 Polypbosphazenes Introduction.-This section deals only with linear polyphosphazenes; neither cyclolinear or cyclomatrix polymers are included, nor is reference made to mixed organic-inorganic polymers. Numerous reviews related to the preparation, physical properties, and application have been published. Readily accessible papers are mentioned here.L,120-127

Poly[bis(halo)phosphazenes].-Much attention has been paid to the polymerization of (NPCI,), in order to increase the yield of the soluble form of (NPCI,),. Thermal bulk polymerization of (NPCI2),has been carried out in the presence of its higher homo10gues.128J28A similar procedure has been reported using a mixture of (NPCl& with small amounts of (NPC12)4,5 and Cl+P(Cl,)N +,PClaO (n = l-10).129 The presence of water or HCl in the polymerization systems 116

G. Schmidt, P. Harangus, and E. Schmidt, Stud. Univ.Babes-Bolyai, [Ser.] Chem., 1981. 26, 49 (Chem. Abstr. 1982, 97, 72 571).

Shin Nisso Kako Co., Ltd., Jpn. Kokai Tokkyo Koho, 83 13 506 (Chern. Abstr., 1983. 98, 156 397). *18 R. J. Dain, G. D. Manning, and A. R. Burkin, PCT Int. Appl., 80 00 796 (Chem. Absfr.. 1981, 94, 68 039). 119 V. V. Kireev, V. I. Astrina, and A. A. Goryaev, Zh. Obshch. Khim.. 1982, 52, 473 (Chem. Abstr., 1982, 96, 223 971). lZo H. R. Allcock, Contemp. Top. Polym. Sci., 1979, 3, 55; Polymer, 1980, 21, 673; Sci. Progr. (Oxford), 1980,66, (263), 355; Macromol. Chem. Phys. Sirppl., 1981,4, 3. lal A. H. Gerber, Org. Coat. Plast. Chem., 1979, 41, 81. 12a D. P. Tate and T. A. Antkowiak, Kirk-Othmer Encyl. Chem. Technol. 3rd ed., 1980, 10, 936. 143 G. L. Hagnauer, f. Macromol. Sci., Chem., 1981, 16, 385. lZ4 T. L. Evans and H. R. Allcock, f. Macromol. Sci., Chem., 1981, 16, 409. E. Devadoss, Znd. Polym. Radiat. Proc. Symp., 1979, 395 (Chem. Abstr., 1981,94, 127 173). las V. V. Kireev, G. I. Mitropol'skaya, and Z. K. Zinovich, Russ. Chem. Rev., 1982, 51, 149 (Usp. Khim., 1982, 51, 266). 12' R. E. Singler, G. L. Hagnauer, and R. W. Sicka, ACS Symp. Ser., 1982, 193, 229. 12* V. V. Kireev, G . I. Mitropol'skaya, V. V. Korshak, and N. B. Smirnova, USSR P.. 761 524 (Chem. Abstr., 1980,93,240 267). 12@ V. V. Kireev, F. A. Bittirova, G. I. Mitropol'skaya, and S. 0. Shumakova, USSR P.. 870 406 (Chem. Abstr., 1982, 96, 52 937). 11'


275

leads to the formation of branched macromo1ecules,130~131 which has a considerable effect on the properties of the polymer.132The polymerization of (NPC12), can also be catalyzed by TiCl, and Et,Al (50% conversion at 220 "C),13, AlCl, and NaCl (60% conversion at 225 "C, gel-free polymer),134PhsSb (49% conversion at 245 "C, gel-free polymer),136and Ph,Sb and I, (91 % conversion at 250°C, gel-free polymer).136 Up to 100% conversions have been obtained by using boron halides or boron halide-triphenylphosphate complexes as catalysts,137 the molecular weight of the polymers depending on the molar ratio (trimer/ catalyst) applied.137J38A study has been made of the catalytic effects of HgCl,, HgI,, and ZnC1, on the polymerization of (NPC12)8.13e The physical properties of uncross-linked (NPCI,), have been examined by different methods. Two stable crystalline modifications have been identified together with a metastable crystalline form.l*O One of the stable modifications shows a chain-repeat distance equal to 4.92 A; a cis-trans planar conformation is proposed for the P-N chain.141 Solution polymerization has been recognized as an important technique for preparing (NPCI,),. The nature of the polymers depends on the solvent (benzene, cyclohexane, c h l o r o b e n ~ e n e ) ~used; ~ ~ J *no ~ polymerization has been observed in toluene, nitrobenzene, and t e t r a h y d r o f ~ r a n .A~ ~linear, ~ ungelled polymer is formed in very high yield when (NPCI,), dissolved in cyclohexane is heated in the presence of BCl, as ~ata1yst.l~~ A n analogous result can be obtained by heating a solution of (NPCI,), in tetralin with 0.5% [based on (NPCI,),] sulphur.14s When decalin is used, a lower degree of conversion is attained.146 S u l t o n e ~sulphamic ,~~~ acid and its and B U , S ~ O have ~ ~also ~ been reported as catalysts for solution polymerization. V. V. Korshak, S. V. Vinogradova, D. R. Tur, N. N. Kasarova, L. I. Komarova, and L. M. Gilman, Acfa Polym., 1979,30,245 (Chem. Absfr., 1979,91, 92 072). I 3 l V. V. Korshak, S. V. Vinogradova, D. R. Tur, and N. N. Kasarova, Acfa Polym., 1980. 31, 568 (Chem. Abstr., 1981, 94, 16 137). 134 V. V. Korshak, S. V. Vinogradova, D. R. Tur, and N. N. Kasarova, Acta Polym., 1980, 31, 669 (Chem. Absfr., 1981, 94, 66 394). Ls3D. L. Snyder, J. W. Kang, and J. W. Fieldhouse,Eur. P. Appl. 4 877 (Chem. Abstr., 1980, IBU

92, 59 456). 134

Otsuka Chemical Co. Ltd., Jpn. Kokai Tokkyo Koho, 80 123 624 (Chem. Abstr., 1981. 94, 31 330).

13s

Otsuka Pharmaceutical Co. Ltd., Jpn. Kokai Tokkyo Koho, 80 120 629 (Chem. Abstr.,

Ise

Otsuka Pharmaceutical Co. Ltd., Jpn. Kokai Tokkyo Koho, 80 123 623 (Chem. Abstr..

1981, 94, 31 323). 1981, 94, 31 331).

J. W. Fieldhouse and D. F. Graves, ACS Symp. Ser., 1981, 171, 315. H. G. Horn and F. Kolkmann, Mukromol. Chern., 1982, 183, 1833. 13@ E. Devadoss and C. P. R. Nair, Makromol. Chem., 1982, 183, 2645. lrlo H. R. Allcock and R. A. Arcus. Macromolecules, 1979, 12, 1130. l*l H.R. Allcock, R. A. Arcus, and E. G. Stroh, Macromolecules, 1980, 13, 919. J. Retuert, S. Ponce, and J. R. Quijada, Polym. Bull., 1979, 1, 653. 149 J. Retuert, C. Aguilera, and F. Martinez, Polym. Bull., 1982, 6, 535. 144 J. W. Fieldhouse and S. L. Fenske, US P., 4 327 064 (Chem. Absfr.. 1982,97, 6 998). 145 Firestone Tire and Rubber Co., Neth. Appl. 7 805 383 (Chem. Absfr., 1980, 92, 130 362); A. F. Halasa and J. E. Hall, Jpn. Kokai Tokkyo Koho, 79 152 693 (Chem. Absfr., 1980, 92, 147 520); A. F. Halasa and J. E. Hall, US P., 4 225 567 (Chem. Absfr., 1981, 94, 137

16 356).

A. F. Halasa and J. E. Hall, Ger. Offen., 2 820 082 (Chem. Absfr., 1980, 92, 59 430). lr17 J. Behnke and D. Huff, Ger. Offen., 2 910 794 (Chem. Absfr., 1981,94, 31 316). 118 D. P. Sinclair, US P., 4 242 316 (Chem. Absfr., 1981, 94, 104 137). lQe

276


A rubber-like (NPCI,), polymer is formed in low yield by exposure of (NPCI,), to a low-pressure radiofrequency A new method for preparing polymeric chlorophosphazenes consists of the thermal condensation of (17) at 240-290 “C under atmospheric pressure, according to : n C1 P=N-P=O ,c1

‘c1

A

-

ClfP(Cl2)=N+ii?O

/c1

c1

+ ( n - 1 ) POcl3

Substitution of the chlorine atoms by OCH2CF3groups leads to polymers which are identical with those prepared from (NPCI2),.l6l

Poly[(organophosphazenes)].--Only a limited number of publications deals with the preparation of organo-substituted polyphosphazenes starting from the with R = alky1,162~163 corresponding cyclic oligomers. Examples are ~,P3C16R], aryl,ls4methyl- or phenylcarboranyl,” and [(NPCI,),NPRR’], (R,R’ = alky1).163 The molecular weights of these hydrolytically unstable polymers depend on the steric dimensions of the group R. Stable polymers can be obtained by replacing the remaining chlorine atoms by OCHzCF3or OPh groups. Polymers with composition ~P(OCH2CF3),CI,], ( x w y x 1) are formed when an equimolar mixture of N,P,(OCH,CF,), and BCI, is heated.166Low molecular weight polymers are obtained from 1 : 1 molar ratio mixtures of NsP3(OCH2CF,),-,CI, (n = 1 4 ) and BClg.16, A new method to synthesize organo substituted polyphosphazenes with direct P-C bonds is based upon thermal decomposition of (18).

-

n Me3SiN=P(OCH2CF3)RR’

A

(NPRR’)n +

n Me3SiOCH2CF3

(18)

The polymeric product with R = R’ = Me is fully characterized. An average molecular weight of 50 OOO has been reported which corresponds with n x 660.8 A widely adopted approach for preparing organophosphazene polymers is the nucleophilic substitution of chlorine atoms in uncross-linked (NPCI,),. Much attention has been paid to alkoxy and aryloxy derivatives being stable polymers. Examination of reactions between (NPCI,), and NaOCH,CF, shows hydrolysis 140

S. Besecke, H. Jaksch, and W. Ude, Ger. Offen., 3 039 602 (Chem. Abstr., 1982, 97, 92 994).

150

151

lSa

lS8

Y. Osada, M. Hashidzume, E. Tsuchida, and A. T. Bell, Nature (London), 1980,286,693; Y. Osada. Y. Iriyama, and M. Hashidzume, Kobunshi Ronbunshu, 1981, 38, 635 (Chem. Abstr., 1982,96,7 893). M. Helioui. R. De Jaeger, E. Puskaric, and J. Heubel, Makromol. Chem., 1982,183, 1137. H. R. Allcock, R. J. Ritchie, and P. J. Harris, Macromolecules, 1980, 13, 1332. R. J. Ritchie and H. R. Allcock, Polym. Prepr., Am. Chem. SOC.,Div. Polym. Chem., 1979, 20, 549.

ls4 lS6

R . L. Dieck and E. J. Quinn, Ger. Offen., 2 838 905 (Chem. Abstr., 1979, 90, 187 610); Can. P., 1 123 451 (Chem. Abstr., 1982, 97, 93 041). H. G. Horn and F. Kolkmann, Makromol. Chem., 1982,183, 1843. H. G. Horn and F. Kolkmann, Makromol. Chem., 1982, 183, 2427.


277

to be an important side-reacti0n.1~~ The degree of substitution has been investigated as a function of various reaction parameters.16BIn dilute solutions (acetone, THF) ~(OCH,CF,),], appears to behave as a poly-electrolyte, which is ascribed to the presence of units NP(OCH,CF,)Cl and NP(OCH2CF,)OH.169J60 The kinetic data of the thermal degradation of ~P(OCH,CF,),], point to a random chain scission followed by a partial unzipping mechanism, the latter leading to cyclic oligomers.161An analogous explanation has been proposed for the degradation of a polymer containing OCH2CF3and O(CF,),CH, groups.162 In addition, the degradation of [NP(OCH,CF,),], by U.V. light or electron beam exposure has been investigated.16, The stabilizing influence of the OCH,CF, moiety has been applied in various p o l y m e ~ s . ~ ~Fluoroalkoxy~-l~~ and fluoroaryloxy-polyphosphaes still claim attention as sealants for b a t t e r i e ~ . l ~ ~ * l ~ ~ Relatively few publications have appeared describing polymers containing non-fluorinated alkoxy residues. When poly[bis(n-octyloxy)phosphazenes] are prepared from (NPCI,), and n-C,H,,ONa the highest yield is obtained with diglyme as solvent. Molecular weights up to 3 x lo6 are The physico-chemical properties of poly[(n-butoxy)phosphazenes] appear to depend on the percentage residual chlorine, as well as on the presence of POH and P(0)NH groupings (arising from hydrolysis).173Temperature-dependent relaxation processes (dielectricrelaxation, spin-latticerelaxation) have been investigated to gain information about the thermal motion in poly[bis(alkoxy)phosphazenes]

S. V. Vinogradova, D. R. Tur, I. I. Minos’yants, L. I. Komarova, and V. V. Korshak, Acfa Polym., 1982,33, 331 (Chem. Abstr., 1982,97, 56 358). 16* S. V. Vinogradova, D. R. Tur, I. I. Minos’yants, 0. L.Lependina, N. I. Larina, and V. V. Korshak, Acfa Polym., 1982,33, 598 (Chem. Abstr., 1983,98, 72 846). V. V. Korshak, S. V. Vinogradova, D. R. Tur, I. I. Minos’yants, L. M. Gil’mhn, T. 1. Borisova, and V. I. Frolov, Acfa Polym., 1982,33, 109 (Chem. Abstr., 1982,97, 39 602). 160 V. V. Korshak, S. V. Vinogradova, D. R. Tur, I. I. Minos’yants, L. M. Gil’man, T. I. Borisova, and V. I. Frolov, Acta Polym., 1982,33, 114 (Chem. Abstr., 1982,96, 218 537). M.Zeldin, W. H. Jo, and E. M. Pearce, Macromolecules, 1980, 13, 1163. leaJ. K. Valaitis and G. S . Kyker, J. Appl. Polym. Sci., 1979, 23, 765. H. Hiraoka, W. Lee, and L.W. Welsh, jun., Macromolecules, 1979, 12, 753. 16* W. L. Hergenrother and A. F. Halasa, US P., 4 175 181; 4 179 556; 4 182 835; 4 182 834; 4 179 554 (Chem. Abstr., 1980, 92, 42 614; 77 181; 111 686; 111 687; 129 659). 160 L. L. Fewell, H. R. Allcock, J. P. O’Brien, and A. G. Scopelianos, US P. Appl., 129 798 (Chem. Abstr., 1980, 93, 187 268). IB6 Firestone Tire and Rubber Co., Jpn. Kokai Tokkyo Koho, 8040779; 8040780; 80 40 775 (Chem. Absfr., 1980,93,47 792; 47 793; 72 876). le7 H.R. Allcock, K. M. Kosydar, and S. D. Wright, US P.,4 242 499 (Chem. Abstr., 1981. 167

94, 140428). 16* 160 170

171

A. F. Halasa and W. L. Hergenrother, US P., 4 242 495 (Chem. Absfr., 1981,94, 84 871). W. L. Hergenrother and A. F. Halasa, Eur. P. Appl., 14 865; US P., 4 247 680; 4 258 170 (Chem. Absfr., 1981,94,4 423; 122 558; 176 461). K. Yokoyama, A. Kawakami, N. Kotani, T. Kudo, and H. Ohbayashi, Jpn. Kokai Tokkyo Koho, 79 10 929; 79 10 928 (Chem. Absfr., 1979,90, 177 129; 177 130). K. Yokoyama, A. Kawakami, N. Kotani, M. Yoshida, T. Kudo, H. Ohbayashi, Jpn. Kokai Tokkyo Koho, 79 10 932; 79 10 933; 79 10 934; 79 01 834; 79 01 837; 79 01 829; 79 01 836; 79 01 835; 79 10 931; 79 10 930; 79 01 833 (Chem. Absfr., 1979, 90, 177 131-177

172

133; 194 697-194703;

212290).

F. A. Bittirova, V. V. Kireev, and A. K. Mikitaev, Vysokomol. Soedin., Ser. B, 1981, 23, 30 (Chent. Absfr., 1981, 94, 122 013). V. V. Kireev, G. M. Raginskaya, W. Sulkowski, and V. V. Korshak, Vysokomol. Soedin., Ser. B, 1981, 23, 554 (Chem. Absfr., 1981,95, 169 924).

278

OrganophosphorusChemistry

with respect to the side groups and the inorganic b a ~ k b o n e . l ~As ~ Jobserved ~~ for the corresponding trimer and tetramer, mP(OCH,),], shows the rearrangement NP(OCH,)? + N(CH,)P(O)(OCH,) when heated at 120-140 "C. A linear relation between the degree of rearrangement and chain scission seems to be A large variety of aryloxy polyphosphazenes has been described. Examples [NP(OC,H,-p-CN),are ~P(OCeH4-rn-C1),],,177[NP(OC6H4-p-CMe,),]n,178 (OCH,CF,),_J, ( X = 0.04_2),179[NP(OC,H,-~-N0,),],,180[NP(OC,H,-p-N0,)(OCH2C~CH)],,le1~P(OPh)x(OC,H,-p-Et),-x]n,la~ and [NP(OPh),(OC6H4p-Et),(OC,H4-o-CH,CH=CH2),-x-,,],,.183 The thermal transition behaviour of [NP(OPh),],lS4as well as of polymers [NP(OC6H4R)x(OCsH4R')2-x],,185 has been investigated in detail. A study of the photochemical behaviour of poly[bis(ptolylamino)phosphazene] in solution shows the photolysis (u.v. and y irradiation) to be influenced by the nature of the solvent and the presence of molecular oxygen,les-le8For the photodegradation of the bis(a-naphthoxy) analogue the influence of 0, has been e~tab1ished.l~~ The reaction between ~ P C I , ] , and PhLi leads to a polymer with a low phenyl content ;chain cleavage appears to be the main process.lS0Less chain cleavage has been observed using (NPF,), as starting material. Non-elastomeric, film-forming materials are obtained by treatment of (NPF,), with PhLi, followed by a reaction with Na0CH2CF3.l*l

Polyphosphazenes as Carriers for Active Groups.-The increasing interest in the application of polyphosphazenes as carrier-polymers for (re)active agents is reflected by a growing number of papers dealing with the preparation of such systems. In all cases the cyclic trimeric system has been used as a small-molecule model to gain information about reaction procedures. Roughly, the polymers can be divided into two classes, one in which the 174 175

V. V. Kochervinskii, I. B. Sokol'skaya, and V. V. Kireev, Vysokomol. Soedin., Ser. A. 1982,24, 1275 (Chem. Abstr., 1982,97, 73 295). I. B. Sokol'skaya, Deposited Doc., 1981, VINITI, 1470 (Chem. Abstr., 1982,97, 24 487; 24 488).

176

17' 178

T. C. Cheng, V. D. Mochel, H. E. Adams, andT. F. Longo, Macromolecules, 1980,13,158. R. E. Singler, B. L. Laliberte, and R. W. Matton, Macromol. Synth., 1982,8, 83. V. M. Chukova and V. V. Kireev, Deposited Doc., 1980. VINITI, 2171 (Chem. Abstr., 1981, 95,98 368).

M. Zeldin, W. H. Jo, and E. M. Pearce, J. Polym. Sci., Polym. Chem. Ed., 1981, 19, 917. F. Halasa and W. L. Hergenrother, US P., 4 242 492 (Chem. Abstr., 1981,94,84 872). lE1Firestone Tire and Rubber Ca., Jpn. Kokai Tokkyo Koho, 80 40 788 (Chem. Abstr., 1980, 179

lE0A.

93, 72 877). S. Futamura, J. K. Valaitis, K. R. Lucas, J. W. Fieldhouse, T. C. Cheng, and D. P. Tate, J. Polym. Sci., Polym. Phys. Ed., 1980, 18, 767. la8 T. C. Cheng, J. W. Fieldhouse, E. A. Oberster, and D. F. Graves, US P., 4 179 555 (Chem. Abstr., 1980, 92, 95 423). lE4S. J. Kozmiski and I. R. Harrison, J. Appl. Polym. Sci.,1982, 27, 1783. la6J. J. Beres, N. S. Schneider, C. R. Desper, and R. E. Singler, Macromolecules, 1979, 12, 566. lEdP. Bortolus, F. Minto, G. Beggiato, and S . Lora, J. Appl. Polym. Sci., 1979, 24, 285. la7G. Beggiato, P. Bordin, F. Minto, and L. Busulini, Eur. Polym. J., 1979, 15,403. lE8M.Gleria, F. Minto, S. Lora, and P. Bortalus, Macromolecules, 1981,14, 687. lag M. Gleria, F. Minto, S. Lora, and P. Bortolus, Eur. Polym. J., 1979, 15, 671. lB0H. R. Allcock and C. T.-W. Chu, Macromolecules, 1979, 12, 551. lgl H. R. Allcock, T. L. Evans, and D. B. Patterson, Macromolecules, 1980, 13, 201.


279

active group is directly linked to the PN backbone, the other in which linkage is effected via the OCQH4‘spacer’ group. Nucleophilic replacement of chlorine atoms in (NPCI,), by sodium steroid salts leads to polymers ~PClx(OR)2-x],,.Stable polymers are formed when the steroidal unit is bonded through an aryloxy moiety; linkage through an alkoxy moiety leads to unstable polymers.1B2Local anaesthetics can be linked to the phosphazene chain through their amino function.lB3Treatment of (NPC12), with the sodium salt of diacetone glucose leads to a complete replacement of chlorine atoms. Deprotection of the glucose units can be accomplished by the use of CF,COOH without skeletal cleavage.43 A versatile starting material for the preparation of compounds belonging to the second class of polymers is (19) (R = Br); via a lithiation step numerous compounds have been prepared;lB4(19) (R = PPh2) readily forms complexes with transition metal compounds.lB6Reduction of (19) (R = NO2) gives (19) (R = NH2), that can be used in diazotization and subsequent diazo coupling reactions.lBe Another application of (19) (R = NHI) involves Schiff base

QQ

ii

0

R = COOH

R = PPh R = Li R = SnPh3 0

0

R = Au( PPh 3 )

(19) R = Br

Reagents: i, BuLi; ii, CO,/H+; iii, Ph,PCI; iv, Ph3SnC1; v, (Ph,P)AuCI

i

(19) R = N02-(19)

R = NH2

(R1,R2,and R3 represent various Reagents: i, Ha/PtO,; ii, HN02, H+; iii, RlH; iv, R2R3C==0 groups) lrt4H. lo3H. lo4 les H.

R. R. H.R. R.

Allcock and T. J. Fuller, Macromolecules, 1980, 13, 1338. Allcock, P. E. Austin, and T. X. Neenan, Macromolecules, 1982, 15, 689. Allcock, T. J. Fuller, and T. L. Evans, Macromolecules, 1980, 13, 1325. Allcock, K. D. Lavin, N. M. Tollefson, and T. L. Evans, Organometallics, 1983.2,

267. lg6

H. R. Allcock, P. E. Austin, and T. F. Rakowsky, Macromolecules, 1981, 14, 1622.


280

coupling reactions.lQ7This type of reaction can also be carried out using (19) (R = CHO) as the starting mate~ia1.l~~ Aromatic centres OC,H,CH,NH, in (19) (R = CH,NH,) can serve as coupling sites for carboxylic acids.1gsBy making use of an elegant reaction cycle, ~P(OC,H,-p-Me),], has been converted into the prospective anti-thrombogenic compound (20).lQr +

lg7H. R. Allcock and P. E. Austin, Macromolecules, 1981, 14, 1616. lo*H. R. Allcock, T. X. Neenan, and W. C. Kossa, Macromolecules, 1982, 15, 693. lg9 X. Neenan and R. Allcock, Biomaterials (Guildford, Engl.), 1982,3,78 (Chem. Abstr.,

T.

1982,97, 60 963).

H.

-.-

P-NH : 1.68 P-N,,,

1.54-1.60

: 1.62 P-Me : 1.79 P-CHI : 1.8 1

200 24 77 71 201 202 203

P-N,,, : 1.605(6) P-N,, : 1.605(8) N-H-CI contacts P-C : 1.820(3) P-C : 1.761(3) P-N, : 1.603(3) P-N,, : 1.61(2) H-bridged dimers P-N,, : 1.618(6) extensive H-bonding P-N,, : 1.62 P-NEt2 : 1.64(1) P-NPPh, : 1.59(1) N=PPha : 1.56(1) : 1.60(1) N=PPh3 : 1.56(1) P-N,,, P-N,,, : 1.617(4) P-N,,, : 1.615(6) P-C : 1.765(1) P-H 1.26(7) P-Fe :2.23(1) Fe-Fe :2.746(3) L(FePFe) : 76.1O P-Fe :2.187(3) Fe-Fe : 2.618-2.647(3) Fe-N : 2.04(1) L(FePFe) : 73.5' P-Fe : 2.272-2.277( 1) Fe-Fe : 3.922( 1) L (FePFe) : 119.1O P-Fe :2.214(1) P-C : 1.813(4) P-Fe : 2.179-2.193(1) Fe-Fe : 2.593(1) L(FePFe) :72.8' P-Fe : 2.256(1) P-Ru : 2.231(1) Fe-Ru :2.698(1) LWePRu) : 73.9' P-C : 1.77(1) 2 independent molecules P-Me : 1.790(6) P-Ph : 1.797-1.818(4) P-NH: 1.67-1.72(2)P-C: 1.78-1.84(3) P-N,,, : 1.669-1.693(5) P-N,,, : 1.664-1.688(5) 2 crystal modifications : 1.675-1.677(5) 'anticlathrate'; N-Cl contacts (3.14 A) P-N,, P-N,,, : 1.67&1.677(2) clathrate; NsP3and C& rings parallel

1.5&1.594(6) 1.546-1.604(7) 1.56%1.578(3) 1.543-1.592(3) 1.552-1.582(4) 1.53-1.61(1) 1.553-1.609(6) 1.55-1.61 1.54-1.64(1) 1.547-1.643(7) 1S76-1.586(4) 1S62-1.583(6) 1S48-1.614(6) 1.53-1.64 1.53-1.67 1.533-1.666(2) 1.54O-1.640(3) 1.537-1.636(3) 1S42-1.656(2) 1.552-1.601(7) 1.58-1.59(2) 1.596-1.610(4) 1.56-1.62(2) 1.548-1.603(4) 1.585-1.600(5) 1.587-1.592(3) 1.590-1.597(2)

78

205 206 207 207 208 75 75 209 210 209 76 211 212 213 214 215 107a 216 217

204

Ref.

Further remarks

Endocyclic P-N bond lengths (A)

4 X-Ray Molecular Structure Determinations

CompoMd

P-N

Further remarks P-NH : 1.663-1.672(5) P = O : 1.483(3) strongly H-bonded dimers P-N,,, : 1.563(7) N=PPh3 : 1.588(8) P-C : 1.756(5) P-Nexo : 1.660-1.675(3) 2 ind. mol. P-N,,, : 1.656-1.679(7) one remarkably short C-C (1.38 A) P-Nexo : 1.691 (mean v.) P-N(Pt) : 1.645-1.672(6) P-C :1.771-1.795(12) Pt-N:2.02(1) P-NH : 1.643-1.682(8) 2 ind. mol. P-N(Pd) : 1.633-1.650(5) Pd-N : 2.079-2.088(5) P-N(C0) : 1.61&1.645(3) CO-N : 2.1 13-2.197(3)

Endocyclic P-N bond lengths (A)

1.559-1.579(5) 1.545-1.591(7) 1.522-1.562(5) 1.511-1.570(4) 1.57&1.575(6) 1.557 (mean v.) 1.591-1.596(8) 1.514-1.597(8) 1 . 5 8 6 1 . 6 1 l(6) 1.579-1.615(3)

21 8 219 72 220 221 222 223 223 224 225

2oo G. J. Bullen, J. Crystallogr. Spectrosc. Res., 1982, 12, 1 1 (Chem. Abstr., 1982,96, 191 086). 201 I. Rayment, H. M. M. Shearer, and H. W. Roesky, J. Chem. SOC.,Dalton Trans., 1982, 883. 202 M. J. Begley, D. B. Sowerby, and T. T. Bamgboye, J. Chem. Sac., Dalton Trans., 1979, 1401. 2os R. Enjalbert, G. Guerch, J.-F. Labarre, and J. Galy, Z. Kristallogr., 1982, 160, 249. 204 G . Guerch, J.-F. Labarre, R. Roques, and F . Sournies, J. Mol. Struct., 1982, 96, 113. 205 Y. Sudakhara Babu, H. Manohar, and R. A. Shaw. J. Chem. SOC.,Dalton Trans., 1981, 599. 208 M. Krishnaiah, L. Ramamurthy, P. Ramabrahmam, and H. Manohar, 2. Naturforsch., Teil B, 1981,36,765. 207 F. R. Ahmed and S. Fortier, Acfa Crystallogr., 1980, B36,1456. 208 R. J. Ritchie, P. J. Harris. and H. R. Allcock, Inorg. Chem., 1980, 19, 2483. 209 H. R. Allcock, P. P. Greigger, L. J. Wagner, and M. Y. Bernheim, Inorg. Chem., 1981,20,716. 210 R. A. Nissan, M. S. Connolly, M. G. L. Mirabelli, R. R. Whittle, and H. R. Allcock, J. Chem. SOC.,Chem. Commun., 1983, 822. A. W. Cordes, P. N. Swepston, R. T. Oakley, N. L. Paddock, and T. N. Ranganathan, Can. J. Chem., 1981,59,2364. 212 P. A. Kamminga and A. Vos, Cryst. Struct. Commun., 1979, 8, 743. 213 M. W. Dougill, N. L. Paddock, and B. Sheldrick, Acta Crystallogr., 1980, B36, 2797. 214 A. Schmidpeter, H. Eiletz, J. von Seyerl, and G. Huttner, Z. Naturforsch., Teil B, 1979,34, 91 1. 215 R. J. Ritchie, T. J. Fuller, and H. R. Allcock, Inorg. Chem., 1980, 19, 3842. 21s J. Galy, R. Enjalbert, and J.-F. Labarre, Acta Crystallogr., 1980, B36, 392. 217 T. S. Cameron, J.-F. Labarre, and M. Graffeuil, Acta Crysfallogr.,1982, B38, 168. 218 K. S. Dhathathreyan, S. S. Krishnamurthy, A. R. Vasudeva Murthy, T. S. Cameron, C. Chan, R. A. Shaw, and M. Woods, J. Chem. Soc., Chem. Commun., 1980,231. 210 Y . Sudakhara Babu and H. Manohar, Acta Crystallogr., 1979, B35,2363. 220 A. Gieren and B. Dederer, Z. Anorg. Allg. Chem., 1980, 467, 68. 221 J. 0. Bovin and J.-F. Labarre, Acta Crystallogr., 1979, B35, 1182. 222 K. D. Gallicano, N. L. Paddock, S. J. Rettig, and J. Trotter, Inorg. Nucl. Chem. Lett., 1979, 15, 417. 223 J. P. O'Brien, R. W. Allen, and H. R. Allcock, Inorg. Chem., 1979, 18, 2230. 224 N. L. Paddock, T. N. Ranganathan, S. J. Rettig, R. D. Sharma, and J. Trotter, Can. J . Chem., 1981, 59, 2429. 225 K. D. Gallicano, N. L. Paddock, S. J. Rettig, and J. Trotter, Can. J. Chem., 1981, 59, 2435.

P-N Rings.-(Cont.)

$ 5 G

9

4

2

%

$ 5

0

N

00 N

283

Cyclic and Polymeric Phosphazenes 2-(l-methylpyrrolyl)

a b u t y l e n e d iamino-bridged

P

ferrocenyl

F F2P-N=P-N

I II S II II

I1

(1,2,4,3,5-trithiadiazol1 - y l i d e n e )amino

N

N

I

F2P=N-P-N F

'

1- p y r r o l i d i n y 1

1-(3,5-dimethylpyrazolyl) S

Me2P"\PMe2

// \

c1 \ c1 /I

N-Pt-N

M e 2 P\\N,PMe2

' Me2P-N=PMe2 II

HN+

I

I

+NH

M e 2P

i

Ph

H ,N-P\

2P-NN

//

f

' k

P=N

/"\N=P

Ph2

B Ph 2

Ph2

II N\#

Me2 V

1-imidazolyl 1 - a z i r i d i ny 1

2

R = 1-piperidinyl

Ph

HN

\;

\

o=p-

\

N

OMe

OMe

N*

PMe

I

N \p& N

Me2

-.Endocyclic S-N bond lengths (A) 1S26-I .596(7) 1.545-1.603(2) 1S29-1.568(7) 1.547-1.591(7) 1.535-1.557(7)

1.553-1.565(4) 1.544-1.556(7) I .557-1.560(5) 1.5&1.583(5) 1 .&I .655(7) 1.594-1.597(3) 1.58&1.596(3) 1.562-1.589(2) 1.585--1.596(5) 1.594-1.603(3) 1.554-1.61 6(8)

Endocyclic P-N bond lengths (A:

1S93-1.594(7)

1.574-1.594(2) 1.591(8) 1.563-1.576(7) I .569-1.623(7)

1.584-1.609(4) 1.582-1.667(9) 1.582-1.671(6) 1.621-1.625(4) I .617-I .627(7) 1.630-1.642(3) 1.62&1.623(3) 1.585-1.650(4) 1.570-1.610(4) 1.580-1.626(3) 1.569-1.623(9)

: 1.631(7) : 1.599(3)

S-C: 1.843-1.845(5) S-S: 2.551(2) P-C: 1.792-1.796(3) S-S : 2.528( 1) P-C: 1.779-1.814(5) S-N,,, : 1.703(3) S-S: 2.385(1) S-S:2.368(3)

S-C: 1.749-1.750(6) S-N,,, : 1.657-1.677(7) P-N,,: 1.642-1.672(9) 2 mol./cell S-I: 2.71 3(3)

P-N,,, S-N,,

Further remarks

230 231 231 232 233 1Ob

1Oa

229 229 lob 1Oa

228 107b

55

226 227

Ref.

826

F. van BoIhuis, C. Cnossen-Voswijk,and J. C. van de Grampel, Cryst. Srruct. Commim., I98 1,10,69. 227 A. Perales, J. Fayos, J. C. van de Grampel, and B. de Ruiter, Acta Crysralfogr., 1980, B36,838. 228 F. van Bolhuis, J. B. van den Berg, and J. C. van de Grampel, Cryst. Struct. Commun., 1981, 10, 1031. z2s T. Chivers, M. N. S. Rao, and J. F. Richardson, J. Chem. SOC.,Chem. Commun., 1983,700. 230 N. Burford, T. Chivers, P. W. Codding, and R. T. Oakley, Inorg. Chem., 1982,21, 982. 23L N. Burford, T. Chivers, and J. F. Richardson, Inorg. Chem., 1983,22, 1482. 233 T. Chivers, M. N. S. Rao, and J. F. Richardson, J. Chem. SOC..Chem. Commun., 1983, 702. 233 T. Chivers. M. N. S. Rao. and J. F. Richardson, J. Chem. SOC.,Chem. Commun., 1983,186.

Compound

P-NS

P

00 N


c1 N'

285

(la,3 a , 5 a )

k ; R = Me

-

*N

I ; R = Ph rn

c1

cis

-

l l0,

I o

Ph

isomer

S 4

F N 4 1 C1 NMe2

n

Ph Ph P2 P2 N/ \NN \\N Me2N-S

\

1 \

N\pON\pO N

Ph2

Ph2

SOAz

Ph

P-ZmN-p,\ S

N

\PEN

Ph2 N

/ \ N=P /

'

Ph Ph,

-

ZP -N

Ph2

Ph2

Ph N-P N

9,h Ph N

\ P-N

g;

/"-"

i

\ S-N

'

p

Ph2P =

I

h ; X = C1

Ph 2

N

x

2

ezo-@-isomer

'N=SN=S-

S-N

10 Physical Methods BY J. C. TEBBY

The abbrevations n2, n3, n4, n5, and ns refer to the co-ordination number of phosphorus, and the compounds in each sub-section are usually dealt with in order of increasing co-ordination number of the phosphorus atom. In the formulae, the letter R represents hydrogen or organic groups, X represents an electronegative substituent such as halogen, alkoxy-group, etc., Ch represents chalcogenides (usually oxygen and sulphur), whilst Y and Z are used when the substituents have a more varied nature. The terminology apical and radial has been retained for the stereochemical description of substituents of n5 atoms that possess trigonal-bipyramidal geometry, so that the terms axial and equatorial can be reserved to describe the conformational preferences of substituents on n4 atoms in six-membered rings and related cyclic systems. The nomenclature ‘phosphane’ is used for n3 phosphorus compounds in general, reserving the term ‘phosphine’for phosphanes which possess three carbon or hydrogen substituents on phosphorus and the term ‘phosphite’ for phosphanes which possess three alkoxy or aryloxy substituents. Some relevant theoretical and inorganic studies are included in this chapter. 1 Nuclear Magnetic Resonance Spectroscopy

Biological Aspects.-The application of 31Pn.m.r. spectroscopy to biological systems continues to grow. There have been reviews of its use in the study of living tissue1 and for n.m.r. imaging.2 In the latter field an alternative sensitivepoint method gives improved full spectra but it has limited ~ensitivity.~ Chemical Shifts and Shielding Effects.-Chemical shifts are usually given without the appellation p.p.m. The scope of n.m.r. pulsed methods has been re~iewed.~ Anisotropy Efects. The deshielding influence of the phosphoryl group on the methylene protons of phosphorinanes has been di~cussed;~ also the anisotropy of

a

K. Yamada, M. Tanokura, and K. Kometani, Seitai No Kagaru, 1982,33,326; G . Vermeersch and G. Palavit, Actual. Chim., 1982,7, 13-23. E. M. Bradbury, G. K. Radda, and P. S. Allen, Ann. Intern. Med., 1983,98,514. K. N. Scott, H. R. Broaker, J. R. Fitzsimmons, H. F. Bennett, and R. G. Mick, J. Magn. Reson., 1982, 50, 339; A. A. Maudsley, S. K. Hilal, W. H. Perman, and H. E. Simon, ibid., 1983,51, 147. R. Benn and H. Gunther, Angew. Chem., Int. Ed. Engl., 1983,22,350. G . S . Bajwa and S. Chandrasekaran, J. Am. Chem. Suc., 1982,104,6385.

286

Physical Methods

287

the thiophosphoryl group in the naphthyl compound (1) is sufficiently strong to shift the aromatic peri-proton signals to 9--10.3.6 Phosphorus-31. A selection of reference standards for use with aqueous samples

have been described.' 6 , of n2 compounds. Two phosphaindoles (2; R = Ph, But) have been prepared. The anion [2; R = L.E.P. (lone electron pair)] resonated 35 p.p.m. upfield of the parent phosphole anion. It is also more basic than the parent phosphole anion.8A record downfield signal (+599.6) has been reported for the diphosphene [3; R1 = R2 = C(TMS)3].gJ0 This is over 100 p.p.m. downfield of the aryl compound (3; R1 = R2 = ~ , ~ , ~ - B U ' ~ C 8, ~494, H ~ which ) , ~ ~ was incorrectly reported in Volume 14.12' A very interesting observation was the similarity of 6, for the two phosphorus atoms (533.1 and 530) in the mixed diphosphene [3; R1 = C(TMS),, R2 = 2,4,6-But3CBH2] which indicates considerable delocalization across the P=P double bond.ll This also occurs for the monosulphide of (3; R1 = R2 = 2,4,6-But,C6H2), 8, 255.8 and 247.8, but not for the monooxide.13 Further examples of methylenephosphenes (4) have extended the range of chemical shifts to 28-328.14 The amino compound (5) resonates at 309.9.16 The incorporation of the -P=C bond into small rings has a shielding effect for N. A. Rozanel'skaya, A. I. Bokanov, V. V. Negrebetskii, and B. I. Stepanov, J . Gen. Chem., 1981,51,1911. M. Batley and J. W. Redmond, J. Magn. Reson., 1982,49,172. F. Nief, C. Charrier, F. Mathey, and M. Simalty, Phosphorus Sulfur,1982,13,259. A. H. Cowley, J. E. Kildu!T, M. Pakulski, and C. A. Stewart. J. Am. Chem. SOC.,1983, 105, 1655; A. H. Cowley, J. E. Kilduff, T. H. Newmann, and M. Pakulski, ibid., 1982, 104,5820. lo C. Couret, J. Escudie, and J. Satge, TetrahedronLeft., 1982,23,4941. l1 G. Bertrand, C. Couret, J. Escudie, S. Majid, and J. P. Majoral, Tetrahedron Lett., 1982, 23,3567. l8 'Organophosphorus Chemistry' ed. D. W. Hutchinson, J. A. Miller, and S. Trippett, (Specialist Periodical Reports), The Royal Society of Chemistry, London: (a) 1983, Vol. 14,Ch. 11; (b) 1982,Vol. 13, Ch. 11; (c) 1970, Vol. 1, Ch. 11; (d) 1978, Vol. 9, Ch. 11; (e) 1980, Vol. 11, Ch. 11; (f)1981, Val. 12, Ch. 11; ( g ) 1977, Vol. 8, Ch. 11. l8 M. Yoshifuji, K. Shibayama, N. Inamoto, K. Hirotsu, and T. Higuchi, J. Chem. Soc., Chem. Commun., 1983,862; M. Yoshifuji, K. Ando, K. Toyota, E. Shima, and J. Inamoto, ibid., 1983,419. l4 G . Becker, W. Uhl, and H. J. Wessely, 2.Anorg. Allg. Chem., 1981,479,41; R. Appel and B. Laubach, Tetrahedron Lett., 1980,21, 2497; L. N. Markovskii, V. D. Romanenko, and T. I. Pidvarko, J. Gen. Chem., 1982 52, 1707; G. Becker and 0. Mundt, 2.Anorg. Allg. Chem., 1980, 462, 130; K. Issleib, H. Schmidt, and C. Wirkner, ibid., 1982, 488, 75; R. Appel, M. Halstenberg, F. Knoch, and H. Kunze, Chem. Ber., 1982, 115, 2371; 0.I. Kolodyazhni and V. P. Kukhar, J. Gen. Chem., 1981,51,1883 lS R. H. Neilson, Inorg. Chem., 1981,20,1679.

288


both the NP=C group16and the NP=N g r o ~ p . l ~The ~ J ' structure and stabilities of various H2NPmolecules have been investigated by ab initio effectivepotential calculations.'* Phosphorus chemical shifts are vital evidence from the structures of phosphenium ions (6).lBSignals are produced at very low field (240-265) in the reactions of (cyclopentadieny1)chlorophosphanes with aluminium chloride. They have been attributed to a fluxional cation [13; R = But, CH(TMS)2]20 since all the methyl groups are equivalent; the very low field signal shows it would have to have a very high phosphenium ion character. The structures of phospholenium ions have been studied using MIND0/3 and ab initio calculations.21 TMS 2NP

-

CHTMS

Y2P+-=OSO2CF3

2G=

NPh

P

C

B

Me

M e o M e Me

A FH=CH2

- OM+.

Me ( R2N)

RP-

Me

Me

Me

R

+ R3POR

X-

+P

R (13)

6, of n3 compounds. 2-Vinyl phosphiranes (7)22are not at as high a field as previously reported phosphiranes.12cThe cis isomer (7; R = But) resonated at - 160 thus extending the observed range for phosphiranes to - 160 to - 341. Only the tertiary butyl phosphirane showed a large shift difference for the cis and trans isomers. Acyl groups23and alkoxycarbonyl groups24have a deshielding influence on the phosphorus atom in the phosphines (8; Y = R, OR; 6, 8-21), and in triacetylphosphine (6, 64).26The empirical relationship of SP to structure has l6

N. Ayed, R. Mathis, F. Mathis, and B. Baccar, C.R. Seances Acad. Sci., Ser. 2, 1981, 292, 187.

J. P. Majoral, R. Kraemer, and J. Navech, Tetrahedron Lett., 1980, 21, 1307. G. Trinquier, J. Am. Chem. Soc., 1982,104,6969. l9 0. Dahl, TetrahedronLett., 1982,23,1493. 2o A. H. Cowley and S. K. Mehrotra, J. Am. Chem. Soc., 1983,105,2074. 81 R. M. Minyaev and V. I. Minkin, Zh. Org. Khim., 1982,18,2009. aa W. J. Richter, Angew. Chem., Int. Ed.Engl., 1982,21,292. 23 E. Lindner, M. Steinwand, and S. Hoehne, Chem. Ber., 1982,115,2181. R. Thamm and E. Fluck, Z . Naturforsch., Teil B, 1982, 37, 965. G. Becker, 2.Anorg. Allg. Chem., 198 1,480,2 1.

289

Physical Methods

been extended to the diphosphines A review of polyphosphines includes a discussion of 31P n.m.r. data.2BThe range of chemical shifts for the PMe groups in a heptaphosphine, thought to be (lo), illustrates the considerable sensitivity of 6, (43 to -58) to steric effects.29Tertiary butylbromophosphinophosphane groups resonate at very high field (-398.9)30 in contrast to other halo-deri~atives.~~ High field signals (-196 to -234) are also reported for various silylphosphanes and polysilylphosphanes.32 Whilst amino groups generally cause downfield shifts in acyclic p h ~ s p h a n e even s ~ ~ in the presence of a PH group,34small rings shift the signals of aminophosphanes well upfield, e.g., On the other hand the three-co6, -73.3 for (11; R = Pr', R1 = ordinate iminophosphinium salts (1 2) resonate at 37 to 42 whether a small ring is involved or 6, of n4 compounds. Oleum has been recommended as a solvent for phosphonium It has also been used,38together with liquid hydrogen chloride,39to study the basic properties of various phosphoryl compounds. The signals of the phosphoryl compounds move downfield when they are dissolved in the acidic media, the shifts being largest for P-phenyl compounds, cf., quasiphosphonium salts (14).40The shielding effect caused by the inclusion of a n4phosphorus atom in a three-membered ring12dg41 is not as great as that observed for phosphines. Long-chain phosphine oxides dissolved in deuterium oxide exhibit concentration dependent chemical shifts.42The solid state spectra of various methylthiophosphonates and phosphine chalcogenides were obtained by the Proton Enhanced Nuclear Induction Technique.43 Electronic effectsinduced by varying the phenyl substituent Y in phosphonate (15)44 and phosphate (16)45 have opposite effects on 6,. Increased electron(9).26927

W. E. Hill, D. M. A. Minahan, J. G. Taylor, and C. A. McAuliffe, J. Chem. SOC.,Perkin Trans. 2,1982,327. J. C. Briggs, C. A. McAuliffe, W. E. Hill, D. M. A. Minahan, and G. Dyer, J. Chem. SOC., Perkin Trans. 2,1982,321. M. Baudler, Angew. Chem., Int. Ed. Engl., 1982,21,492. aB M. Baudler, Y. Aktalay, J. Hahn, and E. Daerr, Z. Anorg. Affg. Chem., 1981, 473, 20. ao M.Baudler and J. Hellmann, Z. Anorg. Allg. Chem., 1982,490,ll. a1 M. Baudler and J. Hellmann, Z. Anorg. Allg. Chem., 1981,480,129. 3a G. Fritz, J. Haerer, and K. H. Scheider, Z. Anorg. A&. Chem., 1982,487,44. 33 R. Appel, M. Huppertz, and A. Westerhaus, Chem. Ber., 1983, 116, 114; M. J. Babin, Z . Anorg. Allg. Chem., 1980,467,218;V.L. FOSS,Yu. A. Veits, T. E. Chernykh, and I. F. Lutsenko, J. Gen. Chem., 1981,51,2059. 54 N.O'Neal and R. H. Neilson, Inorg. Chem., 1983,22,814;A. H. Cowley and R.A. Kemp, ibid., 1983,22,547. 36 E. Niecke, A. Seyer, and D. A. Wildbredt, Angew. Chem., Int. Ed. Engl., 1981, 20, 674. ae M. R. Marre, M. Sanchez, and R. Wolf, Phosphorus Sulfur, 1982, 13, 327; M.Sanchez, M. R. Marre, J. F. Brazier, J. Bellan, and R. Wolf, ibid., 1983,14,331. 37 K.B. Dillon, M. P. Nisbet, and T. C. Waddington, Polyhedron, 1982,1, 123. s8 (a) K. B. Dillon, M. P. Nisbet, and T. C. Waddington, J. Chem. Suc., Dalton Trans., 1982,465;(b) ibid., 1981,212. K. B. Dillon, T. C. Waddington, and D. Younger, J. Inorg. Nucl. Chem., 1981, 43, 2665. 40 R. D. Guthrie and I. D. Jenkins, Aust. J. Chem., 1982,35,767. 41 H.Quast and M. Heuschmann, Liebigs Ann. Chem., 1981, 5, 977. G. C. Kresheck and C. Jones, J. Colloid Interface Sci., 1980,77,278. ra J. P. Dutasta, J. B. Robert, and L. Wiesenfeld, ACS Symp. Ser., 1981,171,581. 44 R. I. Taresova, T. V. Zykova, T. A. Dvoinishnikova, K. A. Salakhutdinov, and N. I. Sinitsyna,J. Gen. Chem., 1981,51,2080. 46 D. Zhang and G. Li, Gaddeng Xuexiao Huaxue Xuebao, 1982,3,77.

290

Organophosphorus Chemistry 0 0

II

k

Me

withdrawal in (15 ) caused shielding, whereas in (1 6) it may cause deshielding. The extra shielding experienced by the phosphorus group in the phosphonate (17) when it occupies the C-4 position is attributed to a sulphur-phosphorus interaction?6 The calculated screening tensor components of dimethyl methylphosphonate were lower than the experimental values for the ester (18).47 The chemical shifts of the cis and trans isomers of the anhydrides (19) vary over a wide range (- 4 to 72).4B 6 , of n5 compounds. Whilst di- and tri-chlorophosphoranes exhibit signals in *~O bromophosphoranes vary more the usual n5 phosphorane r e g i ~ n , ~ ~the widely.f2es60Further work on the chemistry of Wittig oxyphosphetanes has utilized chemical shift data.51 Several polycyclic hydridophosphoranes are reported which have 6, values varying from -4552 to t46.53 6 , of ns compounds. Whilst most compounds of this co-ordination resonate upfield of some ozonides exhibit signals as low as -37.55

Hydrogen-I. The E- and Z- isomers of the en01 phosphate (20) were identified through weak intramolecular hydrogen bonding identified through the spectra of tetrachloromethane and dimethylsulphoxide ~ o l u t i o n s . ~ ~

Carbon-13. Electron density distribution in phenylphosphines (21 ; Y = H) and lithium phenylphosphines (21; Y = Li) have been estimated from 6 , values 46 47 46 40

60

G. Bidan and R. Nardin, J. Chim.Phys., Phys.-Chim. Biol., 1982,79,87. T. F. Weller, U. Franck, G. Klose, and R. Lochmann, 2. Chem., 1982,22 62. N. A. Andreev and 0.N. Grishina, J. Gen. Chem., 1982,52,1581. (a) J. Gloede, M. Pakulski, A. Skowronska, H. Gross, and J. Michalski, Phosphorur Sulphur, 1982,13,163; B. V. Timokhin, V. K. Dmitriev, V. 1. Dmitriev, B. I. Istomin, and V. I. Donskikh, Zh. Obshch. Khim., 1981,51, 1989; (b) B. V. Timokhin, V. K. Dmitriev, and V. I. Dmitriev, J. Gen. Chem., 1982,52,476. J. Gloede, H. Gross, J. Michalski, M. Pakulski, and A. Skowronska, Phosphorus Surfur, 1982,13, 157.

61

E.Vedejs and G. P. Meier, Angew. Chem., Int. Ed. Engl., 1983,22,56.

68

J. M. Dupart, S. Pace, and J. G. Riess, J. Am. Chem. SOC.,1983,105,1051. M. A. Pudovik, S. A. Terent’eva, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1982,1408. B. Garrigues, A. Munoz, and M. Mulhiez, Phosphorus Sulfur, 1980, 9, 183; L. N. Markovskii, A. D. Sinitsa, V. I. Kal’chenko, L. I. Atamas, and V. V. Negrebetski, J. Gen. Chem., 1982,52,389. A. M. Caminade, F. El Khatib, and M. Koenig, Phosphorus Sulfur, 1983, 14, 381; M. Koenig, F. El Khatib, A. Muniz, and R. Wolf, Tetrahedron Lett., 1982, 23, 421. A. Preiss, H. Luthardt, and H. Denther, J. Prakt. Chem., 1982,324,461.

b8 64

66

66

Physical Methods

29 1 0

with the aid of CND0/2 calculation^.^^ The x interactions of the phosphino and phosphide groups were less than and greater than that of the carboxamide group, respectively. A study directed towards non-phosphorus compounds showed that the electronic effects on 6 , should not be interpreted in terms of x changes only and that an increase in electron density will cause SC to move to high field when the gain in x population is greater than the loss of CT population whereas 6 , will move downfield when the electron density gain is dictated by the CT population.68 The electronic effects in 2-aryloxy-l,3,2-dioxyphosphorinanesin comparison with anisoles, was also studied by 13C n.m.r. spe~troscopy.~~ The ylidic carbon of the novel P-iodo-ylide (22) was unusually down field (112.8) and corresponded to a lack of nucleophilic reactivity.60 Studies of o-alkylated phenyl phosphates show that y shielding effects are operative for certain geometries. Carbon-13 n.m.r. spectroscopy has also been applied to stereochemical studies of phosphoramidates,62 phosphor in one^,^^ diazapho~phorinanes,~~ furanose phosphanes,66and glycerophosphates.66 Nitrogen-I5 and Oxygen-17. The spectra of these nuclei have been used to study the electronic character of oxygen and nitrogen bonds when polyfluoroaromatic 67

6*

S. S. Berestova, M. I. Terekhova, N. A. Bondarenko, Yu. S. Bogachev, E. S. Petrov, E.N. Tsvetkov, and A. I. Shatenshtein,J. Gen. Chem., 1982,52,450. S. Fliszar, G. Cardinal, and M. T. Beraldin, J. Am. Chem. Soc., 1982, 104, 5287.

B. A. Arbuzov, R. P. Arshinova, V. S. Vinogradova, and P. P. Chernov, J. Gen. Chem., 1982,52,1937.

84

Th. A. van der Knaap and F. Bickelhaupt, Tetrahedron Lett., 1982,23,2037. J. M. A. Al-Rawi, G. Q. Benham, and N. Ayed, Org. Magn. Reson., 1983,21,75. G. W. Buchanan, R. H. Wightman, and M. Malaiyandi, Org. Magn. Reson., 1982,19, 98. A. P. Logunov, L.P. Krasnomolova, 0.V. Agashkin, Yu. G. Bosyakov, B. M.Butin, and S . D. Dzhailanov, Izv. Akad. Nauk Kaz. SSR,Ser. Khim., 1981, 1, 65; A. P. Logunov, L.P. Krasnomolova, and Yu. G. Bosyakov, ibid., p. 5 5 . E. 1. Smirnova, A. I. Zavalishina, A. A. Borisenko, M. N. Rybina, and E. E. Nifant’ev,

66 66

Zh. Obshch. Khim., 1981,51,1956. E. E. Nifant’ev, S. F. Sorokina, and L. A. Vorob’eva, Zh. Obshch. Khim., 1981,51, 2052. P. Kertscher, H. J. Rueger, K. Gawrisch, and P. Nuhn, Pharmazie, 1980,35, 812.

6o

61 68

63

292


groups are bound to p h o ~ p h o r u s .Another ~~ study showed that 6, values of phosphoryl groups are very sensitive to the nature of phosphorus substituents. Thus the signal moves to much lower field when a sulphur atom is present.*8 Ffuorine-19. Substituent constants have been calculated from 6, values for the imino series (23).69Medium effects were apparent.

Solvation and Shift Reagents.-The solvation parameters for a series of alcohols have been determined using the 31Pn.m.r. chemical shift of tris-n-butylphosphine Ion pair association between tetraphenylboron and cationic centres was used to study the electronic structure of aminonaphthylphosphonium salts (24; X = PhpB-).'ll Shift reagents have been used in the conformational analysis of adenosine phosphates72and aromatic solvent induced shifts to probe the stereochemistry of butadienylphosphonates and their The geometries of difluorophosphinederivatives were evaluated from liquid crystal n.m.r. studies with the aid of electron diffra~tion.~~

Variable Temperature Studies.-Several examples of silylatropic tautomerism have been found to have suitable rates for n.m.r. study. Two were NPN systems, 75 another involved migration across a PCN group.7s Tautomeric migrations of phosphoryl groups across a NCN group are considerably slower.7 7 Rotational barriers for a variety of amino groups have been determined for a cyclic triaminophosphane,7 8 various trifluoromethyl n5-phosphoranes,7B and an intriguing phosphorinyl cation (25).80 Theoretical studies were reported on the rotational barrier for +PHNH,81 and for the hexamethyldiphosphonium cation.8 2

67

G. G. Furin, A. I. Rezvukhin, M. A. Fedotov, and G. G. Yakobson, J. Fluorine Chem., 1983,22,23 1.

68 69

'O

71 72

J. A. Gerlt, P. C. Demon, and S. Mehdi, J. Am. Chem. SOC.,1982,104,2848. M. I. Kabachnik, N. A. Tikhonina, V. A. Gilyarov, B. A. Korolev, M. A. Pudovik, L. K. Kibardina, and A. N. Pudovik, J. Gen. Chem., 1982,52,899. H. Elias, M. Dreher, S. Neitzel, and H. Volz, 2. Naturforsch., Teil B, 1982,37,684. G. P. Schiemenz and E. Papageoriou, Phosphorus Sulfur, 1982,13,41. S . Yokoyama, T. Oida, S. Uesugi, M. Ikehara, and T. Miyazawa, Bull. Chem. SOC. Jpn., 1983,56, 375; C. F. G. C. Geraldes and R. J. P. Williams, J. Chem. SOC.,Perkin Trans. 2, 1982,1279.

73

B. P. Nosov, V. M. Kostenko, L. N. Mashlyakovskii, and B. I. Ionin, J. Gen. Chem., 1982, 52, 1704.

74 76 '13

P. D. Blair, J. Mol. Struct., 1983,97, 147. V. D. Romanenko, A. V. Ruban, S. V. Iksanova, and L. N. Markovskii, J. Gen. Chem., 1982, 52, 510; R. H. Neilson and J. S . Engenito, jun., Organometallics, 1982, 1, 1270. R. Appel, H. Foerster, B. Laubach, F. Knoll, and I. Ruppert, Angew. Chem., Int. Ed. Engl., 1982,21,448.

77 78

V. V. Negrebetskii, L. Ya. Bogel'fer, A. D. Sinitsa, V. I. Kal'chenko, V. S. Krish Tal,and L. N. Markovskii, J. Gen. Chem., 1982,52,1322. 0.J. Scherer, M. Puettmann, C. Krueger, and G. Wolmershauser, Chem. Ber., 1982,115, 2076.

79

R. G. Cave1 and S. Pirakitigoon, Znorg. Chem., 1983,22, 1378. V. V. Negrebetskii, P. Yu. Ivanov, N. N. Bychkov, andB. I. Stepanov, J. Gen. Chem., 1982, 52, 1712.

81 82

G. Trinquier and M. R. Marre, J. Phys. Chem., 1983,87,1903. C . Glidewell,J. Chem. Res. ( S ) , 1983,22.

Physical Methods

293

Studies of Configuration.-The separation of diastereomeric bisphosphonium salts was monitored by 31Pn.m.r.8a N.m.r. was also able to detect < 3 % of a minor isomer of the diphosphine palladium complex (26). 84 Mercury-199 n.m.r. spectra showed extra splitting due to bound diastereomeric phosphorus groups.86 The threo- and erythro- forms of the phosphine (27) gave well separated signals (ap- 17 and -27).86 Diastereomeric anisochronocity of various cx-aminophosphonates (28) has also been reported.87 Spin-Spin Coupling.-Heteronuclear 2D n.m.r. experiments4 allow the correlation of nuclei not directly coupled to the observed nuclei but belonging to a common coupling network.88 The technique has been applied to a-menthyldichlorophosphane in order to determine its lH parameter^.^^ J(PP) andJ(PA4).Many more examples of direct P(n3)-P(n8)couplings have been r e c ~ r d e d All . ~ are ~ ~smaller ~ ~ than -451 Hz;12f however, a coupling as low as - 132 Hz has been reported for a secondary aminodiph~sphine.~~ A unique direct P(n3)-P(n3)coupling (-436.5 Hz) has been reported for the ylide (29hg2 83

N. Gurusamy and K. D. Berlin, J. Am. Chem. Soc., 1982,104,3114. E. P. Kypa and S. P. Rines, J. Org. Chem., 1982,47,4800. J. Eichbichler and P. Peringer,J. Organornet. Chern., 1982,231,95. A. N. Pudovik, G. V. Romanov, and T. Ya. Stepanova, Izv. Akad. Nauk SSSR,Ser. Khim., 1982,1417.

K. L. Seitanidi, I. Ya. Gorban, M. M. Yusopov, M. R. Yugudaev, and N. K. Rozhkova, Dokl. Akad. Nauk Uzb. SSR,1980,41. 88 P. H. Bolton and G. Bodenhausen, Chem. Phys. Lett., 1982,89,139. M. Feigel, G. Haegele, A. Hinke, and G. Tossing, Z. Natwforsch., Teil B, 1982,37, 1661. O0 K. Jurkschat, C. Magge, A. Tzschack, W. Uhlig, and A. Zschanke, Tetrahedron Lett., 1982, 23, 1345; R. Appel and W. Paulen, Angew. Chem., Int. Ed. Engl., 1981, 20, 869; M. Baudler and P. Luetkecosmann, 2. Anorg. Allg. Chem., 1981,472,38; M.Baudler and J. Hellmann, 2. Naturforsch., Teil B, 1981,36,266. *l E. Niecke and R. Rueger, 2. Natwforsch., Teil B, 1982,37,1593. A. H. Cowley and M. C. Cushner, Inorg. Chem., 1980,19,515.

294

Organophosphorus Chemistry 0

(29)

(30)

(31)

(32)

The anion (30) has a much larger geminal P(n3)CP(n3)coupling (175 H z ) than ~~ those previously reported for this group.lZ2The reported P(n3)CP(n4)couplingse4 fall within the established 50-190 Hz range. Unlike the wide range of P(n3)NP (n3)coupling constants the P(n3)NP(n4)geminal coupling is usually only 20-76 Hz;12ehowever, the recently recorded value of 140 Hz for the phospholane (31) considerably extends this range. B5 An exceptionally small P(n4)CP(n4)coupling ( < 2 Hz) has been observed for the trisulphide (32).9s The couplings rise to 58 Hze7and 73 Hzgafor the corresponding PNP and PPP couplings. J-Resolved 2D homonuclear experiments on polyphosphorus compounds such as (33) give an impressive analysis of overlapping multiplets involving A2X and AMX spin = 50 Hz) Lithium diphenylphosphide exhibits a coupling pattern (JpL1 which corresponds to the presence of the dimer (34).looSome interesting POSn and PCCSn coupling constants in the range 20-235 Hz have been analysed with respect to stereochemical relationships.lo1

J(PF). The direct PF coupling constant differs only slightly for the cis and trans isomers of the phosphazene (35).lo2The vicinal PF coupling constants are also similar (f22.1 and +20.7). The fluorophosphate (36) had lJ(PF) = lo00 Hz which is 13 Hz larger than its ~ t e r e o i s o m e r .This ~ ~ ~supports other evidence on the stereochemical assignments. The geminal PCF couplings for dialkoxy(trifluoromethyl)phosphanes104fall within the normal range +20 to +90 Hz. The geminal couplings generally increase as the phosphorus substituents become 83 94

H. H. Karsch, 2. Naturforsch., Teil B, 1982,37,284. I. M. Aladzheva and 0. V. Bykhovskaya, Zh. Obshch. Khim., 1982,52, 1095; H. Schmidbaur and T. Costa, 2. Naturforsch., Teil B, 1982,37,677; H. H. Karsch, Chem. Be?., 1982, 115,1956.

e6

B7

M. A. Pudovik, Yu. B. Mikhailov, T. A. Mironova, and A. N. Pudovik, Bull. Acad. Sci. USSR, 1982,1445. S . 0. Grim, S. A. Sangokoya, I. J. Colquhoun, and W. McFarlane, J. Chem. SOC.,Chcm. Commun., 1982,930. S . S. Krishnamurthy, K. Ramachandran, A. R. V. Murthy, R. A. Shaw, and M. Woods, J. Chem. SOC.,Dalton Trans., 1980,840. K. S . Dhathathreyan, S. S. Kirshnamurthy, and M. Woods, J. Chem. SOC.,Dalton Trans., 1982,2151.

9B I. J. Colquhoun and W. McFarlane, J. Chem. SOC.,Chem. Commun., 1982, 484. looI. J. Colauhoun, H. C. E. McFarlane. and W. McFarlane, J. Chem. SOC.,Chem. Commun..

1982,220. 101

H. Weichmann, C. Muegge, A. Grand, and J. B. Robert, J. Organomet. Chem., 1982,238, 343.

108

R. Keat. D. S. Rwroft, E. Niecke, H. G. Schafer, and H. Zorn, 2.Nuturforsch., Teil B, -~

103

D. S. Milbrath, J. P. Springer, J. C. Clardy, and J. G . Verkade, Phosphorus Surfw, 1981,

1982,37; 1665. 11, 19. 104

I. G. Maslennikov, G. N. Prokof’eva, A. N. Lavrent’ev, and M. M. Shcherbaeva, J. Gen. Chem., 1982,52,816; G . N. Prokof’eva, I. G. Maslennikov, and A. N. Lavrent’ev, ibid.. 1982, 52, 815.

Physical Methods

295 Li

Ph2P(Y)

\CHCH2P(Y)Ph2

/

But

/’ ‘ Ph2P, \

0

‘Li‘

F

)PPh2

F\ /N\ P\N/p-F But

R

more electronegative and they are also dependent on the dihedral angle between the phosphorus lone pair of electrons and the CF bond. The coupling may become negative when the connecting atom is sp2 hybridized.lo6 Vicinal PF couplings of o-fluorophosphines are 53-59 Hz.lo6 This is in accordance with trends for vinyl fluorides where the cis couplings are 53-84 Hz and the trans couplings are only 4-8 Hz.lo6 The very large four bond coupling in the otrifluoromethylphosphine(37) has been shown to be positive (+68.3 Hz).lo7The origins of the enhanced couplings which occur when certain atoms are juxtaposed is still not clear. A theoretical study of ‘through-space’ or ‘proximity’ effects with regard to HF spin-spin coupling indicated that nuclear separation may not be the only factor invo1ved.lo8A very long range PF coupling (6Jpp3.7 Hz) has been observed in the spectrum of a p-fluorophenoxyphosphorane.loB J(Pl’0) and J ( P N ) . Values of lJp0for various phosphates occur in the region 91-133 H z . The ~ ~ three-membered ring of azadiphosphirane does not appear to have a dramatic effect on lJpN1l0 compared to acyclic aminophosphanes.12e Nitrogen-15 labelled cyclophosphazanes (38) possess lJpN 21-29 Hz,ll1 which falls in the previously observed range 11-53 for phosphoramidates. Self consistent perturbation calculations of IJpNusing INDO parameters indicate a sign change as the co-ordination of the phosphorus atom changes from n3 to n4. The observed coupling trends correlate with contact contributions and the s character of the lone pair of electrons on the coupled nuclei.l12 J(PC). Quite different n.m.r. parameters are reported for triphenylphosphoniumcyclopropylide.It appears that the direct PC coupling constant is exceptionA. H. CowleyandN. W. Taylor, J. Am. Chem. SOC.,1969,91,1026. H. B. Stegmann, H. M. Kuehne, G. Wax, and K. Schemer, Phosphorus Sulfur, 1982, 13,

lob

lo6

331. lo’ T. Schaefer, K. Marat, A. Lemire, and lo*R. E. Wasylishen and M. Barfield, J. Am.

A. F. Lanzen, Org. Magn. Resort., 1982. 18. 90. Chem. SOC.,1975,97,4545. logD. B. Denney, D. Z. Denney, and L. T. Liu, PhosphorusSulfw, 1982,13,1. 110 M. Baudler and G. Kupprat, 2.Natwforsch., Teil B, 1982,37,527. ll1 B. Thomas, G. Grossmann, and H. Mayer, Z . Anorg. Allg. Chem., 1982.490, 121. S. Duangthai and G. A. Webb, Org. Magn. Reson., 1982,20,33.

ally small (3.9 Hz).l13 In contrast, trisalkoxyphosphonium ylides are characterized by very large values of lJPcusually in the range 225-250 Hz.l14This coupling constant may be used to establish the exo-endo stereochemistry of trinorbornylphosphonates115and it has been a useful aid for configurational assignments of the spiro-phosphoranes (39).l16 The sign of 2Jpc is different (-2.6 to $23.1) for the two phosphorus atoms of the diphosphine (4O)ll7and two examples have appeared where 2Jpc (em) is considerably smaller than lJPc (endo).lfs Various

0

(EtO) P II

,CF3

'N=C

\ CF3 (42)

PC coupling constants in bicyclic compounds test Karplus relationships11s-121 and highlight the problem of allowing for multiple coupling pathways.120 The analyses of complex ABX and AAlX coupling patterns have been aided considerably by running the spectra at different field strengths.121Vicinal coupling constants have also been used to determine the stereochemistry of the pyrrolidine (41).122Evidence is also discussed relating to the dihedral angle relationships of JpNcc.The model compound (42) did not provide any direct evidence since the trifluoromethyl groups remained equivalent down to -70 0C.123The very large '14 '16

116

H. Schmidbaur, A. Schier, M. B. Milewski, and U. Schubert, Chem. Ber., 1982,115, 722. D. B. Denney and D. Z. Denney, Phorphorus Sulfur, 1982, 13, 315; J. C. Tebby, S. E. Willets, and D. V. Griffiths,J. Chem. Soc., Chern. Commun., 1981,607. E. Haslinger, E. Oehler, and W. Robien, Monatsh. Chem., 1982,113,1321. V. V. Ragulin, A. A. Petrov. V. 1. Zakharov, and N. A. Razumova. Zh. Obshch. Khim.. 1982,52,239.

M. Baudler and F. Saykawski, Z. Anorg. Alfg. Chem., 1982,486,39. 11* B. de Ruiter and J. C. van de Grampel, Phosphorus Sulfur, 1982. 14. 99: J. Bellan, M. R. Marre, M. Sanchez, and R. Wolf, ibid., 1981,12, 11. *I9 U. Kuhne, F. Krech. and K. Issleib, Phosphorus Sulfw, 1982, 13, 153; C. C. Hanstock and J. C. Tebby, J. Chem. Res. ( S ) , 1982, 110; E. L. Clennan and C. H. Poh. J. Org. Chem., 1982,47,3329; E. L. Clennan and P. C. Heah, ibid., 1981,46,4105. 120 M. J. Gallagher, H. Honegger, and J. Sussman, Aust. J. Chem., 1982, 35, 363. lal L. D. Quin, K. A. Mesch, R. Bodalski, and K. M. Pietrusiewicz, Org. Magn. Resnn.. 1982. 11'

20, 83. la2 123

C . Rabiller, A. Dehnel, and G. Lavielle, Can. J. Chem., 1982,60,926. V. V. Negrebetskii, L. Ya. Bogel'fer. A. D. Sinitsa, V. 1. Kal'chenko. and V. S. Krishtal'. Zh. Obshch. Khim.. 1981,51,1485.

four-bond PC coupling (10 Hz) for the phosphine (43),124could have a proximity (throughspace) contribution, whereas the 3.1 Hz value for the sulphide (44)12h is more likely to be due to a favourable W geometry. J ( P H ) . It has been reported that the Fermi contact spin dipolar cross term is the most important contributor to the anisotropy of the nuclear spin-spin coupling tensor related to PH and HH interactions involved for PH2-, PH3, and PHp+.126 The stereospecificity of geminal and vicinal PH coupling constants have been reviewed.12' The influence of phosphorus substituents on the dihedral anglecoupling constant relationship is discussed. The stereochemistry of various phosphorinanes have been investigated using the geminal coupling constant.128p12g The POCH coupling constants identified the 'frozen' chair and twist conformer of the phosphapanes (45; Y = OPh, NMe2)130and the twist conformer of the phosphorinane (46).131The PCCH coupling constants for the cyclopropylphosphonate (47) support the trend JpCCH (cis) > JPCCH (trans) for this type of Two five-bond couplings are reported, one for the phosphine (48) with a possible proximity the other for the oxide (49).134Strong 0

II

(45)

(46)

(47)

M e

Me2P

Ph2P\ S

/SiMe3

I Me-P-Me

0 Pri2P

II

\

/c=c=

Ph

Nve

I. Granoth, J. Chem. SOC.,Perkin Trans. I , 1982,735. J. B. Rampal, K. D. Berlin, and N. Satyamurthy, Phosphorus Sulfur, 1982,13, 179. la6 P. Lazzeretti, E. Rossi, F. Taddei, and R. Zanasi, J. Chem. Phys., 1982, 77, 408. Yu. Yu. Samitov,J. Gen. Chem., 1982,52,1967. 12* B. A. Arbuzov, 0. A. Erastav, S. N. Ignat'eva, T. A. Zyablikova, and I. P . Romanova, Bull. Acad. Sci. SSSR, Ser. Khim., 1981, 2312; H. Yamamoto, Y. Nakamura, H. Kawamoto, Curbohydr. Res., 1982,102, 185; H. Yamamoto, K. Yamamoto, S. Inokawa, M. Yamashita, M. A. Armour, and T. T. Nakashima, J. Org. Chem., 1983,48,435. 12s B. A. Arbuzov, 0. A. Erastov, T. A. Zyablikova, S. N. Ignateva, G. N. Nikonov, R. P. Arshinova, and R. A. Kodyrov, Bull. Acad. Sci. USSR,Ser. Khim., 1982, 119. 130 B. A. Arbuzov, A. W. Aganov, V. V. Klochkov, R. A. Kadyrov, and R. P. Arshinova, Bull. Acad. Sci. USSR, 1982, 1069. 131 S. Chandrasekaran and W. G. Bentrude, TetruhedronLett., 1980,21,4671. laa G . Maas, Phosphorus SuIjiur, 1983,14143. laa A. Antoniadis, U. Kunze, and M. Moll, J. Organomet. Chem.. 1982,235,177. 134 0.I. Kolodyazhnyi, J. Gen. Chem., 1982,52,390. la4

298


evidence for the existence of a proximity coupling mechanism between hydrogen 5.6 Hz for the phosphinophosphonium and n3 phosphorus is provided by 6JpH was largest salt (50).135The PPH coupling constant of 1,2-di-t-butyIdiphosphine (14.2 Hz) for the mesu isomer, i.e., when the hydrogen was closest to the lone pair of electrons on the adjacent phosphorus atom.136 Relaxation, CIDNP, and N.Q.R.-Relaxation. Phosphorus-3 1 and carbon-1 3 relaxation times are reported for dimethyl met hy1pho~phonate.l~~ The mobility of phosphazene polymers has been studied using 31P spin-lattice relaxation param e t e r ~ . ~The ~ * structure and mobility of polycrystalline nitrilotrimethylphosphonic acid was estimated by line shape analysis.139Molecular interactions of guanosine monophosphate and ATP have been studied through their relaxation O ~r0perties.l~ CIDNP. Radical pairs have been detected by CIDNP in the reactions of various phosphanes with l-nitro-l-alkene~.~~~ CIDNP spectra were also observed during the dimerization and trimerization of allylphosphine under photochemical and free radical initiation conditions.142 N . Q.R. The 35Cl n.q.r. spectra of cyclic 1,3,2-n4-diazaphosphorinescorrelate with parameters estimated by CND0/2 calculations,143The structures of the intermediates produced in the reactions of formamides and acetamides with phosphorus pentachloride and phosphoryl trichloride have been studied by n.q.r. The stereochemistry of n5 dichlorodiazadiphosphetane has been and evidence on the polarity of radial chloride atoms in chlorophosphoranes

2 Electron Spin Resonance Spectroscopy

The photochemical decomposition of diphosphenes in the presence of peroxides produce a variety of new n2 phosphorus radicals (51) which have a(P) values 92-108 G.146 The radical (51; X = Cl) was stable for one week. The e.s.r. 135 136

13’ 13*

138

T. Costa and H. Schmidbaur, Chem. Ber., 1982,115,1374. M. Baudler, C. Gruner, H. Tscharbunin, and J. Hahn, Chem. Ber., 1982, 115. 1739. A. M. Hakkinen, H. B. Bjork, J. Enqvist, A. Hesso. and E. Rahkamaa, Proc. Natl. Meet. Biophys. Med. Eng. Finl., 1982,4th, 191. G. Schilling, C. W. Rabener, and W. Lehr, Z . Naturforsch., Teil B, 1982,37, 1489. K. I. Popov, V. E. Larchenko, V. F. Chuvaev, and N. M. Dyatlova, Zh. Neorg. Khim., 1982,27,2756.

140

lQ1

lQ2 lQ3 lQ4 145

L. Jacobson, J. Magn. Reson., 1982, 49, 522; B. Peterson, J. Led, E. R. Jahnston, and D. M. Grant, J. Am. Chem. Soc., 1982,104,5007. R. D. Gareev, A. V. Il’yasov, Ya. A. Levin, E. I. Gol’dfarb, V. I. Morozov, G. M. Loginova, L. M. Shermergorn, and A. N. Pudovik, J. Gen. Chem., 1982, 52, 1116; R. D. Gareev, A. V. Il’yasov, Ya. A. Levin, E. I. Gol’dfarb, V. I. Morozov, I. M. Shermergorn, and A. N. Pudovik, ibid., p. 1123; V. A. Al’fonsov, R. D. Gareev, E. I. Gol’dfarb, E. S. Batyeva, 1. M. Shermergorn, and A. N. Pudovik, ibid., p. 385. B. N. Die1 and A. D. Norman, Phosphorus Sulfur, 1982,12,227. E. A. Romanenko, J. Mol. Struct., 1982,83,337. G. V. Dolgushin, V. P. Feshin, M. G. Yoronkov, C. A. Pensionerova, V. G. Rosinov, and A. V. Kalabina, J. Mol. Struct., 1982,83,336. T. V. Kolodka, M. I. Povolotskii, and Yu. G. Gololobov, Zh. Obshch. Khim., 1982, 52, 1511.

Physical Methods

299

parameters for the monomer and dimer cations of trimethylphosphine have been re~0rded.l~~ Phosphoranyl radicals have been reviewed.14*An e.s.r. study of a single crystal under X-ray irradiation at low temperatures allowed both stereoisomers (52) and (53) of a phosphoranyl radical to be The parameters showed a small excess 3s spin density in the radial bonds in comparison with the apical bond, which refines the hypothesis that sp3d hybridization of phosphorus can be constructed from three radial sp2 ligands and two pd 1igands.lagRadical ions obtained by the reduction of tertiary phosphines and their c h a l c o g e n i d e ~ ~ ~ ~ have been studied by e.s.r. spectroscopy together with adducts of phosphites with 1,3-dialkyltriazenylradicals,1512,6-di-t-butylphenoxy and various spin trapped phosphorus ~adica1s.l~~

3 Vibrational and Rotational Spectroscopy Band Assignments.-The Fourier transform infrared spectrum of C-difluorophosphaethane has been analysed and the P=C band assigned.154The vpsi band assignmentsfor silylphosphineshave been The positions of vp =1 4 and vp =isNH are and used to characterize isomeric phosphineiminium ~a1ts.l~' The vpoz (sym) bands of barium dialkyl phosphates have been compared in liquid crystal and aqueous media.158 146 147

148

149 150 151 152 153

154 165 158 157 150

B. Cetinkaya, A. Hudson, M. F. Lappert, and H. Goldwhite, J. Chem. Soc., Chem. Commun., 1982,609. M. C . R. Symons and G. D. G. McConnachie, J. Chem. Soc., Chem. Commun., 1982, 851. W. G. Bentrude, React. Intermed. (Plenum), 1983,3, 199. J. H. H. Hamerlinck, P. Schipper. and H. M. Buck, J. Org. Chem., 1983, 48, 306; J. Am. Chem. Soc., 1983,105,385. W. Kaim, P. Haenel, and H. Bock, 2. Naturforsch., Teil B, 1982, 37, 1382; W. Kaim, P. Haenel, U. Lechner-Knoblauch, and H. Bock, Chem. Ber., 1982,115, 1265. J. C. Brand and B. P. Roberts, J. Chem. Soc., Perkin Trons. 2, 1982, 1549. B. Cetinkaya, Eczacilik Bul., 1982, 24, 24. N. A. Kardanov, S. A. Trifonova, R. I. Zhdanov, N. N. Godovikov, and M. I. Kabachnik, Bull. Acad. Sci. USSR, 1982, 1283; W. A. Pryor and C. K. Govindan, J. Org. Chem., 1981, 46, 4679; P. P. Kornuta, V. N. Bobkov, 0. M. Polumbrik, and L. N. Markovskii, J. Gen. Chem., 1982, 52, 1330; E. A. Berdnikov, A. A. Vafina, V. L. Poluchina, R. M. Zaripova, F. R. Tantasheva, and A. V. Il'yasov, Bull. Acad. Sci. U S S R , Ser. Khim., 1981, 2320. K. Ohno, H. Matsuura, H. W. Kroto, and H . Murata, Chom.Lett., 1982,981. K. Hassler, Monatsh. Chern., 1982, 113,421 . G. N. Koidan, A. P. Marchcnko. A . A . Kudryavtscv, m d A . M . Pinchuk, J. GPN.Cheiti.. 1982,52,1779. J. Ellermann, M . Ixilz, :incl K . (icihcl, 1.AirorK. A//,y. C'hCJm., 1082,492, 122. H . OkabayaJhi, 'r'. Yo\hitl;r, I.. I hcd;i, I I . M;ilsiiur:i, a i i t l T. Kit;igaw;i. J . A m . C ' h c i r i . Soc., 1982, 104, 5300.

~

~

300


Bonding.-Further work on the force constants of methyl ph~sphines~~O has been reported and the vibrational spectra of trimethylphosphine gallium trichloride adduct analysed for force constant data.160The pseudopotential term for the vibrational Hamiltonian of 3-phospholene is similar to that of 1,3-disilacyclobutane.lsl An analysis of the spectra of triazaphosphorines indicates that all the ring bonds have appreciable double bond character.ls21.r. evidence for conjugation in the iminophosphorane (54) has been presented.ls3 7x3

C1 3P=N-C=NY

The self-association of dipropylphosphine16*and intermolecular hydrogen bonding in alkylphosphines16shave been studied. It has been suggested that traces of phosphoryl compounds in phosphanes are best detected through the i.r. spectra of their hydrogen bonded complexes.lsa A study of the association constants of phenol with substituted mono- and di-arylphosphine oxides indicated that substituent effects occur by an inductive mechanism.ls7 Intramolecular hydrogen bonding has been identified in the anils (55)lse and phosphorylated enamines (56).le0The polarity and basicity of the phosphoryl group in dioxaphosphorinanes have been reviewed.17O Association constants and heats of hydrogen bonding between phenol and the series (57) have been determined.171A combined i.r. and n.m.r. study of the interaction of various amides (58) with p-fluorophenol or perchloric acid showed that the centre of

lse

S. A. Katsyuba, I. S. Pominov, and B. Halepp, Zh. Prikl. Spektrosk., 1982,36,783.

160

J. R. Durig and K. K. Chatterjee, J. Mol. Struct., 1982,81,167.

161

M. A. Harthcock and J. Laane, J. Mol. Spectrosc., 1982,94,461.

lea

E. A. Romanenko, S. V. Iksanava, U. P. Egorov, P. P. Kornuta, and T. N. Kasheva,

Teor. Eksp. Khim., 1982,18,710. A. A. Kisilenko, A. P. Boiko, V. P. Kukhar, and S. I. Vdovenko, J. Gen. Chem., 1982,52, 1153. A. K. Shurubura, E. A. Ryl'tsev, and I. E. Boldeskul, Teor. Eksp. Khim., 1982, 18,635. 165 K. V. Ryl'tsev and A. K. Shurubura, Spektroskopiya MoIekul Z Krystallov. Materialy 4-IResp. Shkoly-Seminara,Chernovtsy, 1979 (Chem. Abstr., 1981,95,203 150). lB6L. M. Epshtein, L. D. Ashkinadze, and Z. S. Novikova, J. Gen. Chem., 1981, 51, 1887. 167 N.I. Dorokhova, A. A. Shvets, L. V. Goncharova, and D. A. Osipov, J. Gen. Chem., 1982, 52,2332. 168 B. A. Arbuzov, N. A. Polezhaeva, and 0. V. Ovodova, J. Gen. Chem., 1982,52,446. A. Yu. Alikin, M. P. Sokolov, B. G. Liober, E. G. Yarmova, A. 1. Razumov, and M. V . Alparova, J. Gen. Chem., 1982,52,728. 170 R. P. Arshinova,J. Gen. Chem., 1982,52,27. I. Neda, I. Motoc, and R. Valceanu, Rev. Chim. (Bucharest), 1982,33,920. lea

Physical Methods

30 1

highest basicity is always the phosphory10xygen.l~~ Another study showed that the hydrogen bonding capacity of trimethyl phosphate is greater than that of triphenyl p h 0 ~ p h a t e . lThere ~ ~ have been two i.r. studies of hydrogen bonding in iminophosphoranes, one of which compared the imino group with the amino group174while the other examined LFER substituent 0

II

Y ZP-NR2 (58)

0

II

F2P- OPY Z (59

1

Trends in vNH were used to study solvent properties involving various phosphoryl and thiophosphoryl a m i d e ~ . The l ~ ~ marked dependence of vpo of difluorophosphino esters (59) upon the phase was interpreted in terms of selfassociation differences.’ 7 7 Stereochemistry.-The conformational analysis of various deuteriated ethylphosphine-borane a d d u c t ~ and l ~ ~ dimethyl methylphosph~nates~~~ were based on vibrational spectral data. The stereochemistry of diethylphosphonyl acetamide,lsothe unusual vinyl compounds(60; X = L.E.P., 0,S),lel and a number of 1,3,2-dio~aphosphorinanes~~~-~~~ have been studied. It was found that the Raman-active ring vibration is related to the orientation of the phosphoryl g r ~ u p . lConformational ~~ data for dioxaphosphepane was compared with calculated parameters.le4 A low-temperature study of several cyclopropylphosphonates (61) revealed rotational isomerization about the P-0 bonds but not about the P-C bond.lEsThe variable temperature i.r. and Raman spectra of the silyl phosphates (62) also revealed rotational isomerism.186

174

E. I. Matrosov, A. A. Kryuchov, E. E. Nifant’ev, A. G. Kozachenko, and M. I. Kabachnik, Phosphorus Sulfur, 1982,13,69. P. Ruotesno, U. Salminen, and J. Karjalainen, Finn. Chem. Lett., 1982, 69. R. Mathis, N. Zenati, N. Ayed, and M. Sanchez, Spectrochim. Acta, Part A , 1982, 38,

176 176 177

I. F. Tsymbal and E. V. Ryl’tsev, Ukr.Khim. Zh. (Russ. Ed.), 1983,49,289. W. F. Ibanez and A. J. Pena, Spectrochim. Acta, Part A , 1982,38,351. E. A. V. Ebsworth, G. M. Hunter, and D. W. H. Rankin, J. Chem. Soc., Dalton Trans.,

178

J. D. Odom, P. A. Brletic, S. A. Johnston, and J. R. Durig, J. Mol. Struct., 1983, 96, 247. B. J. van der Veken and M. A. Herman, J. Mol. Strucf., 1983,96,233. V. I. Molostov, R. L. Yafarova, R. I. Tarasova, and A. I. Razumov, J. Gen. Chern., 1981,

178

17s

1181.

1983,245. 170

180

51,2293. lB1

la4 ls5

A. V. Chernova, R. R. Shagidullin, G. M. Doroshkina, I. V. Tsivunina, V. G. Zaripova, S.Kh. Nurtidinov, and V. K. Kharullin, J. Gen. Chem., 1982,52,1372. R . R. Shagidullin,I. Kh. Shakirov, R. Kh. Musyakaeva, I. I. Vandyukova, S. A. Katsbuya, I. A. Nuretdinov, and E. 1. Matrosov, Bull. Acad. Sci. USSR, Ser, Khim., 1981, 2071; R. Valceanu and I. Neda, Rev. Chim. (Bucharest), 1980,31,964. E. E. Nifant’ev and A. A. Kryuchkov, J. Gen. Chem., 1981,51,2092. R. R. Shagidullin, I. Kh. Shakirov, R. Kh. Musyakaeva, and E. I. Matrosov, Bull. Acud. Sci. USSR, Ser. Khim., 1981,1849. R. D. Gareev, A. V. Chernova, E. A. Ishmaeva, E. A. Bordnikov, R. R. Shagidullin, E. N. Strelkova, G. M. Dorozhkina, I. I. Patsanovskii, and A. N. Pudovik, J. Gen. Chem., 1982,52,2161.

I. A. Lapin, Yu. V. Kolodyazhnyi, N. N. Tsapkova, E. F. Bugerenko, and 0.A. Osipov, J. Gen. Chem., 1981,51,1874.

302


The signs of vpa and vp-o bands in the mid-infrared vibrational circular dichroism of cyclophosphamide and its cogeners correlated with molecular configuration.l The structure of n6 c h l o r ~ p h o ~ p h o r a n ehave ~ ~ ~been ~J~~ studied and a linear relationship was found between vpcl (asym) and the sum of the electronegativities of the apical substituents. The Raman spectra of the bis-trichloromethylphosphorane (63) supported the presence of diapical trichloromethyl groups. Also the P-Cl force constant was lower than that for the monotrichloromethylphosphorane in accordancewith a lower electronegativityfor the apical groups.188 Rotational Spectra.-Phenyl, vinyl, ethynyl, and cyano phosphaethynes have been detected by microwave spectroscopy and their dipole moments and rotational constants calculated.19o

H2Ph

cc13 P

Ph-P\

NY Z

4 Electronic Spectroscopy

Absorption Spectroscopy.-The phospha-azulene (64) has an absorption maximum of 700 nm, which is 23 nm to longer wavelength than 2-benzylaz~lene.~~~ A theoretical study relating to the U.V. spectra of phenylphosphanes(65) indicates that for most phosphanes the preferred conformation has the plane of the phenyl ring bisecting the PY2 plane. However, phenylphosphine (65; Y = Z = H) and phenyldifluorophosphane (65; Y = Z = F) appear to have free rotation about C. N. Su, T. A. Keiderling, K. Misiura, and W. J. Stec. J . Am. Chem. SOC., 1982, 104, 7343.

S. Kozlov and I. E. Boldeskul, J. Gen. Chem., 1982, 52, 936; E. S. Kozlov, I. E. Boldeskul, V. I. Karmanov, A. T. Kozulin, I. A. Kyuntsel’, V. A. Mokeeva, and G. B. Soifer, J. Gen. Chem., 1982,52,2219. L. M. Sergienko, G. V. Ratovskii, V. I. Dmitriev, and B. V. Timokhin, Zh. Obshch. Khim.,

la8E.

ls9

1981, 51,495. lg0

J. C. T. R. Burckett-St. Laurent, T. A. Cooper, H. W. Kroto, J. F. Nixon, 0. Ohashi, and K. Ohno, J. Mol. Struct., 1982,79,215. G. Merkl and E. Seidl. Angew. Chem., Znt. Ed. Engl., 1983,22.57.

Physical Methods

303

the PC bond while the phosphine (65; Y = H, Z = Me) and phosphane (65; Y = Me, Z = F) have their phenyl rings eclipsing the phosphorus lone pair of electrons and the hydrogen or fluorine a a n . l D 2A comparative study of the dioxaphosphorinanes (66; Y = L.E.P.70, S) indicated that the strong band at 251 nm (E 6045) in the n3 compound was due to enforced coplanarity of the x-orbitals and the phosphorus lone pair of electrons. This band was absent in the spectra of the oxide. An intense band at 240 nm ( E 6000) in the spectra of the sulphide was attributed to the P=S group absorption.lD3The orientation of the phenyl ring relative to the phosphoryl group was the subject of a paper on 1,3,5-dioxaphosphorinanes(67). The Kerr effect was also used in the sfudy.lD4 There has also been a U.V. spectral study of the phenoxy derivative with regard to the effect of the phosphorus group on the donor properties of the interposed oxygen to the aryl ring.6D

Ch

The spectra of highly coloured phosphoniovinamidinium salts (68; Y or Z = Ph3P+)have been recorded.ls5 The energy levels and conformations of an extensive series of phosphonium ylides have been deduced from their U.V. spectra.lss In addition there have been studies of phosphonium p o l y i o d i d e ~ phosphinyl ,~~~ and solvent effects on the spectra of thioamides (69).lo0 Photoelectron Spectroscopy.-The spectra of the reactive methylidynephosphines (70; R = Ph, TMS) have been compared with the stable tertiary butyl compound.2ooThe vertical ionization potentials of trimethyl-, methylphenyl-, and triphenyl-phosphines have been measured. The basicity order in the gas phase is the reverse of that in solution and of the basicity order of amines in the gas phase.Bo1

A. Raevskii, I. 0. Umerova, and E. N. Tsvetkov, Teor. Eksp. Khim., 1982. 18, 700. A. Arbuzov, R. P. Arshinova, and V. S. Vinogradova, J. Gen. Chem., 1982,52,2148. lS4 R. A. Kadyrov, R. P. Arshinova, and B. A. Arbuzov, Bull. Acad. Sci. USSR, Ser. Khim.,

lD80.

lDS B.

1982,525. lD5R. lD6R.

Gompper, E. Kujath, and H. U. Wagner, Angew. Chem., Znt. Ed. Engl., 1982,21, 543. A. Loktionova, I. E. Boldeskul, and V. P. Lysenko, Teor. Eksp. Khim., 1983, 19, 30. Yu. P. Makovetskii, V. E. Didkovskii, I. E. Boldeskul, N. G. Feshchenko, and N. N. Kalibalchuk, Zh. Obshch. Khim., 1982,52,1989. lD8K. Berndt and D. Gloyna, Acta Chim. Acad. Sci. Hung., 1982,110,145. lDD Z . Tashma, J. Org. Chem., 1982,47,3012. *O0 B. Solouki, H. Bock, R. Appel, A. Westerhaus, G. Becker, and G. Uhl, Chem. Ber., 1982, 115,3747. S. Ikuta, P. Kebarle, G. M. Bancroft, T. Chan, and R. J. Puddephatt, J. Am. Chem. Soc., 1982,104,5899.


304

Emission Spectroscopy.-The electron impact emission spectra of HC=P+ and D E P + have been observed.202

5 Diffraction

X-Ray Diffraction.-The crystal structure of the diphosphabutadiene (71) and the diphosphacyclobutene (72)have been determined. The P = C bond lengths involving the n2 phosphorus atoms were 168.4 and 167.9 pm, respectively.203 It was slightly larger (169 pm) in a related tetraphospha-l,5-he~adiene~~~ and it was 170 pm in the phosphene (73).206A novel diphosphinylphosphide (74) possessed a very short PP bond (212.2pm).20s A wide range of n3 compounds has been studied. The phosphorine (75) has been shown to have an axial phenyl group,2o7and whilst the acylphosphine (76) shows no evidence of ‘amide type’ conjugation there appears to be enhanced P-phenyl conjugation.208Crystal structures have been determined of a triarylof 3,4-dimethylpho~phole,~~~ a d i p h o ~ p h e t a n evarious ,~~~ p h o ~ p h i n ethe , ~ ~dimer ~ diaza,211triaza,212and tetraaza213polycyclic compounds, the diphosphane (77),214 and the diphosphacyclooctane (78).21s There have been studies of a thiadiphosphiran,216 a six-membered tripho~phatrithiane,~~~ a diphosphadisilylcyclo202

205 206

M. A. King, H. W. Kroto, J. F. Nixon, D. Klapstein, J. P. Maier, and 0. Martholar, Chem. Phys. Lett., 1981,82,543; M. A. King, D. Klapstein, H. W. Kroto, J. P. Maier, and J. F. Nixon,J. Mol. Struct., 1982,80,23. R. Appel, V. Barth, and F. Knoch, Chem. Ber., 1983,116,938. R. Appel, V. Barth, and N. Halstenberg, Chem. Ber., 1982,115,1617. G. Becker, W. Becker, and 0. Mundt, Phosphorus Sulfur, 1983,14,267. D. Weber, K. Peters, H. G. Schnering, and E. Fluck, 2. Naturforsch., Teil B, 1983, 38, 208.

207

208 *09 210

211 21x

Mazhar-al-Haque and W. Horne, Acta Crystallogr., Sect. C, 1983,39,139. E. Lindner, M. Steinwand, and S . Hoene, Angew. Chem., 1982,94,395. T. Butters, I. Haller-Pauls, and W. Winter, Chem. Ber., 1982,115,578. G. De Lauzon, C. Charrier, H. Bonnard, F. Mathey, J. Fischer, and A. Mitschler, J. Chem. Soc., Chem. Commun., 1982,1272. R. Appel, S. Korte, M. Halstenberg, and F. Knoch, Chem. Ber., 1982,115, 3610. 0. J. Scherer, G. Wolmershaeuser, and H. Conrad, Angew. Chem., Znt. Ed. Engf., 1983,22, 404.

214 215

216 217

J. Jaud, M. Benhammou, J. P. Majoral, and J. Navech, Z. Kristallogr., 1982, 160, 69. A. Tarassoli, R. D. Haltiwanger, and A. D. Norman, Inorg. Chem., 1982,21,2684. B. A. Arbuzov, 0. A. Erastov, G. N. Pikonov, I. A. Litvinov, D. S. Yufit, and Yu. T. Stauchkov, Bull. Acad. Sci. USSR,Ser. Khim., 1981,1872. M. Yoshifuji, K. Ando, K. Shibayama, N. Inamoto, K. Hirotsu, and T. Higuchi, Angew. Chem., 1983,95,416. B. Cetinkaya, P. B. Hitchcock, M. F. Lappert, A. J. Thorne, and H. Goldwhite, J. Chem. Soc., Chem. Commun., 1982,12,691.

Physical Methods

305

TMSO TMSO

Bu

P=C

Ph ‘P-c

‘S ( TMS )

I

ButCO (72)

‘But

(71)

(73)

hCN

0

0

*;x

t

Ph2PCOCHC12

Ph

(76)

(74)

Ph P _+,#‘PPh3 3 qc/

1

RN

SePh

butane,21s a silylated tetrapho~phine,~~~ a biarsatriphosphacyclobutane,220and a t etraphosphabicyclobutane.221 As usual reports on n4 compounds predominate, Some novel ylides which have been studied include a chelated potassium complex,222the carbodiphosphorane (79),223and the extraordinary hydroxy ylide Two acyl-stabilized ylides have also been investigated226as well as a variety of tetraphenylphosphonium W. Clegg, M. Haase, U. Klingebiel, and G. M. Sheldrick, Chem. Ber., 1983, 116, 146. K.F. Tebbe and R. Froehlich, 2. Naturforsch., Teil B, 1982,37, 534. M. Baudler, Y. Aktalay, T. Heinlein, and K. F. Tebbe, 2.Naturforsch., Teil B, 1982, 37, 299. 82*

z2s 824

E. Niecke, R. Ruger, and B. Krebs, Angew. Chem., Int. Ed. Engl., 1982,21,544. H. Schmidbaur, U. Deschler, and B. Milewski-Mahrla, Chem. Ber., 1982, 115, 3290. H. Schmidaur, C. E. Zybill, Angew. Chem., Int. Ed. Engl., 1982,21,310. T. A. Mastryukova, I. M. Aladzheva, 0.V. Bykhovskaya, P. V. Petrovskii, M. Yu. Antipin, Yu. T. Struchkov, and M. I. Kabachnik, Dokl. Akad. Nauk USSR,1982, 264, 1396.

za6

C.He, Q. Zhang, F. Shen, S.Don, and G. Lin, Wali Xuebao, 1982,31, 825 (Chem. Abstr., 1982, 97, 206012); M. Shao, X. Jin, Y. Tang, Q. Huang, and Y. Huang, Tetrahedron Lett., 1982,23,5343.

306


salts226and triphenylphosphonium a triphenylphosphonium dithioate betaine,228a bis-phosphonium and a pho~pha-adamantane.~~~ The structures of six-membered,2O O 231 five-membered,232and f o ~ r - m e m b e r e d ~ ~ ~ cyclic phosphine oxides have been established together with a bicyclic oxide,234a dithianyl and a phosphinylethyltin derivative.lol By comparing the conformational data from a thousand triphenylphosphorus compounds the transition-state structure of the phenyl ring rotation has been calculated.236The thiophosphinyl carbanion (81),2 several trip henylphosphonia nitrogen comp o u n d ~and , ~ a~ ferrocenyl ~ have been studied. There were relatively few studies of n4 compounds possessing two PC bonds. They included a phosphindoline-3-0ne,~~~ a phosphinic two nitrogensulphur two imidophosphinic acid and a cyclotriphosphazene.244 Compounds which have been studied in the phosphonic group included an a-aminophosphonic and ester,246a thiamin betaine,24 a cyclopropanep h o ~ p h o n a t ea, ~cyclic ~ ~ ester (82),248and two p h o s p h a z e n e ~ . ~ ~ ~ 1

228

U. Mueller, N. Mronga, C. Schumacher, and K. Dehnicke, Z. Naturforsch., Ted B, 1982, 37, 1122; U. Mueller, A. F. Shihada, K. Dehnicke. ibid., 1982, 37, 699; B. Krebs, A. Schaeffer, and M. Hucke, ibid., 1982, 37, 1410; M. P. Bogaard and A. D. Rae, Cryst. Struct. Commun., 1982, 11, 175. G. Moggi, J. C. J. Bart, F. Cariati, and R. Psaro, Znorg. Chim. Acta, 1982, 60, 135; F. W. B. Einstein and T. Jones, Can. J. Chem., 1982,60,2065; D. W. Allen, I. W. Nowell, and L. A. March, Tetrahedron Lett., 1982, 23, 5479; I. V. Borisova, N. N. Zemlyansky, V. K. Belsky, N. D. Kolosova, A. N. Sibolev, Y. N. Luzikov, Y. A. Ustynyuk, and I. P. Beletskaya, J. Chem. SOC.,Chem. Commun., 1982,1090. U.Kunze, R. Merkel, and W. Winter, Chem. Ber., 1982,115,3653.

229

N. Gurusamy, K. D. Berlin, D. Van der Helm, and M. B. Hossain, J. Am. Chem. SOC.,

3p8

227

1982,104,3107. 230

231

232

233 284 a36

H. J. Meeuwissen, G. Sirks, F. Bickelhaupt, C. H. Stam, and A. L. Spek, Red: J.R. Neth. Chem. Soc., 1982,101,443. S. Inokawa, K. Yamamoto, N. Kawamoto, H. Yamamoto, M. Yamashita, and P. Luger, Curbohydr. Res., 1982,106, 31; H. Yamamoto, K. Yamamoto, S. Inokawa, and P. Luger, ibid., 1983,113, 31 ; B. A. Arbuzov, 0. A. Erastov, I. V. Litvinov, D. S. Yufit, and Yu. T. Struchkov, Bull. Acud. Sci. USSR,1982,529. R. Bodalski, T. Janecki, Z. Galdecki, and M. Glowka, Phosphorus Sulfur, 1982, 14, 15; P. Luger, H. Yamamoto, and S. Inokawa, Curbohydr. Res., 1982, 110, 187. Mazhar-al-Haque and W. Horne, Acta Crystallogr., Sect.B, 1982, 38, 2944. Mazhar-al-Haque, J. Ahmed, and W. Horne, Acta Crystallogr., Sect. C , 1983, 39, 383. E. Juaristi, L. Valle, and C. Mora-Uzeta, J. Org. Chem., 1982,47, 5038. E. Bye, W. B. Schweizer, and J. D. Dunitz, J. Am. Chem. SOC.,1982,104,5893. S . 0. Grim, R. D. Gilardi, and S. A. Sangokoca, Angew. Chem., Znt. Ed. Engl., 1983,22, 254.

288

23g 240

241 a42

243 244 245

R. Reck, L. Zsolnai, G. Huttner, S. Herzberger, and J. C. Jochims, Chem. Ber., 1982,115, 2981; J. Szmuszkovicz, M. P. Kane, L. G . Laurian. C. G. Chidester, and T. A. Scahill, J. Org. Chem., 1981, 46, 3562; K. Maartmann and I. Songstad, Acta Chem. Scand., Sect. A , 1982,36,829. G. V. Gridunova, V. E. Shklover, and Yu. T. Struchkov, J, Orgunomet. Chem., 1982,238, 297. B. R. Stults, F. L. May, and T. M. Balthazor, Cryst. Struct. Commun., 1982, 11, 1179. E. F. Paulus and S. Grabley, 2. Kristallogr., 1982,160,63,39. N. Burford, T. Chivers, and J. F. Richardson, Znorg. Chem., 1983, 22, 1482; T. Chivers, M. N. Raa, and J. F. Richardson, J. Chem. SOC.,Chem. Commun., 1982,982. H. Noeth, 2. Nuturforsch., Teil B, 1982,37,1491. H. R. Allcock, A. G. Scopelianos, R. R. Whittle, and N. M. Tollefson,J. Am. Chem. SOC., 1983,105,1316. L. M. Shkol'nikova, M. A. Porai-Koshits, N. M. Dyatlova, G. F. Yaroshenko, M. V. Rudomino, and E. U. Kolova, Zh. Strukt. Khim., 1982,23,98.

307

Physical Methods 0

II

( MeO) 2PNHR

( PhO)2PNHC1

Me

0

MeN 1

NMe

c1

(85)

Most of the phosphoric series possess at least one PN bond, viz., the esters (83; R = Ar, COPh),250the chloroamide (84),251 some phosphamides,26e a dia~adiphosphetidine,~~~ several cyclopho~phazenes,~~~ and three thioamides,266 e.g., (85). Other studies were directed towards adenosine monophosphate,266 salts of pho~phoenolpyruvate,~~~ O-ethyl-O-phenyl phosphorothioic and a phosphobiotin Amongst the n5 compounds studied is the first five-co-ordinate phosphole,260 246 247 248 249

250

262 268 254

M. M. Sidky, M. F. Zayed, K. Praefcke, W. Wong-Ng, and S. C. Nyburg, Phosphorus Sulfur, 1982,13,319. A. Turano, W. Furey, J. Pletcher, M. Sax, D. Pike, and R. Kluger, J. Am. Chem. SOC., 1982,104,3089. R. S. Macomber, G. A. Krudy, K. Seff, and L. E. Rendon-Diazmiron, J. Org. Chem.. 1983,48,1425. R. D. Sharma, S. J. Rettig, N. L. Paddock, and J. Trotter, Can. J. Chem., 1982, 60, 535;

I. E. Baldeskul, A. S. Tarasevich, M. Yu. Antipin, Yu. T. Struchkov, and Yu. V. Balitskii, J. Gen. Chem., 1982,52,1368. V. Mizrahi and T. A. Modro, Cryst. Struct. Commun., 1982, 11, 627; M. P. Du Plessis, T. A. Modro, and L. R. Nassimbeni, J. Org. Chem., 1982, 47, 2313; Actu Crystullogr., Sect. B, 1982,38,1504. K. Drewelies and H. Pritzkav, 2.Nuturforsch., Teil B, 1982,37, 1402. A. Camerman, H. W. Smith, and N. Camerman, J. Med. Chem., 1983, 26, 679; N. Camerman, J. K. Fawcett, and A. Camerman, ibid., 1983,26,683. E. Fluck, H. Richter, H. Riffel, and H. Hess, Phosphorus Sulfur, 1982,14,87. G. Guerch, J. F. Labarre, and R. Roques, J. Mol. Struct., 1982, 96, 113; G. Guerch, M. Graffeuil, J. F. Labarre, R. Enjalbert, R. Lahana, and F. Sournies, ibid., 1982, 95, 237; R. Visalakshi, T. N. Ranganathan, G. S. Rao, and K. V. Muralidharan, Curr. Sci., 1982, 51, 508.

256

256 268

260

M. G. Newton, N. Pantaleo, W. G. Bentrude, and S. Chandrasekaran, Tetrahedron Lett., 1982,23, 1527; M. Mikolajczyk, J. Omelanczuk, W. S. Abdukakharov, A. Miller, M. W. Wieczarek, and J. Karolak Wojciechowska, Tetrahedron, 1982, 38, 2183; I. A. Litvinov, D. S. Yufit, Yu. T. Struchkov, B. A. Arbuzov, L. I. Gurarii, and E. T. Mukmenev. Dokl. Akad. Nuuk SSSR, 1982,265,884. K. I. Varughese, C. T. Lu, and G. Kartha, J. Am. Chem. Soc., 1982,104,3398. M . A. Viswamitra, M. V. HOSUT, and S . K. Katti, Conform. Biol., 1983,439. S. Dou, Q. Zheng, J. Dai, C. Tang, and G. Wu., Wuli Xuebuo, 1982, 31, 554 (Chem. Abstr., 1982,97, 136 889). C. Blonski, M. B. Gasc, A. Klaebe, J. J. Perie, R. Roques, J. P. Declercq, and G. Germain. J. Chem. SOC.,Perkin Trans. 2,1982,7. I. Bkouche-Waksman, P. L'Haridon, Y. Leroux, and R. Burgada, Actu Crystullogr., Sect. B, 1982,38,3024.

308


the hydroxyphosphorane (86),2s1the related carbon disulphide salt,z6zand a bis(difluorophosphorany1)a~etylene.~~~ The structures of two polycyclic PN compounds are reportedzs4- one exhibiting distinct ‘anti-Berry’ distortion.266 The structure of an indolylidene cyclophosphorane was consistent with the Wittig reaction mechanism postulated by Bestmann.266 Electron Diffraction.-The gas-phase study of the chlorophosphane (87) showed the presence of an elongated P-Cl bond.zs7

6 Dipole Moments, Kerr Effects, and Polarography Dipole moment and Kerr effect measurements are frequently used for conformaand tional analyses, e.g., the recent studies of the phosphepanes (88)1301z68 1,3,2,5-dioxasilaphosphorinanes (89).269On the other hand the anisotropy of polarization and conformational analysis of triphenylphosphine, trimesitylphosphine, and their chalcogenidesalso incorporated Raleigh scattering measurem e n t (cf. ~ ~ref. ~ 236), ~ whilst conformation studies of 1,3,5-dioxaphosphorinanes combined dipole moments with n.m.r.lZ9or U.V. datalg4or reactive field calculat i o n ~71. ~ Other phosphoryl compounds which have been studied through their dipole moments are the and substituted b e n ~ y l diphenylphosphine -~~~ oxides,

-

O\

262 263 264

26s

Me S‘ ’0

Me

’i ‘0

A. Dubourg, R. Roques, B. Garrigues, D. Boyer, A. Munoz, and A. Klaebe, CR Seances Acad. Sci., Ser. 2, 1981, 293, 757; A. Dubourg, R. Roques, and G. Germain, J. Chem. Res. (S), 1982,180. A. Dubourg, R. Roques, G. Germain, J. P. Declercq, A. Munoz, A. Klaebe. B. Garrigues. and R. Wolf, Phosphorus Sulfw, 1982,14,121. E. Fluck, J. Svara, and J. J. Stezowski, Chem.-Zfg., 1982,106,439. R. 0. Day, A. Schmidpeter, and R. R. Holmes, Inorg. Chem., 1982,21, 3916. A. Schmidpeter. K. Gross. E. Schrenk, and W. S. Sheldrick. Phosphorus Sulfur, 1982, 14. 49.

266 a87 268

3R0

2io

272

273

R. Boehme and E. Wilhelm, Cryst. Struct. Commun., 1982,11,7. L. S. Khaikin, 0. E. Grikina, and L. V. Vilkov, J. Mol. Sfruct., 1982, 82, 115. B. A. Arbuzov, R. A. Kadyrov, V. V. Klochkov, R. P. Arshinova, and A. V. Aganov. Bull. Acad. Sci. USSR, Ser. Khim., 1982,520. E. N. Strelkova, I. I. Patsanovskii, E. A. Ishmaeva, N. M. Kudyakov, M. R. Voronkov, and A. N. Pudovik, J. Gen. Chem., 1982,52,1493; E. A. Ishmaeva, I. I. Zyablikova, E. N. Strelkova, and I. P. Rornanova, ibid., p. 2002. A. P. Timosheva, G . V. Romanov, S. G. Wul’fson, A. N. Vereshchagin,T. Ya. Stepanova, and A. N. Pudovik, Bull. Acad. Sci. USSR, 1982,533. R. R. Shagidullin and S. A. Katsyuba, J. Gen. Chem., 1982,52,1973. I. I. Mai, V. K. Byistro, M. G. Finaeva, and K. A. Ayapbergeno, Deposited Document, 1982, VINITI 71 1 (Chem. Abstr., 1983, 98, 160 837). E. A. Ishmaeva, E. N. Tsvetkov, E. N. Strelkova, and I. I. Patsanovskii, Bull. Acad. Sci. USSR, 1982,1052.

Physical Methods

309

and also the phosphorylated a l l e n e ~ and ~ ~cyclopropylphosphonates.lss ~ Dipole moments and Kerr effects were used to support i.r. studies for silyl thiophosphates.lS6 In the conformational analysis of triphenylphosphinimines the problem of evaluating the polarizability tensor for the C,P=N segment was overcome by assuming that it has Ca0symmetry.276Theoretical studies related to the dipole moments of trimetaphosphimic and several fluorophosp h ~ r a n e s are ~ ' ~also reported. Polarography has been used to analyse the role of amine catalysts in phosphonate hydr01yses.~~~ Voltammetry data is reported for triphenylphosphine sulphide triethyl p h o s p h o r o t h i ~ a t eand ~ ~ ~various triphenylphosphonium salts and ylides.280

7 Mass Spectrometry This topic was the subject of the occasional review in last year's volume.12a Pulsed electron beam high energy source pressure mass spectrometry has been used in combination with photoelectron spectra to determine the gas-phase basicities of methyl and phenyl tertiary phosphines201and also primary phosphines.281Fragmentation patterns in the mass spectra of various phosphanes,282 cyanoph~sphines,~~~ and the naphthyldiphosphine (90)284 have been described.

An improved method of obtaining the appearance potential of phosphorus trichloride from electron impact spectra is reported.28sThe mass spectra of various diazadiphosphetidines(at 20 and 70 eV) have been analysed286as have the

27*

I. I. Patsanovskii, E. N. Strelkova, E. A. Ishmaeva, A. B. Remizov, N. G. Khusainova, L. V. Naumova, and A. N. Pudovik, J. Gen. Chem., 1982,52,909. S.B. Bulgarevich, N. A. Ivanova, D. Ya. Movshovich, T. A. Yusman, V. A. Kogan, and D. A. Osipov,Zh. Obshch. Khim., 1982,52,577. I. A. Rozanov, L. N. Alekseiko, I. A. Gloriozov, T. V. Rezvova, Yu. A Ustynyuk, and V. M. Mamaev, Koord. Khim., 1982,8,880. A. V. Fokin and M. A. Landau, Bull. Acad. Sci. USSR, 1982,1553. R. F. Bakeeva, L. A. Kudryavtseva, S. B. Fedorov, V. E. Bel'skii, and B. E. Ivanov. J. Gen. Chem., 1982,52,2210. R. L. Blankespoor, M. P. Doyle, D. J. Smith, D. A. Van Dyke, and M. J. Waldyke, J.

2Ao a81 282

Org. Chem., 1983,48,1176. R. R. Mehta, V. L. Pardini, and J. H. P. Utley, J. Chem. Soc., Perkin Trans. I , 1982,2921. S. Ikuta and P. Kebarle, Can. J. Chem., 1983,61,97. A. I. Mikaya, E. A. Trusova, 0.L. Butkova, and V. G. Zaikin, J. Gen. Chem., 1982, 52,

274 475

276

277 278

1776. a83 a84

a85 286

R. G. Kostyanovsky, A. P. Pleshkova, V. N. Voznesensky, and Yu. 1. Tel'natanov, Org. Mass Spectrom., 1980,15,397. T. Costa and H. Schmidbaur, Chem. Ber., 1982,115,1374. T. Ozgen, Int. J. Mass Spectrom. Ion Phys., 1983,48,427. E. Fluck and H. Richter, Chem. Ber., 1983,116,610.


310

spectra of the bicyclic phosphite (91),287its and some alkylcyclotriborylphosphines.288Positive and negative chemical ionization mass spectra of fluorinated phosphonium y l i d e ~resemble ~ ~ ~ the spectra of other ylides. The thermal desorption spectra of arylphosphonium salts gave mostly even electron ions which decomposed by four centred reactions.290The stereoisomer compositions of the phosphorins (92; Ch = 0, S , Se) were investigated by mass spectrom e t ~ y Structures . ~ ~ ~ are suggested for the various fragment ions observed in the mass spectra of diphenylstyrylphosphine The mass spectra of the amides (93) indicate initial rearrangement to the phosphinate (94).293This did not occur to the related p h o ~ p h i n i m i n e s . ~ ~ ~

0

II R2PNR ' COR"

Me C

f 'Ph

(93)

0

II

R 2POCR"NR ' (94)

The mass spectra of a number of heterocyclic compounds have been reported. The fragmentation patterns of thiophosphoryl derivatives of phosphorinanes are ~ ~ ~ for the series (95) facile loss of the HS sensitive to s t e r e ~ c h e m i s t r y ,thus radical is indicative of an axial PS bond.29s The seven-membered heterocycles (96; Ch = S, Se) undergo a remarkable migration of sulphur or selenium from phosphorus to carbon with ring cleavage.297While exocyclic P-C bonds of fiveand six-membered heterocycles in the phosphonic class may be readily cleaved with retention of the phosphorus ring the seven-membered ring (97) exhibits facile expulsion of a phosphorus Field desorption mass spectrometry has been applied to the identification of phosphamide metabolites,300whilst negative ion mass spectra was found to be the most suitable method of identifying zinc dithioate oil additives.301Abundant H. I. Kenttamaa, Int. J . Mass Spectrom. Ion Phys., 1983,47,459. L. Cantu and R. C. Olivares, Rev. Latinoam. Quirn., 1982,13, 1. G . Fu, Y. Xu, R. Peng, Y. Shen, Y. Xin, and Y . Huang, Huaxue Xuebad, 1982, 40, 840 (Chem. Abstr., 1982,98, 52 964). 290 A. L. Yergey and R. J. Cotter, Biomed. Mass Spectrom., 1982,9,286. 291 A. E. Lyuts, V. V. Zamkova, A. P. Logunov, B. M . Butin, and Yu. G. Bosyakov, Izv. Akud. Nauk Kaz. SSR, Ser. Khim., 1982,72. 292 L. Alder and D. Gloyna, J. Prukt. Chem., 1981, 323, 578; K. G. Berndt, D. Gloyna. and H. G . Henning, ibid., p. 445. 2B3 V. Mizrahi and T. A. Modro, J. Org. Chem., 1982,47,3533. 294 V. Mizrahi, T. Hendrickse, and T. A. Modro, Can. J . Chem.. 1983,61,118. 295 R. S. Edmundson, Org. Muss Spectrom., 1982,17,558. 296 H. Halimi, D. Bouchu, and J. Dreux, Phosphorus Sulfur, 1983,14,323. 297 H. Keck, W. Kuchen, and H. F. Mahler, Org. Mass Spectrom., 1980,15,591. 298 B. Y . Kim and D. Y. Oh. Phosphorus Sulfur, 1982, 13, 337; B. M. Kwon and D. Y. Oh, ibid., 1981,11, 177. 2 9 9 V. Yu. Vitkovskii, M. G. Voronkov, and G. A. Kuznetsova,Zh. Obshch. Khim., 1981,51, 1769. 300 U. Bahr and H. R. Schulten, Biomed. Muss Spectrom., 1981, 8, 553. 301 Z. Przybylski and A. Borkowska, Nufta, 1981,37, 16 (Chem. Abstr., 1981,95, 172 191). 287

288

Physical Methods

311

I

Y (951

molecular ions which decompose by loss of HS radicals was the common fragmentation pathway for dithiophosphonic Acyclic phosphonates undergo facile P-C bond c1eavage3O3 and in some cases this results in low intensity molecular ions. However, abundant molecular ions may be obtained using ammonia chemical ionization.304Isomeric 0,sdialkyl methanediphosphonates may be distinguished by the ratio of single to double hydrogen migration, i.e., M-olefin for SR groups vs. M-CH2=CR for OR groups.3o6There have also been further studies of the application of mass spectrometryto the analysis of pesticides.306 Pulsed ion cyclotron double resonance spectroscopy was used to study the enthalpy of deuteriation abstractions from dimethyl phosphonate by various bases.307 8 Acidities and Basicities

The high gas phase proton affinity of phenylphosphines compared to methylphosphines has been attributed to x donation from the phenyl rings to the phosphorus x* orbitals in the protonated phosphine.201,281 It is suggested that the weak basic properties of phenylphosphines in solution is due to adverse solvent effects for the phenylphosphonium groups. An ab initio SCF theoretical study on the methyl phosphines do not need d orbitals in order to obtain good fits of pK, values with experimental data.308The basicities of tertiary phosphines in nitromethane correlated well with Kabachnik’s constants (8‘) and with ionization potentials. 309 A study of diary1 and alkyl aryl secondary phosphines showed that bulky groups decreased the acidity which was attributed to decreased s character of the lone pairs of electrons as the bond angles H. Keck and W . Kuchen, Phosphorus Sulfur, 1983,14,225. N. S. Ovchinnikova, L. T. Zhuravlev, K. Ya. Shengeliya, M P. Glazunov, and Yu. A. Losovoi, Zzv. Akad. Nauk SSSR, Ser. Khim., 1981,1814; P. A. Manninen and P. Savolahti, Znt. J. Mass Spectrom. Zon Phys., 1983, 47, 487; N. M.Vafina. Yu. Ya. Efremov, T. A. Zyablikova, A. V. Il’yasov, and I. M. Shermergorn, J. Gen. Chem., 1982,52,2236. 804 D. W. Hutchinson, P. A. Cload. and M. C. Haugh, Phosphorus Surfur, 1983,14,285. 305 2.Tashma, Anal. Chem., 1982,54,2130. *06 Y . Ozoe and M. Eto, Agric. Biol. Chem., 1982,46,411; H. J. Stan and G. Kellner, Recent Dev. Food Anal., Proc. Eur. Conf. Food Chem., lst, 1981 (Publ. 1982), p. 183. 307 W. J. Pietro and W. J. Hehre, J. Am. Chem. SOC., 1982,104 3594. 808 C. Glidewell and C. Thomson, J. Comput. Chem., 1982,3,495. *09 T. Allman and R. M. Goel, Can. J. Chem., 1982,60,716. slo M. I. Terekhova, N. A. Bondarenko, I. G. Malakhova, E. N. Tsvetkov, E. S. Petrov, and A. I. Shatenshtein,.!. Gen. Chem., 1982,52,452. 802

303

312


The acidities of phosphonous heterocycles (98) decreased with increased ring size, with small ring compounds such as (99) favouring a n3 31Pn.m.r. s p e c t r o s c ~ p ywas ~ ~used to follow the protonation of various phenylphosphoryl and thiophosphoryl compounds and also to investigate the tautomeric Similar equilibria equilibrium between phosphine oxides (100)and ylide (101).312 for the amides (102)have also been The pK, values of various phosphoryl compounds (103; Y = C02Me, Z = COAr),314(103;Y = H, Z = subst. f ~ r y l ) and , ~ ~(104)31s ~ have been determined. The basicities of phosphinimines have been discussed in terms of the compound’s hydrolytic stability317and Kabachnik’s substituent constants The basicities of the amines (105) were also correlated with substituent Structurereactivity relationships have been reviewed for the acids (106)319and the nonadditive effects of the phosphorus substituents emphasized. The problems which arise in similar studies of l73,2-diheterophospho1anes have also been ~eviewed.~~O

0

II

Ph2PCHX2

311 312

313 314

315

316 317 318

310

320

V. V. Ovchinnikov, D. A. Charkasova, and L. V. Verizhnikov, J. Gen. Chem., 1982, 52, 615. 0. I. Kolodyazhnyi, J. Gen. Chem., 1982,52, 1358; Tetrahedron Lett,, 1982,23,499. K. S. Dhathathreyan, S. S. Kirshnamurthy, A. R. V. Murthy, R. A. Shaw, and M. Woods, J. Chem. SOC.,Dalton Trans., 1982, 1549. V. G. Sakhibullina, N. A. Polezhaeva, and B. A. Arbuzov, J. Gen. Chem., 1982,52, 1112. L. M. Pevzner, V. M. Ignat’ev, and B. I. Ionin, J. Gen. Chem., 1982,52, 1703.

M. G. Zimin, G. A. Lazareva, N. I. Saval’eva, R. G. Islamov, N. G. Zabirov, V. F. Toropova, and A. N. Pudovik, J. Gen. Chem., 1982,52,1573. E. S. Kozlov and L. G. Dubenko, J. Gen. Chem., 1982,52,1992. A. M. Kurguzova, L. A. Kudryavtseva, A. B. Teitel’baum, V. E. Bel’skii, and B. E. Ivanov, Bull. Acad. Sci. USSR, 1982,1126. B. I. Istomin and V. A. Baranskii, Russ. Chem. Rev., 1982,51,223. R. A. Cherkasov, V. V. Ovchinnikov, M. A. Pudovik, and A. N. Pudovik, Russ. Chern. Rev., 1982,51,7461.

Physical Methods

313

The ionization constants of diphosphonic acid derivatives of amino ethane-l,2-di01,~~~ and fluoro- and difl~oro-rnethane~~~ have been determined, as well as those of the w i d e (107)324and the monoester (108).326

A r ( CH2)nP-OH

I

OR ( 108 1

Further results on the acidities of n6 hydroxyphosphoranes have been gublished. The pK, values of the dicarboxy compound (86) were in the range 0-4 depending on the that of (109; X = CF3)at 2,328whilst calculations on tetrahydroxyoxyphosphorane indicated that they should have pK, values of 10-20.327 The acidity of the hydroxyphosphorane(110) has been compared with other acidic phosphoranes.338 N

9 Chromatography

Gas-Liquid Chromatography.-Liquid-liquid partition data on O-alkyl-O-aryl phenylphosphonothioates was obtained by g . l . ~ There . ~ ~ ~have also been several reports on the determination of inositol phosphates. 330 T. A. Bandurina, V. N. Konyukhov, and T. K. Krynina, Deposited Document, 1982, SPSTL, 115 KHP-D82 (Chem. Abstr., 1982,98,126 261). 822 J. A. Mikroyannidis, A. K. Tsolis, and D. J. Gourghiotis, Phosphorus Sulfw,1982, 13, 279. 323 D. J. Burton, D. J. Pietrzyk, T. Ishihara, T. Fonong, and R. M. Flynn, J. Fluorine Chem., 1982,20,617; C . E. McKenna and P. Shen, J. Org. Chem., 1981,46,4573. 324 T. W. Engle, G. Zon, and W. Egan, J. Med. Chem., 1982,25,1347. C . Yuen, W. Ye, and C. Wang, Huaxue Xuebao, 1981, Zengkan, 230, (Chem. Abstr., 1982, 98, 179 504). 326 G. V. Roeschenthaler and W. Storzer, Angew. Chem., Int. Ed. Engl., 1982,21,208. 327 S . Zbaida and E. Breuer, J. Org. Chem., 1982,47,1073. 388 D. Boyer, L. Lamande, B. Gerrigues, and A. Munoz, Phosphorus Sulfur, 1983, 14, 335. K. Valko and A. Lopata, J. Chromatogr., 1982,252,77. 380 A. L. Leavitt and W. R. Sherman, Carbohydr. Res., 1982,103,203; G . C. J. Irving and D. J. Cosgrove, Comrnun. Soil Sci. Plant Anal., 1982, 13, 957; A. L. Leavitt and W. R. Sherman, Methods Enzymol., 1982,89 (Carbohydr. Metab., Pt. D ) , 9.


314

Thin-layer and Paper Chromatography.-The determination of trichlorometap h 0 s - 3 , ~p~h ~o ~ p h a t i d eand , ~ ~amido ~ phosphatesSS3have been accomplished by t.1.c. Methods for the separation of n ~ c l e o s i d e and s ~ ~p~h o ~ p h o n o l i p i d shave ~~~ also been established. Paper chromatography was used to determine p o l y p h ~ s p h a t eand ~~~ 32Pand SSPc o r n p o ~ n d s . ~ ~ ~ High Performance Liquid Chromatography.-This technique has been applied to a wide range of natural products, i.e., steroidal phosphates,338retinyl phos-

phate, dansylated protein hydrolysates,34 O thiamine phosphates,341 dibutyl c-AMP cytosine arabinoside t r i p h o ~ p h a t eand , ~ ~di~ and tri-nucleoside phosphates.344 Ion Exchange and Electrophoresis.-The ion exchange separation of diastereomeric phosphodipeptide~~~~ has been reported, as have some problems associated with the analysis of 2-aminoethylphosphonic The isolation of thiamine triphosphate utilized paper electrophoresis and ion exchange c h r o m a t ~ g r a p h y . ~ ~ ~ Two-dimensional separation of phosphinoamino acids has been achieved by electrophoresis.348 Surface Properties.-The surface tension and other physical properties of some tris(alkoxysily1)ethylphosphinates have been determined at 20-80 0C.349

331

L. D. Gorelik, Konservn. Ovoshchesush. Prom.-St., 1982, 8, 40 (Chem. Abstr., 1982, 97,

338

J. K. Daun and D. R. Declercq, Anal. Chem. Rapeseed Its Prod., Symp., 1980, p. 128 (Chem. Abstr., 1982,97,125 786). F. Kasparek, Acta Univ. Palacki.Olomuc Fa Rerum Nut., 1982,73 (Chem 21), 11 (Chem. Abstr., 1982,97,84 392). R. C. Payne and T. W. Traut, Anal. Biochem., 1982,121,49. M. C. Moschidis and C. A. Demopoulos, J. Chromatogr., 1983, 259, 504; K. S. Bjerve, ibid., 1982,232,39. K. Berg-Nielsen and P. E. Joner, Nor. Veterinaertidsskr., 1982, 94, 420 (Chem. Abstr.,

196 948).

333 334

336

836

1982,97,196 923). 337 838 380 840

341 342 343

844

w 5 346 347 848 340

Y. Sasaki, Y. Arima, and K. Kumazawa, Radioisotopes, 1982,31,279. R. E. Isaac, N. P. Milner, and H. H. Rees, J. Chromatogr., 1982,246,317. J. Frot-Coutaz and R. Letoublon, Anal. Left., 1981,14 (B2), 69. L. F. Congote, J. Chromatogr., 1982,253,276. M. Kimura, B. Panijpan, and Y. Itokawa, J. Chromatogr., 1982, 245, 141; D. M. Hilker and A. J. Clifford, ibid., 1982,231,433. H. Kitaoka and K. Ohya, J. Chromatogr., 1982,238,495. P. Linssen, A. Drenthe-Schonk, H. Wessels, G. Vierwinden, and C. Haanen, J. Chromatogr., 1982,232,424. J. Jacobson, Z. El Rassi, and C. Horvath, J. Chromatogr., 1982,253,252; P. J. Basseches, A. Durski, and G. Powis, ibid., 1982,233,227. J. Szewczyk, B. Lejczak, and P. Kafarski, Experientia, 1982,38,983. J. E. Cockburn and A. P. Williams, J. Chromatogr., 1982,249, 103. Yu. M. Parkhomenko and S . A. Klimchuk, Ukr. Biokhim. Zh., 1982, 54, 551 (Chem. Abstr., 1982,97,158 994). M.Manai and A. J. Cozzone, Anal. Biochem., 1982,124,12. I. A. Lavygin, I. I Skorokhodov, 0. V. Leitan, A. M. Pribytko, A. S.Akat’eva, and E. F. Bugerenko, Deposited Document, 1980, SPSTL, 765, KHP-D80, 7 pp. (Chem. Abstr., 1982,97,110 115).

Author Index Abart, J., 219 Abatjoglou, A. G., 24 Abbad, E. G., 168 Abbott, M. S., 198 Abdel-Gawad, M. M., 55 Abdou, W. M., 49 Abdukakharov, W. S., 307 Abicht, H. P., 19 Abo, M., 158, 171 Acher, F., 120 Ackermann, K., 11 Adams, B. E., 273 Adams, H. E., 278 Adams, J., 18 Adams, J. L., 153 Adams, S. P., 93, 186 Adams, W. J., 37 Agafonov, S. V., 21, 104 Aganov, A. V., 297, 308 Agashkin, 0. V., 291 Agawa, T., 239 Agranoff, B. W., 150 Aguilera, C., 275 Ahmad, K. Sh., 272 Ahmed, F. R., 282 Ahmed, J., 306 Aizawa, Y., 15 Akagi, H., 262 Akat'eva, A. S., 314 Akatsuka, R., 67 Akelah, A., 20 Akimova, G. S., 22 Akkerman, W., 272 Akroyd, J., 245 Aksnes, G., 224 Aktalay, Y., 6, 289, 305 Aladzhera, I. M., 294, 305 Alam, M., 104 Albonica, S. M., 20 Alder, L., 215, 310 Alekseiko, L. N., 309 Alemagna, A., 233 Alewood, P. F., 144 Al'fonsov, V. A., 103, 298 Al-Hakim, A. H., 226 Alig, B., 19, 82 Alikin, A. Yu., 300 Alix, A. J. P., 273 Al-Jibori, S., 20 Allahdad, A,, 230 Allaudeen, H. S., 180 Allcock, H. R., 20, 260, 265, 266, 267, 269, 270, 273, 274, 275, 276, 277, 278, 279,280,282,306

Allen, C. W., 265, 269, 271, 273

Allen, D. W., 21, 58, 306 Allen, P. S.,286 Allen, R. W., 282 Allfrey, V. G., 198 Allman, T., 3 11 Alnajjar, M. S., 19 Alparova, M. V., 300 Al-Rawi, J. M. A., 291 Altona, C., 214 Alunni, S., 24 Al-Zaidi, S., 230 Amer, A., 23 Amer, B. N., 181 Amirzadeh-Asl, D., 56, 87 Anand, B. N., 51 Anderson, B. M., 147 Anderson, D. M., 102 Anderson, L. W., 261 Ando, K., 29,60,102,287,304 Ando, T., 208 Andreev, N. A., 290 Andreeva, M. A., 270 Andrews, R. C., 14 Andriamizaka, J . D., 28, 32, 100

Ang, H. G., 43 Angeletti, E., 225 Angelov, C. M., 13, 66, 81, 134,136,138

Angelov, Kh. M.,134, 137 Annan, W. D., 144 Antipin, M. Yu., 305, 307 Antkowiak, T. A., 274 Antoniadis, A., 297 Antonovich, V. A., 2 Aoki, S., 191 Appel, R., 15, 29, 30, 31, 97, 218, 287, 289, 292, 293, 303, 304 Arad, G., 193 Araki, S., 123 Araki, Y., 151 Arbuzov, B. A., 12, 34, 65, 291, 297, 300, 303, 304, 306, 307, 308, 312 Arcus, R. A., 275 Arima, Y., 314 Armour, M. A., 65, 297 Arnold, D., 85 Arpac, E., 7 Arshady, R., 5 Arshinova, R. P., 291, 297, 300, 303, 308

315

Asato, A. E., 242, 244 Ash, D. E., 153 Ash, D. K., 18 Ashkinadze, L. D., 300 Ashley, G. W., 153 Aslanidis, P., 4 Aso, Y., 162 Asseline, U., 162 Astrina, V. I., 260, 274 Atamas, L. I., 290 Atkins, J. F., 202 Atkinson, T. C., 216 Ator, M., 179 Atovmyan, L. O., 26 Atsuta, K.,273 Atton, J. G., 13 Atwood, J. L., 6, 31 Aulabaugh, A., 212 Auld, D. S., 178 Ault, B. S., 23 Auner, M., 7 Auron, P. E., 207 Austin, P. E., 265, 279,280 Axelrad, G., 8 1, 111 Ayapbergeno, K. A., 308 Ayed, N., 103, 288-291, 301 Azhaev, A. V., 180, 191 Azols, A., 191 Baalmann, H. H., 264 Baasov, T., 243 Babin, M. J., 289 Babkina, G. T., 178 Babushkina, T. A., 15 Baccar, B., 288 Baccolini, G., 13 Bacher, A., 148 Badanyan, Sh. O., 140 Badashkeeva, A. G., 198,213 Baggiolini, E. G., 75 Bahr, J., 242 Bahr, U., 310 Bailar, J. C., jun., 3 Baird, M. C., 9 Bajwa, G. S., 286 Bakeeva, R. F., 309 Baker, M. S., 203 Bakhmutov, Y.-L., 44 Baldinger, H., 131 Balgobin, N., 184, 185 Balitskii, Yu. V., 307 Balland, A., 188 Balogh-Nair, V., 243 Balszuweit, A., 83, 115 Baltenas, V., 160

Author Index

316 Balthazor, T. M., 306 Balzarini, J., 180 Bamgboye, T. T., 282 Bancroft, G. M., 18, 303 Bandurina, T. A., 313 Banerjee, S., 81, 111 Banfi, S., 133 Banville, D. L., 215 Baracco, L., 78 Baraldi, P. F., 112 Baralt, O., 255 Baraniak, J., 168 Baranova, L. V., 160 Baranskii, V. A., 104, 312 Barbier, C., 162 Barbugian, N., 252 Barciszewski, J., 206 Barfield, M., 295 Barluenga, J., 104 Barnett, J. W., 193 Barr, P. J., 161 Barrans, J., 32, 97 Barrick, J. C., 26 Barrio, J. R., 146 Barry, C. N., 14 Bart, J. C. J., 23, 306 Bartell, L. S., 37 Barth, V., 29, 304 Bartlett, P. A., 141, 142, 152, 153, 172 Bartmann, W., 252 Bartsch, M., 206 BArzu, O., 198 Bashinova, V. M., 125 Basseches, P. J., 314 Batail, P., 226 Batley, M., 287 Batyeva, E. S., 49, 81, 103 Baudler, M., 6, 9, 289, 293, 295, 296, 298, 305 Baumeister, U., 19 Baumrucker, S. J., 14 Beabealashvili, R., 180 Beaujean, M., 127 Becerra, S. P., 216 Bechtolsheimer, H. H., 26 Beck, G., 252 Becker, G., 29, 30, 31, 287, 288, 303, 304 Becker, K. B., 221 Becker, W., 29, 304 Bednar, R. A., 160 Beechey, R. B., 200 Beggiato, G., 278 Begley, G. S., 146 Begley, M. J., 282 Behe, M., 214 Behnke, J., 275 Behrman, E. J., 161 Bekasova, N. I., 270 Belagaje, R., 189 Beletskaya, I. P., 235, 306 Bell, A. T., 276 Bell, L.,216

Bellan, J., 32, 98, 289, 296 Belletire, J. L.,27 Bel'skii, V. E., 133, 309, 312 Belsky, V. K., 235, 306 Belyaeva, T. N., 3, 138 Belyalov, R. U., 92 Bendel, P., 215 Beneken genaamd Kolmer, M. H., 273 Benezra, C., 113 Benham, G. Q., 291 Benhammou, M., 11, 103, 304 Benkovic, S. J., 172 Benn, R., 286 Bennett, H. F., 286 Bentrude, W. G., 9, 60, 297, 299,307 Beraldin, M. T., 291 Beranek, D. T., 204 Berdnikov, E. A., 134, 143, 299 Beres, J. J., 278 Berestova, S. S., 291 Bergeret, W., 66 Berg-Nielsen, K., 3 14 Berkner, K. L., 207 Berkoff, C. E., 24 Berlin, K. D., 69, 293, 297, 306 Berlin, Yu. A., 183, 186 Bernard, M., 20, 225 Berndt, K. G., 303, 310 Bernheim, M., 131 Bernheim, M. Y., 270, 282 Berrias, M., 199 Bertrand, G., 27,287 Besecke, S., 276 Bestmann, H. J., 22, 26, 220, 221, 227, 229, 231, 232, 235, 248 Beuttler, T., 114 Bhadani, S. N., 13 Biagini, R., 207 Bickelhaupt, F., 9, 28,31,99, 291,306 Bicknell, R., 175 Bidan, G., 290 Biernat, J., 191 Bijlaart, J. H., 263 Bild, G. S., 146 Bingham, S. E., 93, 190 Binnewies, M., 95 Birkofer, L., 229 Bittirova, F. A., 274, 277 Bjerve, K. S., 314 Bjork, H. B., 298 Bkouche-Waksman, I., 35, 307 Blackburn, G. M., 113, 238 Blattler, W., 175 Blair, P. D., 292 Blakely, R. L., 179 Blan, H., 236

Blanck, K., 268 Blankespoor, R. L., 67, 124, 309 Blanquet, S., 181 Blizzard, T. A., 259 Blobel, G., 199 Block, M. R., 179 Blocker, H., 215 Blonski, C., 156, 307 Bloom, J. D., 60 Bobkov, V. N., 299 Boche, G., 131 Bochner, B. R., 181 Bock, H., 31,33, 67,299,303 Bodalski, R., 62, 66, 68, 226, 296,306 Bodenhausen, G., 293 Bodley, J. W., 199 Bodor, N., 109, 155 Boeckmann, R. K., 255 Bohme, E., 174 Boehme, R., 308 Bogaard, M. P., 306 Bogachev, V. S., 160 Bogachev, Yu. S., 291 Boganova, N. V., 89 Bogel'fer, L. Ya., 292, 296 Bohlmann, F., 250, 255 Boiko, A. P., 262, 300 Bokanov, A. I., 9, 287 Boldeskul, I. E., 37, 300,302, 303,307 Bolhuis, J. K., 273 Bollmacher, H., 11 Bolton, P. H., 293 Bomhard, A., 220 Bondarenko, N. A., 291,311 Bonicamp, J. M., 119 Bonini, C., 259 Bonnard, H., 33, 304 BOOS,K.-S., 179 Bopp, T. T., 244 Bordin, P., 278 Bordnikov, E. A,, 301 Borisenko, A. A., 291 Borisova, I. V., 235, 306 Borisova, T. I., 277 BO~~SSOV, G., 26 Borkowska, A., 310 Bornstein, P., 144 Borowiecki, L., 248 Bortolus, P., 278 Bosch, D., 190 Bose, C. C., 189 Bose, S. N., 204 Bosyakov, Yu. G., 291, 310 Bottaro, D., 25 Botteghi, G., 5 Bouchu, D., 124, 310 Bourque, D. P., 197 Bourson, J., 24, 60 Bovin, J. O., 282 Boyer, D., 36, 308, 313 Bradbury, E. M., 286

Author Index Bradshaw, J. S.,132 Brain, E. G., 20 Bramson, H. N., 168 Branch, C. L., 245 Brand, J. C., 299 Brandi, A,, 34 Brandolin, G., 179 Brandt, K., 265 Branscomb, E. W., 203 Brauer, M., 214 Brautigan, D.-L., 144 Brazier, J. F., 32, 98, 289 Breckenridge, B. M., 199 Bredikhina, 2.A., 140 Brehm, S. L., 196 Brel’, A. K., 112 Brel’, V. K., 136, 137, 138, 140

Breque, A., 66 Breuer, E., 313 Brevet, A., 181 Brewer, C. F., 151 Bridger, W. A., 144 Briggs, J. L., 9, 289 Bright, H. J., 153 Bright, J. H., 7 Bright, R. P., 265, 269 Brill, T. B., 103 Bringmann, G., 15 Brletic, P. A., 301 Brooker, H. R.. 286 Brooks, S.,237 Brosche, T., 248 Broser, E., 256 Brown, C., 40, 102 Brown, J. M., 3 Brown, R. S., 211 Bruce, A. G., 202 Briintrup, G., 224 Brunden, M. J., 191 Brunner, H., 8 Brunst, G. E., 269 Brush, C. K., 189 Bruzik, K., 150, 151 Bryant, F. R., 172 Buc, H., 206 Buchanan, A. P., 291 Buchanan, G. W., 129 Buchardt, O., 225 Buck, H. M., 35, 38, 299 Buck, J. C., 247 Buckley, R. G., 20 Biilow, L., 195 Biinemann, H., 197 Bugerenko, E. F., 301, 314 Buina, N. A., 17 Bukachuk, 0.M., 22 Bulgarevich, S. B., 309 Bullen, G. J., 282 Bulycheva, E. G., 270 Burckett-St. Laurent, J. C. T. R., 31, 302 Buren, L. L., 23 Burford, N., 261, 284, 306

317 Burgada, R., 35, 50, 307 Burger, W., 6, 67 Burghardt, G., 248 Burkin, A. R., 274 Burman, D. L., 250 Burnaeva, L. A., 56 Burton, D. J., 23, 24, 113, 231,313

Buss, A. D., 72 Busulini, L., 278 Butin, B. M., 291, 310 Butkova, 0. L., 10, 309 Butkus, V., 186 Butler, I. R., 11 Butsugan, Y.,123 Buttero, P. O., 233 Butters, T., 304 Buzzetti, F., 252 Bychkov, N. N., 292 Bye, E., 66, 306 Byers, B., 216 Byistro, V. K., 308 Bykhovskaya, 0. V., 294, 305

Cabre-Castellri, J., 127 Caglioti, L., 267 Cain, B. D., 151 Calva, K. C., 121 Camerman, A., 307 Camerman, N., 307 Cameron, T. S., 273, 282 Caminade, A. M., 290 Cammarano, P., 207 Campbell, K. P., 198 Campbell, M. M., 80, 106, 152

Canning, L. R., 3 Cantu, L., 310 Cao, T. M.,93, 190 Capdevila, J., 245 Capponi, V. J., 213 Capuano, L., 231 Caradonna, J. P., 213 Caras, I. W., 199 Cardinal, G., 291 Cariati, F., 23, 306 Carlson, G. M., 198 Carpentier, Y.,273 Carrie, R., 34 Carriker, J. D., 243 Carruthers, N. I., 80, 106, 142, 152

Cartwright, I. L., 208, 210 Caruthers, M. H., 92, 181, 185, 186, 190

Casida, J. E., 106, 127 Cassaigne, A., 141, 152 Castro, B., 85, 182 Cattan, A., 273 Cavalla, D., 72, 75 Cavazza, M.,4, 25, 221 Cavell, R. G., 38, 39, 292 Cayley, P. J., 193

Cech, C. L., 190 Cech, D., 189, 215 Cech, T. R., 196 Cesarotti, E., 12, 95 Cetinkaya, B., 299, 304 Chacos, N., 245 Chadaeva, N. A,, 12 Chaikovskaya, A. A., 104 Chakhmakhcheva, 0. G., 189

Chambers, D. A., 198 Chambers, R. W., 205 Chan, C., 282 Chan, T., 18, 303 Chan, T. H., 155 Chandrasegaran, S., 192 Chandrasekara, W., 307 Chandrasekaran, S.,286,297 Chandrasekhar, V., 263 Chang, H. W., 108 Chapleur, Y., 85 Chapron, Y., 179 Charalambous, J., 20 Charkasova, D. A., 312 Charrier, C., 33, 287, 304 Charubala, R., 193 Chatt, J., 29, 100 Chatterjee, K. K., 300 Chatterji, D., 214 Chattopadhyaya, J. B., 184, 185, 193

Chauhan, H. P.S., 23 Chaus, M. P., 54 Chauzov, V. A., 21,104 Chawla, R. R., 171 Chen, C.-W., 214 Chen, J.-T., 172 Chen, K. K., 181 Cheng, D. M., 166 Cheng, T. C., 278 Cheng, Y.-C., 180 Cherkasov, R. A., 104, 117, 118, 126,132, 312

Cherkina, M.V., 56 Chernov, P. P., 131, 291 Chernov, V. A., 272 Chernova, A. V., 143, 301 Chernykh, T.-E., 289 Chernyshev, E. A., 260 Chertopolokhova, E. A., 129 Chervin, I. I., 26 Chetsanga, C. J., 204 Chiacchio, U., 233 Chidester, C. C., 306 Chiesa, A,, 12, 95 Chistokletov, V. N., 22 Chivers, T., 261, 284, 306 Chopra, R., 14 Chottard, J.-C., 213 Chow, F., 190 Christie, M.A., 237 Christodoulou, C., 183 Christol, H., 21, 25, 26 Christopfel, W. C., 9

318 Christov, C. Zh., 136 Chu, C. T. W., 278 Chukova, V. M., 278 Churchich, J. E., 176 Chuvaev, V. F., 298 Ciampolini, M., 6 Cieslinski, L. B., 245 Cimarusti, C. M., 108 Cini, R., 6 Cirakoglu, B., 181 Claesson, A,, 123 Clardy, J. C., 294 Clare, P., 269, 271 Clark, V. M., 145 Clausen, K., 132 Clayden, N. J., 213 Clegg, W., 4, 305 Cleland, W. W., 212 Clemance, M., 20 Clennan, E. L., 47, 296 Clifford, A. J., 314 Clin, B., 141 Cload, P. A., 156, 311 Cnossen-Voswijk, C., 264, 284

Cockburn, J. E., 314 Codding, P. W., 284 Cohen, J. S., 214 Cohen, S., 144 Cohen-Solal, M., 179 Cohn, M., 153,175,176, 178 Coleman, J. E., 153 Coleman, M. M., 271 Coleman, R. F., 160 Collard, J. N., 113 Collignon, N., 117, 156 Colman, R. F., 200 Colquhoun, I. J., 4, 60, 294 Colvin, E. W., 131 Compagnini, A., 233 Comstat, M., 36 Congote, L. F., 314 Coninx, P., 273 Connell, A. C., 71 Connelly, A., 272 Connolly, B. A., 166, 176, 177

Connolly, M. S., 267, 282 Conrad, H., 304 Constable, A. G., 2 Constantin, E., 156, 166 Cook, R. L., 3 Cooke, M. P., jun., 250 Cooney, D. A., 147 Cooney, J. V., 223 Cooper, P., 19 Cooper, T. A., 31, 302 Corbin, J. D., 168 Cordes, A. W., 261, 282 Cordis, G. A., 159 Corey, E. J., 218,247, 253 Cornforth, Sir J., 33, 63, 112 Cornforth, Lady R. H., 33, 63, 112

Author Index Cornish, C. A., 72 Corrie, J. E. T., 17 Corrie, R., 227 Corsara, A., 233 Cosgrove, D. J., 313 Costa, T., 219, 294, 298,309 Coste, J., 26 Costisella, B., 79, 110, 133 Cotter, R. J., 310 Courft, C., 27, 28, 32, 100, 287

Covitz, F., 36 Coward, J. K., 178 Cowley, A. H., 9, 27, 28, 30, 31, 88, 99, 287, 288, 289, 293, 295 Cox, D. L., 23, 231 Cozzone, A. J., 314 Crandall, J. K., 227 Crea, A., 247 Crea, R., 194 Creary, X., 140 Cistau, H. J., 21,25,26 Crombie, L., 225 Cross, T. A., 215 Crouch, R. K., 243 Cullen, W. R., 11 Cullis, P. M., 174, 175 Cummings, S. C., 5 Curti, B., 147 Cushner, M. C., 293 Czarnecki, J. J., 198 Czekanski, T., 79, 110 Czownicki, Z., 110 Czuppon, A., 194

Dabkowski, W.. 89, 105 Dabrowiak, J. C., 207 Daerr, E., 289 Dahl, O., 13, 81,225, 288 Dahlenburg, L., 7 Dahmann, D., 269 Dai, J., 307 Dain, R. J., 274 D’Alfonso, G., 12, 95 Dangyan, Yu. M., 140 Danilyuk, N. K., 192 Darby, M. K., 176 Dash, K. C., 268 Daun, J.-K., 314 Davidowitz, B., 130 Davies, D. B. 213 Davies, J. E., 192 Davies, R. J. H., 204 Day, R. O., 26, 36, 37, 308 De Bernardini, S., 186 De Brosse, C., 172 Debruyne, I., 156 de Castro Dantas, T. N., 20 Declercq, D. R., 314 de Clercq, E., 180 Declercq, J.-P., 36, 307,308 Dederer, B., 282 Degetto, S., 78

de Haseth, P. L., 190, 195 Dehnel, A., 296 Dehnicke, K., 306 De Jaeger, R., 276 Dekerk, J.-P., 234 de Lauzon, G., 33, 304 Delmas, M., 225 Demidova, N. I., 9 Demon, P. C., 292 Demopoulos, C. A., 314 Denney, D. B., 41, 42, 49, 51, 81, 84, 89, 295, 296

Denney, D. Z., 41, 42, 49, 51, 81, 84, 89, 295, 296

Dennis, D., 191 Dennis, E., 36 Denny, M., 242, 244 Denther, H., 290 Depner, J., 20 Deppisch, B., 100 De Renzi, A., 5 DeRosa, M., 207 de Ruiter, B., 263, 264, 267, 271, 284, 296

Dervan, P. B., 208 Desai, K., 239 de Sarle, F., 34 Descamps, J., 180 Deschler, U., 22, 219, 220, 305

Deshong, P., 255 Desiderio, D. M., 144 Desorcie, J. L., 267 Desper, C. R., 278 Detera, S. D., 216 Devadoss, E., 274, 275 Devash, Y., 196 DeVos, M. J., 229 de Vroom, E., 190 Dewan, J. C., 211 Dhathathreyan, K. S., 265, 266,267,282,294,

312

Diallo, 0. S., 92 Dianova, E. N., 34 Diaz, E., 146 Dickerhof, K., 24 Didkovskii, V. E., 303 Dieck, R. L., 276 Diel, B. N., 298 Diemert, K., 2, 86 DiGregorio, F., 267 Dijkgraaf, P. A. M., 168 Dillon, K. B., 289 Dimroth, K., 34 Dimukhametov, M. N., 17 Di Radde, P., 155 Dirheimer, G., 207 Di Stefano, F. V., 266 Dixon, K. R., 29, 100 Djarrah, H., 19 Djerassi, C., 259 Dmitriev, V. I., 290, 302 Dmitriev, V. K., 290 Dodson, L. A., 203

319

Author Index Dopfer, K.-P., 83, 115 Dorper, T., 186 D~rskeland,S. O., 167, 168 Dotz, K. H., 11 Dogadina, A. V., 3, 138 Doglia, S., 217 Doi, T., 202 Dolgushin, G. V., 298 Dominick, T. F., 261 Don, S., 305 Donelson, J. E., 181 Donohue, J. J., 151 Donskikh, V. I., 110, 290 Doorakian, G. A., 23 Dormoy, J. R., 182 Dorokhova, N. I., 66, 300 Doroshkina, G. M., 143,301 DOU,S., 307 Dougill, M. W., 282 Douthwaite, S., 206 Dow, D. L., 192 Downie, I. M., 131 Doyadina, A. V., 138 Doyle, M. P., 67, 124, 309 Drach, B. S., 116 Drake, A. F., 193 Dreher, M., 292 Drenthe-Schonk, A., 314 Dresskamp, H., 234 Dreux, J., 124, 310 Drewelies, K., 86, 307 Duangthai, S., 295 Duarte, H. C., 14, 234 Dubenko, L. G., 312 Dubourg, A., 36, 308 DUC,G., 21 Duggan, M. E., 114 Duhl-Emswiler, B. A., 223 Dulenko, V. I., 20 Dumora, C., 152 Duncan, J. A. S., 102 Dunitz, J. D., 66, 306 Dupart, J.-M., 40, 290 Du Plessis, M. P., 307 Dupont, Y., 179 Durig, J. R., 300, 301 Durski, A., 314 Dutasta, J. P., 289 Dvoinishnikova, T. A., 289 D’yachenko, 0. A., 26 Dyatlova, N. M., 298, 306 Dyer, G., 9, 289 Dzhailanov, S. D., 291 Eaborn, C., 3 Eaton, M. A. W., 189 Ebel, J.-P., 201, 206 Ebsworth, E. A. V., 9, 30, 44, 102, 301

Eckl, E., 19, 82 Eckstein, F., 165, 166, 172, 174, 177

Edge, M. D., 216 Edmundson, R. S., 109, 310

Edwards, B. H., 6 Efimov, V. A., 189 Efimova, E. V., 198 Efremov, Yu. Ya., 12, 110, 311

Egan, W., 131, 313 Egorov, U. P., 300 Egorov, Yu. P., 272 Ehrenberg, A., 217 Ehresmann, B., 201 Eichbichler, J., 293 Eichhorn, G. L., 213 Eide, S. J., 175 Eiletz, H., 282 Einstein, F. W. B., 306 Ekanger, R., 167 El-Deek, M. A. K., 111, 240 Elgavish, G. A., 213 Elgin, S. C. R., 181,208,210 El-Hamouly, W. S., 55 Elias, H., 292 Eliseeva, G. D., 141 El Khatib, F., 290 El-Khrisy, E. E. A. M., 132 Ellermann, J., 23, 299 Elliot, R. C., 77, 78 Ellis, F., 247 El’natanov, Yu. I., 26 El Rassi, Z., 314 Elsner, G., 7 El’Wassimy, M. T. M., 132 Engel, R., 81, 111 Engels, J., 94, 163, 166 Engenito, J. S., jun., 2, 292 Engenito, J. S., 85 Engle, T. W., 131, 313 Enikeev, K. M., 83, 115 Enjalbert, R., 273,282, 307 Enqvist, J., 298 Eppstein, D. A., 193 Epshtein, L. M., 300 Erastov, 0. A., 12, 65, 297, 304, 306

Erdmann, V. A,, 206,207 Eriksson, S., 199 Erneux, C., 144 Escudih, J., 27, 28, 32, 100, 287

Etemad-Moghadam, G., 156 Eto, E., 122 Eto, M., 106, 108, 311 Evans, F. E., 204 Evans, S. A,, jun., 14 Evans, T. L., 20, 265, 266, 274, 278, 279

Evreinov, V. I., 119 Ewen, G. D., 111, 240 Fadeley, C. L.,268 Faedda, G., 5 Faggin, M., 78 Falck, J. R., 245 Fanestil, D. D., 151 Fasold, H., 200

Faucher, J.-F., 273 Fawcett, J. K., 307 Fayos, J., 284 Fedorov, S. B., 309 Fedorov, S. G., 273 Fedotov, M. A., 292 Feigel, M., 293 Fenske, S. L.,275 Ferrar, W. T., 266, 273 Fersht, A. R., 203 Feshchenko, N. G., 303 Feshin, V. P., 298 Fewell, L. L., 277 Fieldhouse, J. W., 261, 275, 278

Fields, R., 19 Filipowicz, W., 196 Filippova, A. Kh., ,110 Finaeva, M. G., 308 Finck, M. S., 113, 239 Finke, M., 68 Finkelstein, J. A., 245 Finter, J., 273 Fischer, E., 267 Fischer, G. W., 131 Fischer, H., 200 Fischer, J., 33, 304 Fisher, B. L.,265 Fisher, E. F., 186 Fisher, P. A., 199 Fitzsimmons, J. R., 286 Flemming, H. W., 118 Flick, M. B., 196 Fliszar, S., 291 Flitsch, W., 25, 228 Flockhart, D. A., 168 Florent’ev, V. L., 160 Floyd, R. A., 208 Floyd-Smith, G., 199 Fluck, E., 11, 87, 264, 288, 304, 307, 308, 309

Flynn, K. M., 29, 100 Flynn, R. M., 24, 113, 313 Foeckler, R., 181 Foerster, H., 292 Fokin, A. V., 309 Folk, W. R., 207 Fongers, K.-S., 23, 32, 63 Fonong, T., 113,313 Foote, R. S., 203 Forbush, B., 111, 178 Ford, W. J., 225 Ford, W. T., 20 Fortier, S., 282 FOSS, V. L., 84, 289 Fosse, V. M., 206 Foucaud, A., 83, 112 Fourrey, J.-L., 93, 163 Fox, J. J., 180 Fraenkel-Conrat, H., 203 Franck, U., 290 Frank, R., 215 Franklin, W. A., 205 Franzen, D., 194

Author Index

320 Fredrich, M. F., 66 Freedman, L. D., 65 Freeman, H. S., 65 Frey, P. A., 173, 177 Friedman, N., 262 Frijns, J. H. G., 10 Fritz, G., 6, 289 Fritzsch, G., 200 Froehlich, R., 305 Frolov, V. I., 277 Frot-Coutaz, J., 314 Fu, G., 310 Fuchita, Y.,20 Fuji, H., 152 Fujitaki, J. M., 156 Fukata, S., 117 Fukuda, C., 256 Fukui, T., 149, 180 Fukumoto, R., 202 Fuller, T. J., 265, 266, 279, 282

Furey, W., 148,307 Furin, G. G., 292 Furstenberg, G., 6 Furuichi, Y., 181 Furukawa, I., 14 Furukawa, M., 120 Futamura, S., 278 Futatsugi, T., 84, 107, 145 Gabay, Z., 262 Gabriele, P., 79 Gait, M. J., 188, 213 Galdecki, Z., 62, 306 Galeeva, I. Z., 34 Galieva, F. A., 17 Gall, T. S., 198 Gallagher, M. J., 296 Gallicana, K. D., 261, 269, 282

Gallis, B., 144 Galluppi, G. R., 93, 186 Galy, J., 273, 282 Galynker, I., 17 Gambacorta, A., 207 Gander, J. E., 175 Gandolfi, C. A., 252 Gangleff, J., 207 Gans, W., 6 Gantzer, M. L., 178 Ganzer, M., 255 Garbe, E., 273 Garbers, D. L., 144 Garcia-Luna, A., 17, 59 Gareev, R. D., 48, 81, 143, 298,301

Gargiulo, G., 210 Garner, A. Y., 273 Garrett, D. R., 51 Garrett, R. A,, 206, 207 Garrigues, B., 36, 290, 308, 313

Gasc, M. B., 156, 307 Gaset, A., 225

Gassen, H. G., 192 Gaughan, R. G., 253 Gautier, J. C., 66 Gavrilova, G. V., 110 Gawrisch, K., 291 Gazizov, T. K., 83, 92, 115 Gebeyehu, G., 147 Gebhard, J. S., 132 Gehret, J.-C. E., 153 Geibel, K., 23, 299 Geiger, C. C., 140 Geraldes, C. F. G. C., 292 Gerber, A. H., 274 Gerlt, J. A., 153, 292 Germa, H., 11, 103 Germain, F., 85 Germain, G., 36, 307, 308 Gesteland, R. F., 202 Gettins, P., 153 Giegk, R., 206 Gieren, A., 282 Gilardi, R. D., 66, 306 Gilbert, J. C., 238 Gilham, P. T., 191 Gilje, J. W., 55 Gilman, A. G., 198 Gilman, L. M., 275, 277 Gilyarov, V. A., 104,128,292 Ginzburg, B. I., 110 Gioeli, C., 184, 193 Giordano, L. A., 113, 239 Girault, J.-P., 213 Giulietti, G., 24 Gladiali, S., 5 Glancey, B. M., 250 Glazunov, M. P., 311 Gleason, J. G., 245 Gleria, M., 278 Glidewell, C., 292, 311 Gloede, J., 45, 290 Gloriozov, I. A., 309 Glowka, M., 62, 306 Gloyna, D., 21, 303, 310 Glukhikh, V. I., 110 Gnuchev, N. N., 191 Goda, T., 213 Godovikov, N. N., 119, 299 Goel, R. M., 311 Goerlich, O., 181 Goguillon, J., 24, 60 Gokita, N., 187 Goldberg, I. H., 210 Goldberg, N. D., 175 Gol’dfarb, E. I., 48, 56, 81, 125, 298

Goldfield, E. M., 214 Gol’din, G. S., 273 Goldman, R. A., 190 Goldman, Y. E., 178 Goldschmidt, J. M. E., 262 Goldstein, R., 262 Goldwhite, H., 299, 304 Gololobov, Yu. G., 43, 54, 113, 115, 116,298

Gol’tser, S. I., 6 Gompper, R., 22,303 Gonbeau, D., 27, 100 Goncharova, L. V., 66, 300 Good, A. L., 9, 61 Goodman, M. F., 203 Goody, R. S., 157, 176 Gorban, I. Ya., 293 Gordon, M. D., 61 Gorelik, L. D., 314 Gorenstein, D. G., 122, 214 Gorgues, A., 226 Goryaev, A. A., 265, 274 Gosselin, G., 193 Goswami, B. B., 194 Gotor, V., 104 Gottikh, B. P., 160, 191 Gottikh, M. B., 193 Gough, G. R., 191 Gourghiotis, D. J., 83, 106, 313

Govindan, C. K., 299 Grabley, S., 306 Grabowski, P. J., 196 Graslund, A., 217 Graffeuil, M., 273, 282, 307 Graham, D. R., 210 Graifer, D. M., 201 Grand, A., 294 Granoth, I., 36, 297 Grant, D. M., 298 Grapov, A. F., 104, 118, 129 Graves, D. F., 261, 275, 278 Gray, R. T., 33, 63, 112 Green, J. C., 271 Green, R. H., 245 Greene, A. R., 216 Greigger, P. P., 282 Gridunova, G. V., 15, 306 Griend, L. V., 38, 39 Griffiths, D. V., 296 Grikina, 0. E., 308 Grim, S. D., 60, 66, 294, 306 Grisham, C. M., 178, 214 Grishina, 0. N., 125, 290 Grobe, J., 4, 7 Grochowski, E., 16, 42 Groody, E. P., 19, 186 Gross, H., 45, 79, 110, 290 Gross, H. J., 196 Gross, K., 308 Grossbruchhaus, V., 94, 191 Grossmann, G., 271, 295 Grotjahn, L.,215 Grunberg, S. M., 210 Gruner, C., 298 Gruys, K. J., 177 Gryaznov, P. I., 92 Grzejszczak, S., 133 Guadliana, M., 239 Guarneri, M., 112 Guastini, C., 233 Gubaidullin, M. G., 119, 141 Guerch, G., 263,273,282,307

321

Author Index Guerriero, A,, 4 Guidotti, S., 203 Guittet, E. R., 213 Gunther, H., 286 Guo, H., 111 Gupalo, A. P., 124 Gupta, A., 172 Gupta, B. G., 17, 59 Gupte, S. M., 151 Gurarii, L. I., 307 Gurusamy, N., 293,306 Gusar, N. I., 54 Guthrie, R. D., 16, 42, 289 Guy, A., 117, 156, 182, 183

ILIaack, J. L., 227 ILIaake, P., 119 1FIaanen, C., 3 14 I3aase, M., 4, 305 Igacker, M. P., 273 1Haddad, M., 32, 97 IHaegele, G., 293 1Hanel, P., 33, 67,299 1Haerer, J., 289 IHagnauer, G. L., 274 IYahn, J., 6, 289, 298 IHai, T. T., 158, 171 IHakkinen, A. M., 298 IHalasa, A. F., 275, 277, 278 1Halepp, B., 300 1Haley, B. E., 198 1Halimi, H., 310 1Hall, J. A., 203 1Hall, J. E., 275 1Hall, R. G., 132 IHaller-Pauls, I., 304 1Wstenberg, M., 29,97,287, 304

ILIalstenberg, N., 304 ILIaltiwanger, R. C., 12, 86 IXaltiwanger, R. D., 304 1LIamerlinck, J. H. H., 35, 299

IXammond, P. J., 41, 51, 84, 89

Igamp, D., 79 ILIampton, A., 158, 171 Iqan, C.-N. A., 148 ISanawalt, P. C., 193 13anessian, S., 95 1Sanke, W., 8 ISansen, D. E., 146 1LIansen, S. W., 24 IXanstock, C. C., 22, 296 1gao, W. M., 204 1Xarada, F., 207 1Sarangus, P., 274 Igarger, M. J. P., 142 IXarkins, P., 272 1Xarpp, D. N., 18, 85 Hams, P. J., 265, 267, 268, 271, 276, 282

Harrison, I. R., 278 Harrison, S., 131

Idarthcock, M. A., 300 1Xartke, K., 230 1Xartl, F. T., 179 ILIartley, F. R., 1 IHartley, J. L., 181 ISartung, H., 19 IXartz, G., 224 IXarvey, D. A., 87 Igasegawa, T., 261 1LIaseltine, W. A., 205, 208, 210, 211

IXashidzume, M., 276 1gashimoto, S., 14 IXashimoto, Y.,203,204 1LIaslinger, E., 296 ILIassett, A., 175 IXassler, K., 5, 299 1LIaszeldine, R. N., 19 1Jata, T., 84, 145, 159, 186, 187

ILIatziantoniou, C. T., 256 ISaugh, M. C., 156, 193, 311 IHanske, J. R., 239 Iqayakawa, Y.,162 ILIayashi, J., 170 Igayatsu, H., 169, 207 1gaynie, S. L., 145, 169 13e, C., 305 13eah, P. C., 47, 296 13ea1, H. G., 260 1geathcliffe, G. R., 216 1Hebda, C. A., 146 1Hecht, S. M., 201, 202, 208, 211 1Heckler, J. G., 202 1kIedberg, K., 37 1Hedberg, L., 37 1gedden, D., 102 1Xeerschap, A., 150 1LIeesing, A., 16 1gehre, W. J., 102, 311 IXeid, E., 26, 235 IXeinicke, J., 3, 33,86 IXeinlein, T., 305 I3elioui, M., 276 1Xellman, J., 6, 9, 289, 293 1LIemmes, P., 216 IXenderson, M. A., 227 ILIendrickse, T., 310 1LIeney, G., 151 ILIengefeld, A., 2 IXenkel, G., 19 1Xenne, A., 10 IXenner, W. D., 208,210,217 IXennessy, B. M., 75 1Senning,H. G., 3 10 ILIenzen, A. V., 75 IXergenrother, W. L., 277, 278 Ilerman, M. A., 301 Ilermann, E., 79 Iqerring, F. G., 215 ISerrmann, R. G., 197 Ilerrmann, W. A., 31

Hertzberg, R. P., 208 Herzberger, S., 306 Hess, H., 268, 307 Hesso, A., 298 Hetru, C., 156,166 Heubel, J., 276 Heuschmann, M., 69,289 Hewlett, N. G., 197 Heydenreich, F., 234 Hibberd, M. G., 178 Hiester, E., 15 Higashi, F., 273 Higashi, M., 273 Higuchi, T., 29, 102,287,304 Hilal, S. K., 286 Hilker, D. M., 314 Hill, N. E., 289 Hill, W. E., 9, 289 Hiller, W., 2 Hilliard, P. R., jun., 215 Hilton, B. D., 16,42 Hilton, K., 140 Himmelsbach, F., 120, 182 Hines, A. H., 226 Hingerty, B. E., 211 Hinke, A., 293 Hiraki, K., 20 Hirama, M., 259 Hiramatsu, K., 5 Hirao, I., 113, 229, 239 Hiraoka, H., 277 Hiratsuka, T., 167 Hirotsu, K., 29, 102, 287, 304

Hirschbein, B. L., 84, 145 Hitchock, P. B., 29, 33, 100, 112, 304

Ho, H.-T., 173 Hobbs, J. B., 188 Hock, K., 34,63 Hodge, P., 10 Hogel, J., 34, 268 Hoehne, S., 11,288 Hoene, S., 304 Honle, W., 6 Hoffmann, E. G., 234 Hoffmann, J., 156,166 Hoffmann, J. F., 178 Hoffmann, M., 132 Hofstetter, F., 212 Hogenkamp, H. P. C., 199 Hogeveen, H., 23, 32, 63 Holden, I., 127 Holder, S. B., 93, 186 Holland, D., 216 Holler, E., 181 Holmes, J. M., 36 Holmes, R. R., 36, 37, 308 Holmes-Smith, R. D., 4 Holtz, W. H., 237 Holy, A., 159, 170, 171, 197 Honda, T., 245 Honegger, H., 296 Hong, C.-I., 150

Author Index

322 Hood, J. N. C., 221 Hoover, D. J., 247 Hopf, H., 243 Hoppe, K. D., 6 Horejsi, V., 197 Horie, K., 261 Horlein, D., 144 Horn, H. G., 275, 276 Home, W., 304, 306 Horner, L., 2, 24, 118 Horska, K., 171 Horvath, C., 314 Hosokama, Y., 26 Hossain, M. B., 104, 306 Hosur, M. V., 307 House, H. O., 227 Howard, F. B., 195 Hsiung, H. M., 183 HSU,C.-Y. J., 191 Huang, C., 51, 84 Huang, Q., 218, 305 Huang, R. C., 180 Huang, T., 194 Huang, Y., 111, 218, 305, 310 Hucke, M., 306 Hudson, A., 299 Hudson, J. W., 261 Hudson, R. F., 40, 102 Huebner, M., 17 Hunerbein, J., 30 Huff, D., 275 Hughes, A. N., 9, 61 Hughes, B. G., 196 Hulla, F. W., 200 Hunt, B. J., 10 Hunt, J. T., 153 Hunter, G. M., 301 Hunter, W. E., 31 Huppertz, M., 15, 218, 289 Hutchinson, D. W., 81, 156, 311 Hutchison, C. A., 111, 203 Huttner, G., 282,306 Huvenne, J. P., 271 Huynh-Dinh, T., 213 Iacobelli, J. A., 75 Ibanez, W. F., 301 Ibers, J. A., 20 Idoux, J. P., 26 Iga, H., 78 Igarashi, T., 53 Ignat'ev, V. M., 312 Ignat'eva, S. N., 297 Ignatov, S. M., 26 Igolen, J., 21 3 Ikeda, T., 299 Ikehara, M., 166, 181, 182, 186,188,191,202,210,292 Iksanova, S. V., 30,116,272, 292, 300 Ikuta, S., 18, 303, 309 Ilie, R., 273

Il'yasov, A. V., 48, 81, 298, 299, 31 1 Imai, J., 193, 194 Imai, M., 202 Imbach, J.-L., 193 Imoto, T., 256 Imura, J., 166 Imuta, J., 169 lnamoto, N., 27, 28, 29, 60, 99, 102, 236, 287, 304 Indzhikyan, M. G., 7, 25 Ineri, G., 179 Inoguchi, Y., 5 Inokawa, S., 5 , 65, 297, 306 Inoue, T., 192 lnouye, M., 183 Inouye, S., 183 Inoue, Y., 166, 181 Ionin, B. I., 3, 136, 137, 138, 140, 292, 312 lriyama, Y., 276 Irving, C. C. J., 3 13 Irving, J. R., 245 Isaac, R. E., 314 Isaguliants, M. G., 193 Ishido, Y., 187 Ishihara, J., 113, 313 Ishii, T., 236 Ishizaki, T., 203 Ishmaeva, E. A., 143, 301, 308, 309 Islamov, R. G., 131, 312 Ismagilova, N. M., 110 Isono, K., 208 Issleib, K., 6, 7, 19, 30, 83, 99, 115, 287, 296 Istomin, B. I., 104, 123, 141, 290, 312 Itakura, K., 181, 194 Ito, E., 151 Ito, T. I., 262, 273 Itokawa, Y., 314 lvanov, B. E., 309, 312 lvanov, P. Yu., 292 Ivanova, E. M., 183 Ivanova, N. A., 309 Ivanovskaya, M. G., 193 Iwai, S., 182 Iwano, T., 207 Iwata, C., 148 lwata, M., 113 Iyengar, R., 154 Jackson, W. R., 12,95 Jacob, L., 123 Jacobs, G. A., 108 Jacobsen, N. E., 141 Jacobson, G. R., 146 Jacobson, J., 3 14 Jacobson, L., 298 Jacobson, R. A., 19 Jager, A., 94, 163, 166 Jaffe, E. K., 153, 176 Jahngen, J. H., 212

Jain, D. V. S., 14 Jaksch, H., 276 James, T. L., 215 Jamieson, S. V., 225 Janecki, T., 62, 306 Jaozara, R., 207 Jarden, J., 104 Jarvest, R. L., 175 Jaryaram, H. N., 147 Jastorff, B., 168 Jaud, J., 27, 100, 304 Jayaraman, K., 93, 190 Jayawant, M., 23 Jedlinski, Z., 26, 265 Jekel, A. P., 262, 272, 273 Jenkins, I. D., 16,42,44,289 Jenkins, J. M., 20 205 JeriEevic, Jessee, B., 210 Jezekova, D., 273 Jiang, R. T., 150, 151 Jiazhi Xia, 111 Jin, X., 218,305 Jo, W. H., 277, 278 Jochims, J. C., 306 John, A., 271 Johns, D. G., 147 Johns, R. B., 144 Johnson, C. R., 77, 78 Johnston, E. R., 298 Johnston, M. I., 193, 194 Johnston, S. A., 301 Jonak, J., 178 Joner, P. E., 314 Jones, B. A., 132 Jones, C., 289 Jones, D. N., 252 Jones, R. A., 31, 187 Jones, T., 199, 306 Jordan, F., 150, 153, 216 Jordan, R. R., 153 Jorgensen, K. A., 132 Joseph-Nathan, P., 66 Josephson, S., 185 Joussef, A. C., 14, 234 Juaristi, E., 66, 306 Jugk, S., 24, 60 Julia, M., 123 Jullien, J., 99 Juodka, B., 160 Jurkschat, K., 293

z.,

Kabachnik, M. I., 119, 128, 292,299. 301, 305 Kader, H. A., 18 Kadlubar, F. F., 204 Kadyrov, R. A,, 297, 303, 308 Kafarski, P., 152, 314 Kaim, W., 33, 67, 299 Kaiser, E. T., 168 Kajthr, M., 194 Kakiuchi, H., 26 Kalabina, A. V.,1 10,141,298

323

Author Index Kalbitzer, H.-R., 176 Kal’chenko, V. I., 140, 290, 292, 296

Kalcher, W., 3 1 Kalechits, I. V., 81 Kaletsch, H., 34 Kalibalchuk, N. N., 303 Kalinin, V. N., 264,270 Kamaike, K., 183 Kamalov, R. M., 117, 126 Kametani, S.,132 Kametani, T., 245 Kamminga, P. A., 282 Kan, L. S., 166, 192 Kanaya, N., 245 Kane, M. P., 306 Kane, P. D., 242 Kanegasaki, S., 151 Kane-Maguire, L. A. P., 13 Kaneyasu, T., 166 Kang, J. W., 275 Kapicak, L. A,, 24 Kaplan, J. H., 178 Kaplan, S., 151 Kappert, M., 229 Kappler, F., 171 Karaghiosoff, K., 33,98 Karanewsky, D. S., 114 Karaulov, E. S., 7 Kardanov, N. A., 299 Kargin, Yu. M., 110 Karjalainen, J., 301 Karlik, S. J., 213 Karlsttdt, N. B., 89 Karmanov, V. I., 302 Karolak Wojciechowska, J., 307

Karpeiskii, M. Ya., 157, 167 Karpitschka, E. M., 131 Karpov, V. S., 6 Karpova, G. G., 201 Karsch, H. H., 20, 294 Kartha, G., 307 Kasarova, N. N., 275 Kascheres, A., 14, 234 Kasheva, T. N., 272, 300 Kashkin, A. V., 44 Kashmirov, B. A,, 114 Kasparek, F., 130, 314 Kasperczak, W., 265 Kasuga, K., 183 Katagiri, N., 241 Kato, H., 256 Kato, N., 207 Kato, T., 241 Katsyuba, S. A., 300, 301, 308

Katti, K. V., 263 Katti, S. K., 307 Kavka, K. S., 93, 186 Kawakami, A., 277 Kawakami, Y., 9 Kawamoto, H., 297 Kawamoto, N., 306

Kawasaki, Y., 4 Kawashima, T., 236 Kayushin, A. L., 183 Kazakova, N. D., 49 Kazankova, M. A., 103 Kazantsev, A. V., 2 Kazmierzcak, K., 56 Kazubski, A., 248 Keat, R., 87, 97, 294 Kebarle, P., 18, 303, 309 Keck, H., 310, 311 Kecskemethy, N., 197 Keekstra, D., 273 Keenan, R. W., 151 Keener, S., 203 Keiderling, T. A., 302 Kelley, J. A., 147 Kellner, G., 311 Kellner, K., 8 Kemal, D., 120, 164 Kemp, B. E., 144 Kemp, R. A., 9, 30, 88, 289 Kempe, T., 190 Kensett, M. J., 20 Kenttamaa, H. I., 310 Kern, D., 206 Kern, H., 17 Kerr, I. M., 193 Kertscher, P., 291 Kessler, R. J., 151 Kessler, R. M., 24 Khachatryan, R. A., 7, 25 Khaikin, L. S., 308 Khairullin, V. K., 141, 301 Khalimskaya, L. M., 183 Khaskin, B. A., 124 Khmil’ovskaya, M. I., 124 Khokhlov, P. S., 114 Khoshdel, E., 10 Khristov, V., 134 Khusainova, N. G., 134, 140, 309

Kibardin, A. M., 83, 92, 115 Kibardina, L. K., 90,91,292 Kiely, J. S., 187 Kierzek, R., 194 Kigoshi, H., 253 Kiji, J., 1, 5 Kikuchi, Y., 196 Kikukawa, K., 20 Kilbourn, M. R., 14 Kilduff, J. E., 27,28, 99,287 Kim, B. Y., 310 Kimmel, E. C., 127 Kimura, M., 314 King, J., 218 King, M. A., 31, 34 King, M. M., 198, 200 King, R. B., 88 Kingma, R. F., 23, 32, 63 Kini, A., 242 Kinnel, R. B., 259 Kinoshita, I., 261 Kirby, A. J., 145

Kirby, G. W., 17, 131 Kireev, V. V., 260, 265, 274, 277,278

Kirilov, M., 134 Kirkegaard, K., 206 Kirschleger, B., 240 Kirveliene, V., 160 Kisielowski, L., 22, 229, 232 Kisilenko, A. A., 300 Kitagawa, T., 299 Kitaoka, H., 314 Kitazato, K., 272 Kittler, J., 229 Kiyamoto, I., 256 Klaebe, A., 36, 156, 307, 308 Klapstein, D., 304 Klautke, S., 6 Klebach, Th. C., 31 Klebanskii, A. L., 271 Kleijn, H., 10 Kleiner, H. J., 68, 117 Kleppe, K., 206 Klevickis, C., 178, 214 Klimasauskus, S., 186 Klimchuk, S. A., 314 Klingebiel, U., 4, 305 Klochkov, V. V., 297, 308 Klotzer, W., 131 Klose, G., 290 Klug, A., 211 Kluger, R., 36, 148, 307 Knauf, W., 248 Knight, D. W., 230, 248 Knoch, F., 29,30,97,287,304 Knoflach, J., 131 Knoll, F., 292 Knorre, D. G., 198 Knowles, J. R., 146, 175 Knowles, W. S., 9 Knunyants, I. L., 218 Kobayashi, S.,9, 47 Kobayashi, T., 5 Kobayashi, Y., 210 Kobzev, V. F., 160 Kochervinskii, V. V., 278 Koehler, F. H., 219 Koenig, M., 290 Koepsell, H., 200 Koster, H., 94, 184, 189, 191 Koga, Y., 256 Kogan, V. A., 309 Kohli, V., 188 Koidan, G. N., 299 Koizumi, T., 113 Kok, D. M.,266 Kok-Hettinga, A. M. G., 266

Kolbina, V. E., 110 Kolesnik, N. P., 44 Kolich, C. H., 261 Kolkmann, F., 275, 276 Kolodka, T. V., 43,298 Kolodyazhnyi, 0. I., 30, 31, 287, 297, 312

Author Index

324 Kolodyazhnyi, Yu. V., 301 Kolosov, M. N., 183 Kolosova, N. D., 235, 306 Kolotilo, N. V., 264, 266 Kolova, E. U., 306 Komarova, L. I., 275, 277 Kometani, K., 286 Komissarov, V. D., 17 Konarska, M., 196 Kondor-Koch, C., 200 Konig, W., 247 Konijn, T. M., 168 Konishi, H., 1, 5 Konno, S., 15 Kono, T., 184 Konovalova, I. V., 56 Kontoleon, B. D., 113, 239 Konyukhov, V. N., 313 Kormachev, V. V., 110 Kornuta, P. P., 246,262,266, 272, 299, 300 Korolev, B. A., 292 Koroleva, T. L., 124 Koroteev, M. P., 80 Korshak, V. V., 265, 270, 274, 275, 277 Korte, S., 29, 97, 304 Koschatzky, K. H., 248 Kossa, W. C., 280 Kostenko, V. M., 292 Koster, J., 230 Koster, W. H., 108 Kostin, V. G., 7 Kostyanovski; R. G., 26: 309 Kosydar, K. M., 272 Koszuk, J., 68 Kotani, N., 277 Koueger, C., 292 Kourilsky, R., 179 Koval’chuk, E. P., 124 Koyama, T., 152 Kozachenko, A. G., 301 Kozarich, J. W., 209 Kozhushko, B. N., 116 Koziara, A., 128 Kozlov, E. S., 37, 302, 312 Kozminski, S. J., 278 Kozulin, A. T., 302 Kraemer, R., 11, 103,288 Kraevskii, A. A., 191 Krasil’nikova, E. A., 10, 60 Krasnomolova, L. P., 291 Kratzer, R. H., 262, 273 Krauspe, R., 198 Krawczyk, H., 68 Krayevsky, A., 180 Krebs, B., 19, 305, 306 Krech, F., 7, 296 Krenitsky, T., 179 Kresheck, G. C., 289 Kricheldorf, H. R., 2 Krick, T. P., 175 Kriechbaum, G. W., 31

Krief, A., 229 Krishnaiah, M., 282 Krishnamurthy, S. S., 262, 263, 264, 265, 266, 267, 271,272,282,294, 312 Krishnamurthy, V. V., 222 Krish Tal, V. S., 292, 296 Krohn, K., 256 Kroschwitz, H., 266 Kross, J., 208 Kroto, H. W., 29, 31, 299, 302,304 Krudy, G. A., 138, 140, 307 Krueger, C., 219 Krug, M., 195 Kruger, M., 255 Kruglik, L. I., 113 Kruk, C., 264 Krylova, A. I., 15 Krynina, T. K., 313 Kryuchkov, A. A., 123, 301 Kubota, K., 273 Kubota, T., 12, 43 Kuc‘an, I., 205 Kuchen, W., 2, 86, 310, 311 Kudo, T., 277 Kudrya, T. N., 104 Kudryavtsev, A. A., 299 Kudryavtseva, T. N., 89 Kudryavtseva, L. A., 309,312 Kudyakov, N. M., 308 Kuhne, H. M., 2, 295 Kuhne, U., 7,296 Kuhe, U., 224 Kuhn, E. S., 169 Kuipers, G., 263 Kuivala, H. G., 19 Kujath, E., 22, 303 Kukhar, V. P., 30, 262, 287, 300 Kukhtin, V. A., 110 Kumagai, I., 206 Kumar, A., 230 Kumar, K., 232 Kumarev, V. P., 160 Kumazawa, K., 314 Kume, A., 187 Kunz, H., 17,26 Kunz, W., 20 Kunze, H., 287 Kunze, U., 23,230,297, 306 Kuo, D. J., 150 Kupper, R. J., 16, 42 Kupprat, G., 295 Kuprijanova, E. A., 189 Kurguzova, A. M., 312 Kurogi, K., 120 Kurz, J., 255 Kusano, T., 208 Kdsmierek, J. T., 202, 203 Kutateladze, T., 180 Kuttan, R., 158 Kutter, J., 2, 86 Kutyrev, A. A., 118

Kutyrev, G. A., 118,126,134 Kuz’menko, L. S., 262, 264 Kuzmich, S., 187 Kuznetsov, E. V., 6 Kuznetsova, G. A., 310 Kuznetsova, S. S., 263 Kwiatkowski, M., 185, 193 Kwon, B. M., 310 Kyashenko, G. S., 110 Kyba, E. P., 20, 132, 238 Kyker, G. S., 277 Kyogoku, Y.,210 Kypa, E. P., 293 KyuntseI’, I. A., 302 Laane, J., 300 Labarre, J. F., 263, 272, 273, 282,307 L‘abbe, G., 234 Labuschagne, A. J. H., 221, 226 Lacoste, A. M., 152 Lagueux, M., 156,166 Lahana, R., 263, 307 Laidlaw, W. G., 261 Lakenbrink, M., 95 Laliberte, B. L., 278 Lallemand, J.-Y., 213 Lam, B. L., 24 Lamande, L., 313 Lambed, P. H., 227 Lamberts, H. B., 272 Lambeth, P. F., 245 Lamden, L. A., 152 Landau, M. A., 309 Landon, S. J., 103 Landvatter, E. F., 19, 65 Lane, M. J., 207 Langrick, C. R., 2 Lansinger, J. M., 257 Lanzen, A. F., 295 Lapidot, Y., 193 Lapin, I. A., 301 Lappert, M. F., 299, 304 Larchenko, V. E., 298 Large, G. B., 23 Larina, N. I., 277 Larsen, M. A., 193 Larsen, R. O., 224 Lashmet, P. R., 178 Latscha, H. P., 86 Lattes, A., 20 Lattman, M., 51 Lau, K. W., 13 Laub, O., 215 Laubach, B., 30,287, 292 Lauquin, G. J.-M., 179 Laurian, L. G., 306 Laval, J.-P., 20 Lavallk, P., 95 Lavielle, G., 296 Lavin, K. D., 20,279 Lavrent’ev, A. N., 294 Lavrik, 0. I., 198

325

Author Index Lavygin, I. A., 314 Lawesson, S. O., 132 Lawson, H. F., 9, 61, 69 Lazareva, G. A., 131, 312 Laznicka, J., 130 Lazzeretti, P., 297 Le, P. H., 259 Leach, C. A,, 186 Leavitt, A. L., 313 Lebedev, A. V., 198, 213 Lebedev, V. B., 134 Lebedeva, N. Yu., 21 Le Bigot, Y., 225 Leblanc, Y., 95 Lechner-Knoblauch, U., 298 Lecocq, J. P., 188 Le Coq, A., 226 Led, J., 298 Lee, C., 193 Lee, K.-J., 22, 233 Lee, P. C., 181 Lee, T.-J., 237 Lee, W., 277 Leeper, F. J., 148 Legrand, P., 271 Lehmann, H. A., 266 Lehousse, C., 32, 97 Lehr, W., 298 Leitan, 0. U., 314 Leitz, M., 299 Lejczak, B., 152, 314 Lelieveld, P., 272 Lemire, A., 295 Lengyel, P., 199 Leonard, N. J., 146, 179 Leonard, R., 26 Lependina, 0. L., 277 Leroux, Y., 35, 307 Lesiak, K., 193 Letham, D. S., 215 Letin, A. S., 273 Letoublon, R., 314 Letsinger, R. L., 19, 186 Levin, M. L., 270, 273 Levin, Ya. A., 48, 81, 298 Levy, G., 273 Levy, G. C., 215 Levy, H. M., 175 Lewis, C. A., 208 Lewis, E. S., 79 Lewis, J. J., 24 Lewis, R. J., 193 Leyh, T. S., 177 L'Haridon, P., 35, 307 Li, B.-L., 2, 85 Li, G., 289 Li, M., 259 Licandro, E., 233 Licht, E., 262 Lieberknecht, A., 114 Lienert, J., 26, 235 Lietz, M., 23 Lin, G., 305 Lindner, E., 2,11,17,288,304

Lingley, D. J., 263 Linke, S., 255 Linssen, P., 314 Liober, B.-G., 300 Liorancaite, L., 160 Lippard, S. J., 213 Litinas, K. E., 256 Little, D. A., 225 Little, T. S., 257 Litvinov, I. A., 34, 304, 306, 307

Liu, L-T., 41, 42, 51, 84, 89, 295

Liu, R. S. H., 242, 244 Liu, T.-Y., 151 Liu, V., 265 Lloyd, D., 221 LO, K.-M, 195, 205 Lobanov, 0. P., 116 Lochmann, R., 290 Lofgren, C. S., 250 Loginova, G. M., 81,298 Logunov, A. P., 291, 310 Loktionova, R. A., 303 Lomakin, A. I., 189 Londei, P., 207 Longo, T. F., 278 Lopata, A,, 3 13 Lopusinski, A., 125 Lora, S., 278 Losovoi, Yu. A., 3 11 Lourens, R., 31 Lovel, C. G., 12. 95 Lowe, G., 147,174,175 Lowe, P. N., 148, 200 Lowmaster, N. E., 255 Lu, C. T., 307 Lucas, K. R., 278 Ludmann-Salanky, L., 273 Ludwig, J., 169 Luck, A., 207 Lucken, U., 179 Luetkecosmann, P., 293 Luger, P., 306 Lukashev, N. V., 84 Lumbard, K. W., 252 Luoma, G. A., 215 Luppold, E., 19 Luthardt, H., 290 Lutsenko, I. F., 84, 89, 103, 289

Lutskaya, N. V., 110 Luu, B., 156,166 Luzikov, Y. N., 235, 306 Lygin, A. V., 126 Lysek, M., 28,99 Lysenko, V. P., 303 Lyubman, Ts. A., 49 Lyuts, A. E., 310 Maartmann, K., 306 Maas, G., 297 McAuliffe, C. A., 9,289 McBride, L. J., 92, 185

Maccioni, R. B., 199 McClard, R. W., 242 McClaugherty, H., 93, 190 McClelland, B. W., 37 McClelland, R. A., 38 McCloskey, J. A., 204 McConnachie, G. D. G., 299 McCormack, J. J., 273 MacCoss, M., 150 McCray, J. A., 178 McDaniel, W.C., 227 MacDiarmid, J. E., 61 Macdonald, W. A., 221 McDougal, P. J., 242 McDougall, J., 206 McEwen, W. E., 13, 26, 223 McFarlane, H. C. E., 5,294 McFarlane, W., 4, 5, 60,294 McGall, G., 38 Mack, K., 198 McKay, J. A., 273 McKenna, C. E., 313 McKittrick, B. A., 259 McLaughlin, L. W., 195 MacLennan, D. H., 198 McManus, N. T., 44 McMorris, T. C., 259 Macomber, R. S., 138, 140, 307

McPartlin, M., 20 MBrkl, G., 6, 19, 33, 34, 63, 67,82, 302

Magaha, H. S., 227 Magdeeva, R. K., 81 Magge, C., 293 Mahler, H. F., 310 Mahran, M. R., 49 Mai, I. I., 308 Maidanovich, N. K., 116 Maier, J. P.,304 Maier, L., 20, 104, 156 Mainka, L., 199 Maiorana, S., 233 Maiorova, E. D., 22 Majid, S., 27, 287 Majoral, J.-P., 11, 20,27, 30, 33, 98, 103, 287, 288, 304

Makovetskii, Yu. P., 303 Malaiyandi, M., 291 Malakhova, I. G., 311 Male, R., 206 Malisch, W., 236 Mamaev, V. M., 309 Manabe, S., 123 Manai, M., 314 Mandal, S. B., 150, 191 Manfart, M., 273 Mann, J., 242 Manna, S., 245 Manninen, P. A., 311 Manning, G. D., 274 Manning, R. G., 24 Manohar, H., 282 Manoharan, P. T., 271

Author Index

326 Manriquez, V., 6 Manson, W., 144 Marat, K., 295 Marcelis, A. T. M., 213 March, L. A,, 21, 306 Marchenko, A. P., 299 Marchetti, M., 5 Marconi, W., 267 Marecek, J. F., 106, 121, 123, 150, 151, 169, 170, 175, 191 Marinetti, A., 32 Markham, A. F., 216 Markham, G. D., 159 Marko, L., 8 Markovskii, L. N., 30, 32, 44,95, 262, 266, 287, 290, 292, 299 Marky, L. A., 187 Maron, A., 40, 102 Marquetant, R., 176 Marquez, V. E., 147 Marre, M. R., 32, 98, 289, 292, 296 Marschall, H., 237 Marsh, L. A,, 58 Marsh, Y.U., 193 Mnrshall, A. G., 215 Martensen, T. M., 144 Martholar, O., 304 Martin, D. W., jun., 199 Martin, J. C., 36 Martinez, F., 275 Martinez, R. A., 151 Marugg, J. E., 190 Maruta, M., 113 Maryanoff, B. E., 223 Marzilli, L. G., 215 Mashima, M., 216 Mashlyakovskii, L. N., 292 Masker, W. E., 203 Maslennikov, I. G., 294 Maslennikova, V. I., 81 Massey, V., 147 Masterlerz, P., 152 Mastryukova, T. A., 305 Masuda, S., 261 Masui, M., 23 Matevosyan, G. L., 127 Mathey, F., 9, 32, 33, 77, 287, 304 Mathis, F., 288 Mathis, R., 92, 103, 288, 301 Matrosov, E. I., 301 Matsuda, T., 20 Matsugi, J., 191, 202 Matsumura, K., 262, 265, 266 Matsushita, T., 28, 150 Matsuura, H., 299 Matsuura, T., 205 Matsuzaki, J., 187 Matthes, D., 34, 63 Matthes, H. W. D., 188

Matton, R. W., 278 Matzura, C., 89 Maudsley, A. A., 286 May, F. L., 306 May, H. E., 144 Mayer, H., 295 Mayer, P., 55 Mazenod, F. P., 84, 145 Mazhar-al-Haque, 304, 306 Mead, D., 244 Meanwell, N. A.. 78 Medveder, 0. S., 9 Meek, D. W., 5 Meeuwissen, H. J., 9, 306 Megera, I. V., 20, 22 Mehdi, S., 153, 292 Mehrotra, R. C., 23 Mehrotra, S. K., 28, 99, 288 Mehta, R. A., 220, 309 Meier, G. P., 45, 222, 290 Meiramov, M. G., 2 Mel’nikov, N. N., 104, 118, 129 Meriem, A., 30, 33, 98 Meriwether, H. T., 117 Merkel, R., 23, 230, 306 Mertel, H. E., 117 Mesch, K. A., 66, 296 Metzler, D. E., 148 Meyerson, S., 169 Michaelis, K., 248 Michalik, M., 267 Michalski, J., 45, 89, 105, 125,290 Michejda, C. J., 16, 42 Michel, S. J., 106, 152 Michels, W., 163 Michelson, A. M., 195 Michelson, S., 198 Mick, R. G., 286 Mickel, S. J., 80 Middleton, D. L., 18 Mihart, C., 271 Mikamori, Y.,261 Mikaya, A. I., 309 Mikhailov, S. N., 157, 167 Mikhailov, Y. B., 91, 294 Mikitoev., A. K., 277 Mikolajazyk, M., 108, 133, 307 Mikroyannidis, J. A., 83. 106,313 Milbrath, D. S., 294 Miles, H. T., 195 Milewski, M. B., 286 Milewski-Mahrla, B., 5, 22, 219, 220, 305 Miller, A., 307 Miller, D. W., 181 Miller, J. P., 167, 168 Miller, P. S., 192 Millican, T. A., 189 Mills, L. S.,246 Milner, N. P., 314

Milner-White, E. J., 178 Minahan, D. M. A., 9, 289 Minami, T., 113, 229, 239 Minkin, V. I., 288 Minas’yants, I. I., 277 Minowa, N., 117 Minto, F., 278 Minyaev, R. M., 288 Mirabelli, M. G. L., 282 Mironova, T. A., 294 Mirskova, A. N., 110 Misiura, K., 302 Misiura, M., 110 Mitchell, G. N., 19 Mitra, S., 203 Mitrasov, Yu. N.. 110 Mitropol’skaya, G. I., 274 Mitropol’skaya, S. S., 265 Mitschler, A., 33, 304 Mitsuhashi, K., 53 Miura, K., 207 Miwa, H., 253 Miyake, T., 191 Miyakoshi, T., 14 Miyamoto, I., 256 Miyasaka, H., 23 Miyazawa, T., 292 Mizrahi, V., 307, 310 Miuakh, L. I., 15 Mkrtchyan, G. A., 25 Mochel, V. D., 278 Mochida, K., 122 Mochizuki, T., 245 Mock, G. A., 189 Modro, T. A., 130, 307, 310 Moerat, A., 130 Moggi, G., 23, 306 Mohri, A., 50 Mokeeva, V. A,, 302 Molbach, A., 234 Molinari, H., 133 Molko, D., 182, 183 Moll, M., 287 Mollin, J., 130 Molostov, V. I., 301 Monkiewicz, J., 226 Mora-Uzeta, C., 66, 306 Morelli, G., 5 Moresca, A., 78 Morganti, G., 4, 25, 221 Mori, H., 159 Morin, C., 161 Morita, Y., 261 Moriyama, M., 9, 60 Muruder, F., 112 Morozov, V. I., 48, 81, 298 Morse, J. G., 3 Morton, D. W., 80 Mosbach, K., 195 Moschidis, M. C., 314 Motoc, I., 300 Motoki, S., 132 Movshovich, D. Ya., 309 Mracec, M., 271,

Author Index Mronga, N., 306 Muegge, C., 294 Mueller, R. A., 22 Mueller, U., 306 Miilsch, A., 174 Muftah, M. A., 65 Mujica, C., 6 Mukai, K., 119 Mukerjee, D., 20 Mukmenev, E. T., 307 Mulder, N. H., 272,273 Mulhiez, M., 290 Mulzer, J., 224,229 Mundt, O., 29, 287, 304 Muniz, A., 290 Munoz, A., 36,290,308,313 Munson, K. B., 199 Muralidharan, K. V., 307 Murata, H., 299 Murdasov-Murda, B. D., 6 Murray, L., 97 Murray, S. G., 1 Murthy, A. R. V., 294, 312 Murthy, P. P. N., 150 Murthy, R. A,, 9 Muse, D. D., 196 Musin, R. Z., 12, 110 Musyakaeva, R. Kh., 301 Mysina, S. D., 198 Nadeau, J. G., 191 Nagy-Magos, 2, 8 Naigibi, M., 55 Nair, C. P. R., 275 Naka, T., 202 Nakagawa, K., 109, 155 Nakahara, J. H., 273 Nakai, S., 23 Nakamura, Y.,297 Nakanishi, K., 243 Nakana, M., 82 Nakashima, J. T., 65, 297 Nakatani, K., 5 Nakayama, C., 180 Namie, M. W., 27 Narang, S. A., 181 Narang, S. C., 17, 59 Nardi, N., 6 Nardi, T. J., 190 Nardin, R., 290 Narukawa, Y.,47 Nasca, S., 273 Nasibov, Sh. S., 26 Nassimbeni, L. R., 307 Nast, R., 2 Natsias, K., 243 Naumova, L. V., 134, 309 Navech, J., 11, 20, 30, 33,98, 103, 104,288, 304

Nazar, R. N., 206 Neda, I., 300, 301 Nee, G., 127 Neenan, T. X.,279,280 Negishi, K., 207

327 Negrebetskii, V. V., 124, 129, 287,290,292,296

Neidle, S., 204 Neilson, R. H., 2, 80, 85, 88, 261, 287, 289,292

Neilson, T., 195 Neitzel, S., 292 Nesterova, L. I., 115 Neuzil, E., 141 Newman, R. A., 273 Newman, T. H., 27,99,287 Newton, C. R., 216 Newton, M. G., 307 Ng, S.-W., 23 Nicholson, P. N., 1 Nick, J., 153, 176 Nicolaides, D. N., 256 Nicolaou, K. C., 259 Niecke, E., 9, 28, 88, 97, 99, 101, 289, 293, 294, 305

Nief, F., 33, 287 Nielsen, P., 148 Niemeyer, U., 110 Niewiarowski, W., 164 Nifant’ev, E. E., 80, 81, 123, 291, 301

Niida, T., 117 Nikanorov, V. A., 110 Nikitin, E. V., 110 Nikitina, G. S., 273 Nikonov, G. N., 12,29,65 Nimmo, J. A., 144 Nisbet, M. P., 289 Nishikawa, K., 201 Nishikawa, S., 216 Nishimoto, K., 28 Nishimura, K., 239 Nishio, T., 208 Nishiuchi, K., 261 Nishiwaki, K., 4 Nissan, R. A., 267, 282 Nixon, J. F., 31, 302, 304 Noack, R., 85 Noble, M. C., 261 Noda, L. H., 176 Noeth, H., 306 Nogami, Y.,256 Noguchi, T., 1 Noguchi, Y., 120 Nomoto, T., 183 Nona, S. N., 19 Nonnenmacher, G., 110 Nordheim, A., 204 Nordhoff, E., 255 Norman, A. D., 12, 86,298, 304

Norman, D. G., 193 Norman, N. C., 28,99 North, P. C., 246,247 Northrup, J. K., 198 Noskovh, D., 3 Nosov, B. P., 292 Novikova, Z. S., 300 Nowak, T., 146

Nowell, I. W., 21, 58, 306 Noyori, R., 162 Nuhn, P., 291 Nuretdinov, I. A., 17, 301 Nurtdinov, S. Kh., 110, 301 Nyburg, S. C., 72,307 Oakley, R. T., 261,269, 282, 284

Oberster, E. A., 278 O’Brian, C. A., 168 O’Brien, J. P., 270, 277, 282 Occhinnikov, V. V., 312 Odom, J. D., 301 Odorisio, P., 89 Oeberg, B., 193 Oehler, E., 296 Otvos, L., 194 Ofengand, J., 199, 201 Ofitserov, E. W., 49, 81 Ogata, N., 15 Ogata, Y.,261 Ogawa, E., 26 Ogawa, H., 256 Ogreid, D., 167 Ogura, K., 152 Oh, D. Y.,310 Ohashi, O., 31, 302 Ohbayashi, H., 277 Ohlman, C., 26 Ohmasa, N., 81, 111 Ohmori, H., 23 Ohmura, H., 132 Ohno, K., 31,299,302 Ohtsuka, E., 181, 182, 186, 188, 191, 202

Ohya, K., 3 14 Oida, T., 292 Ojhara, B., 248 Ojika, M., 253 Okabayashi, H., 299 Okamoto, T., 203, 204 Okamoto, Y.,82 Okamura, W. H., 75 Okano, T., 1, 5 Okazaki, H., 106 Okruszek, A., 110, 124 Olah, G. A., 17,59,222 O’Leary, M. H., 146 Olejniczak, B., 128 Olesen, S. O., 207 Olivares, R. C., 310 Olmstead, M. M., 29, 100 Olsen, A. S., 199 Omelanczuk, J., 307 Omoto, T., 256 Ondrejkovicovh, I., 17, 59 Ondrejovic, G., 17, 59 O’Neal, C. C., jun., 146 O’Neal, H. R., 2, 88 O’Neal, N., 289 Onur, G., 179 Opella, S. J., 215 Orezkaja, T. S., 189

Author Index

328 Orgel, L. E., 192 Orioli, P. E., 6 Orkin, S. H., 195 Orr, G. A., 151 Osada, Y.,276 Osei, R. D., 4 Oshevski, S. I., 195 Oshikawa, T., 5 Osipov, 0. A., 66, 300, 301, 309

Osman, F. H., 55 Osowska, K., 128 Osuka, A., 81, 111 O’Sullivan, W. J., 150 Otsuka, S., 4 Ousema, W. H., 273 Ovchinnikov, V. V.,

104,

132,312

Ovchinnikova, N. S., 3 11 Ovodova, 0. V., 300 Ozborne, N. F., 235 Ozgen, T., 309 Ozoe, Y., 108, 122, 311 Pace, S., 40, 290 Pachali, M., 264 Paciorek, K. J. L., 262, 273 Paddock, N. L., 261, 269, 282, 307

Padyukova, N. Sh., 157, 167 Paetzold, P., 97 Pahl, C., 31 Pailliez, J.-P., 181 Painter, P. C., 271 Pakulski, M., 27, 28, 45, 99, 287, 290

Palacios, F., 104 Palacios, S. M., 6 Paliichuk, Yu. A., 116 Palni, L. M. S., 215 Palomo-Coll, A., 127 Panasenko, A. A., 17 Pandl, K., 228 Panet, A., 193 Paneth, P., 124 Panijpan, B., 314 Pankiewicz, K., 110 Panosyan, G. A., 140 Pantaleo, N., 307 Papageorgiou, E., 2, 292 Paradisi, C., 13 Parakin, 0. V., 110 Pardi, A., 214 Pardini, V. L., 220, 309 Parkhomenko, Yu. M., 314 Parra, F., 145 Parratt, M. J., 113, 238 Pastor, S. P., 89 Patel, T. P., 189 Patratii, V. K., 22 Patsanovskii, I. I., 143, 301, 308,309

Patterson, D. B., 278 Patu’g, D., 266

Paulen, W., 30, 31, 293 Paulson, B., 190 Paulus, E. F., 306 Pavlov, V. Ya., 6 Payne, R. C., 314 Pearce, E. M., 277, 278 Pearson, M. J., 245 Pechine, J. M., 99 Pedersen, U., 132 Pelter, A., 218 Pena, A. J., 301 Peng, R., 310 Penne, J. S., 127 Pensionerova, C. A., 298 Penz, G., 117 Pepper, D. C., 14 Perales, A,, 284 Perchonock, C. D., 245 Perez, F., 99 Perham, R. N., 148 Perie, J. J., 156, 307 Peringer, P., 293 Perlman, M. E., 269 Perman, W. H., 286 Perri, M., 108 Perrone, E., 245 Peseekis, S. M., 257 Petasis, N. A., 259 Peters, K., 304 Peterson, B., 298 Peterson, S. M., 190 Peticolas, W. L., 216, 217 Petrenko, V. A., 197 Petridis, G., 168 Petrov, A. A., 3,50, 136, 137, 138, 140,296

Petrov, E. S., 291, 311 Petrov, K. A., 104 Petrova, J., 134 Petrova, L. N., 119 Petrovskii, P. V., 305 Petters, W., 247 Pevzner, L. M., 312 Pfeiffer, B., 123 Pfister-Guillouzo, G., 27, 100 Pfleiderer, W., 120, 182, 193 Piade, J. J., 99 Picker, D., 158 Pidcock, A., 29, 100 Pidvarko, T. I., 30, 287 Pietra, F., 4, 25, 221 Pietrasanta, F., 25 Pietro, W. J., 102, 311 Pietrusiewics, K., 68 Pietrusiewicz, K. M., 226, 296

Pietrzyk, D. J., 113, 313 Pike, D., 148, 307 Pikonov, G. N., 304 Pilichowska, S., 128 Pilkington, N. J., 44 Pinchuk, A. M., 104, 109, 299

Pintado, E., 178

Pirakitigoon, S., 38, 292 Piskala, A., 45 Pitchumani, K., 17 Pizzomo, M. T., 20 Plateau, P., 181 Platonov, A. Yu., 22 Platz, H., 248 PIBnat, F., 25 Pleshkova, A. P., 309 Pletcher, J., 148, 307 PodlahovB, J., 3 Podobedova, N. L., 15 Poh, C. H., 296 Pohl, S., 28, 99 Pokrovskaya, I. K., 141 Polezhaeva, N. A., 300, 312 Pollack, S. E., 178 Pollini, G. P., 112 Polonskaya, L. Yu., 15 Poluchina, V. L., 299 Polumbrik, 0. M., 299 Pominov, I. S., 300 Ponce, S., 275 Ponse, G., 179 Ponsold, K., 17 Pontzen, Th., 6 Pope, L. M., 210 Popov, K. I., 298 Popov, S. G., 189, 192 Porai-Koshits, M. A., 306 Porte, A. L.,272 Porter, D. J. T., 153 Potekhina, M. I., 125 Potrzebowski, M., 125 Potter, B. V. L., 165, 166 Pougeois, R., 179 Poulter, C. D., 253 Povilionis, P., 160 Povirk, L. F., 210 Povolotskii, M. I., 43, 298 Powell, J., 12 Power, P. P., 29, 100 Powis, G., 314 Pozdnyakov, P. I., 192 Praefcke, K., 307 Preiss, A., 290 Preus, M. W., 259 Preusser, S. H., 129 Pribytko, A. M., 314 Price, M. F., 127 Prince, J. B., 199 Pring, B. G., 255 Prisbe, E. J., 193 Pritula, N. A., 10 Pritzkav, H., 307 Probster, M., 8 Prodanchuk, N. G., 22 Profy, A. T., 195 Prokof‘eva, G. N., 294 Prons, V. N., 271 Proskurnina, M. V., 89 Prostov, Yu. P., 133 Pruskil, I., 11 Pryor, W. A., 299

329

Author Index Przybylski, Z., 310 Psaro, R., 23, 306 Puddephatt, R. J., 18, 303 Pudova, J. A., 119 Pudovik, A. N., 7, 8, 39, 48, 49, 56, 66, 81, 83, 90, 91, 92, 103,104,110,115, 117, 118, 126, 131, 132, 134, 140, 141, 143, 290, 292, 293, 294, 298, 301, 308, 309,312 Pudovik, M. A., 39, 90, 91, 104,290,292,294, 312 Puettmann, M., 292 Pulferd, S. M., 192 Purrello, G., 233 Puskaric, E., 276

Quader, A., 123 Quast, H., 69, 289 Quijada, J. R., 275 Quin, L. D., 9, 61, 66, 69, 296

Quinn, E. J., 273,276 Rabener, C. W., 298 Rabiller, C.,296 Rackwitz, H. R., 195 Radda, G. K., 286 Radziejewski, C., 105 Rae, A. D., 306 Raevskii, 0. A., 303 Rafikov, S. R., 49 Raginskaya, G. M., 277 Ragulin, V. V., 50,296 Rahkamaa, E., 298 Rajbhandary, U. L., 207 Rakhimov, A. I., 112 Rakowsky, T. F., 279 Ramabrahmam, P., 263,271, 282

K., 263, 264, 265, 269, 272, 294 Ramakrishna, J., 272 Ramamoorthy, V., 271 Ramamurthy, L., 282 Rambaud, M., 237,240 Ramirez, F., 106, 121, 123, 150, 151, 169, 170, 175, 191 Rampal, J. B., 69, 297 Ranganathan, T. N., 271, 282, 307 Rankin, D. W. H., 9, 30,44, 301 Rannels, S. R., 168 Rao, G. S., 271, 307 Rao, M. N. S., 261,265,284, 306 Rapoport, H., 187,214 Rappaport, S., 193 Rastetter, W. H., 18 Rasumov, A. I., 60 Rathgeber, G., 199 Ramachandran,

Ratovskii, G. V., 302 Rauchfuss, T. B., 19, 65 Rauhut, M. M., 7 Rauleder, H., 2 Rausch, M. D., 6 Rauschenbach, P., 148 Rayment, I., 282 Raynal, S., 66 Razhabov, A., 53 Razumov, A. I., 10,300,301 Razumova, N. A., 50,296 Razvi, F., 210 Razvodovskaya, L. V., 104 Reca, E., 248 Reck, R., 306 Redmond, J. W., 287 Reed, G. H., 177 Reedijk, J., 213 Rees, H. H., 314 Reese, C. B., 120, 164, 183, 193

Reeve, A. E., 180 Reich, K. A., 210 Reichenbach, N. L., 196 Reimschussel, W., 124 Reist, E. J., 167 Reitz, A. B., 223 Remizov, A. B., 309 Remy, P., 201 Rendon-Diazmiron, L. E., 138,307

Renzulli, L. A., 113, 239 Respondek, J., 22, 218 Retta, N., 3 Rettig, S. J., 269, 282, 307 Retuert, J., 275 Reuschenbach, G., 6 Reutel, E., 7 Reutov, 0.A., 110 Revankar, G. R., 166 Revel, M., 30 Reverdatto, S. V., 189 Rezvova, T. V., 309 Rezvukhin, A. I., 282 Rich, A., 204,207 Richardson, J., 19 Richardson, J. F., 261, 284, 306

Richter, H., 87, 307, 309 Richter, W. J., 2,288 Riding, G. H., 265 Ridley, D. D., 33, 63, 112 Riedel, N., 200 Riehl, N., 201 Riess, J. G., 40, 290 Rietrusiewicz, K. M., 66 Riffel, H., 268, 307 Rijkmans, B. P., 130 Rill, R. L., 215 Rines, S. P., 20, 293 Ritchie, R. J., 276, 282 Rivkin, M. I., 160 Robert, J. B., 289, 294 Roberts, B. P., 299

Roberts, R. M. G., 20 Robey, F. A., 151 Robien, W., 296 Robins, M. J., 161 Robins, P., 253 Robins, R. K., 158, 166, 196 Robinson-Steiner, A. M., 168

Rocca, J. R., 250 Roczniak, S. D., 168 Rodenhuis, S., 273 Rodewald, G., 5 Rodgers, W. R., 273 Rodionov, I. L., 103 Rodney, K., 87 Rodriguez, L. O., 211 Roeschenthaler, G. V., 313 Roesky, H. W., 19, 56, 87, 282

Rossler, M., 30 Rogers, R. D., 6 Rokach,, J., 245,247 Rokhlin, E. M., 218 Rolando, C., 123 Romakhin, A. S., 110 Romanenko, E. A., 272,298, 300

Romanenko, V. D., 30, 32, 95, 287, 292

Romanenko, V. P., 183 Romaniuk, E., 195 Romaniuk, P. J., 165, 195 Romanov, G. V., 7, 8, 66, 110, 293, 308

Romanova, I. P., 12, 297, 308

Romby, P., 206 Ronald, R. C., 226, 257 Roques, R., 36, 263, 282, 307, 308

Rose, H., 269 Rose, 1. A., 154 Rosenberg, I., 159, 170, 171 Rosenberger, M., 292 Rosendahl, M. S., 179 Rosenthal, A., 189, 215 Rosenthal. L. P., 199 Rosinov, V. G., 298 Roskoski, R., jun., 179 Ross, R. J., 150 Rossi, E., 297 Rossi, J. J., 194 Rossi, R. A., 6 Rossomando, E. F., 159,212 Rotard, W., 250 Roth, K., 231, 248 Roundhill, D. M., 102 Roush, W. R., 257,259 Rozanel’skaya, N. A., 287 Rozanov, I. A., 309 Rozenberg, V. I., 110 Rozhkova, N. K., 283 Rozhkova, Z. Z., 44 Rozinov, V. G., 110

Author Index

330 Roztikova, Z. Z., 104 Rozzell, J. D., 121 Ruban, A. V., 30, 32, 95, 292 Rudomino, M. V., 306 Ruger, C., 85 Rueger, H. J., 291 Ruger, R., 9, 28, 88, 97, 99, 101, 293, 305 Ruostesuo, P., 66, 301 Ruppert, I., 292 Rusch, J., 262 Russkamp, P., 25, 228 Ruth, J. L., 180 Ryan, B., 14 Rybina, M. N., 291 Rybkina, V. V., 110 Rychlik, I., 178 Rycroft, D. S., 87, 97, 178, 294 Ryl’tsev, E. V., 300, 301 Ryu, E. K., 150 Saalfrank, R. W., 228 Sadakari, N., 256 Sadanani, N. D., 88 Sadeh, U., 262 Sadikot, H., 213 Sadykov, R. A., 17 Saegusa, T., 9, 47 Sanger, H. L., 196 Saffhill, R., 203 Safonova, T. S., 272 Shgi, J., 194 Saha, N., 212 Sahlberg, C., 123 Sahu, U. S., 13 Sainsbury, M., 237 Saito, I., 205 Saito, S., 14 Saitou, J., 78 Sakairi, N., 187 Sakhibullina, V. G., 312 Sakulin, G. S., 133 Sakurai, H., 82, 213 Salakhutdinov, K. A,, 289 Salam, M. A., 161 Salamone, S. J., 150, 153 Salminen, U., 66, 301 Samitov, Yu. Yu., 34, 297 Sammons, R. D., 173, 177 Samsel, E. G., 18 Sanchez, M., 32, 98, 103, 289, 296, 301 Sander, J., 68 Sanders, M. M., 199 Sandifer, R. M., 253 Sanduja, R., 104 Sandyurev, M. V., 138 Saneyoshi, M., 180 Sangokoya, S. A,, 60, 66, 294, 306 Santi, D. V., 161 Santiago, A. N., 6

Santini, C. C., 9, 77 Sanui, K., 15 Sarau, H. M.,245 Sartori, P., 11 Sasaki, Y., 151, 314 Sass, V. P., 271 Satgt, J., 27, 28, 32, 100, 287 Sato, N. L., 212 Sato, S., 241 Sato, T., 109, 155 Sato, Y., 273 Satyamurthy, N., 69, 297 Sau, A. C., 36, 264 Sauerwald, R., 188 Saunders, J., 253 Saunders, P. P., 158 Sauveur, F., 117, 156 Savel’eva, N. I., 131, 312 Savignac, P., 117, 156 Savolahti, P., 3 11 Sawai, H., 192, 193 Sax, M., 148, 307 Sayadyan, S . V., 7 Saykowski, F., 296 Scaf, A. H. J., 273 Scahill, T. A., 306 Scalone, M., 5 Scanlon, L. G., 5 Scarpa, A., 178 Schabacher, U., 114 Schade, G., 227 Schafer, G., 179 Schlfer, H., 100 Schafer, H. J., 199 Schafer, K. P., 197 Schaefer, T., 295 Schaeffer, A,, 306 Schafer, H. G., 294 Schattekerk, C.. 120 Schatzlein, P., 228 Schaub, B., 22,218,223 Schemer, G., 110 Schemer, K., 2,295 Scheider, K. H., 289 Scheinmann, F., 245 Scheit, K. H., 195 Scherer, 0. J., 292, 304 Scheuer, P. J., 259 Schiavon, G., 13 Schick, H., 20 Schiebel, H. M., 37 Schiemenz, G. P., 2,292 Schier, A., 296 Schierling, P., 228 Schilling, G., 298 Schipper, P., 35, 299 Schlimme, E., 163, 179 Schloss, J. V., 212 Schlosser, M., 22, 45, 218, 222,223 Schmid, G., 229 Schmidbaur, M. S., 22, 26, 219, 220, 234, 268, 294, 296, 298, 305, 309

Schmidpeter, A., 33, 34, 37, 5 5 , 98, 268, 282, 308 Schmidt, E., 273,274 Schmidt, G., 273, 274 Schmidt, H., 30,99,287 Schmidt, P., 7 Schmidt, Th., 9 Schmidt, U., 114 Schmutzler, R., 37, 55 Schnatterer, S., 234 Schneider, D. F., 221, 226 Schneider, I., 248 Schneider, N. S., 278 Schneider, P., 131 Schneider, S., 15 Schnering, H. G., 304 Schnockel, H., 95 Schoeller, W., 28, 99 Schomburg, D., 37 Schonauer, K., 229 Schow, S. R., 60 Schraffordt Koops, H., 273 Schrenk, E., 308 Schroeter, D., 266 Schroth, G., 234 Schrott, W., 131 Schryver, B. B., 193 Schubert, U., 11, 236, 296 Schulten, H. R., 310 Schultz, P. G., 208 Schumacher, C., 306 Schumann, C., 117 Schumann, H., 5 Schuster, S. M., 177 Schwalke, M. A., 265 Schwartz, I., 201 Schwarz, G., 273 Schwarz, S., 20 Schweizer, E. E., 22,233 Schweizer, W. B., 66, 306 Schwetlick, K., 85 Scopelianos, A. G., 265,270, 277, 306 Scott, K. N., 286 Scovell, W. M., 213 Sebesta, K., 171 Secrist, J. A., 111, 146 Seeds, N. W., 199 Seela, F., 194 Seff, K., 138, 307 Segall, Y.,36, 127 Seger, M., 262 Sehgal, R. K., 180 Seifert, G., 271 Seidl, E., 33, 302 Seitanidi, K. L., 293 Seki, H., 170 Sekine, M.,84, 107, 145, 159, 186, 187 Sekine, T., 78, Sekioka, M., 120 Sekizuka, M., 273 Selman, B. R., 198 Sen, R., 243

331

Author Index Sendyurev, M. V., 3 Senter, P. D., 174 Serafinowska, H. T., 120, 164,193 Sergienko, L. M., 302 Sethi, S. K., 204 Seyer, A., 289 Seyferth, D., 11, 22 Shabanzadeh, B., 2 Shabarova, Z. A,, 189, 193 Shafikov, N. Ya., 17 Shagidullin, R. R., 143, 301, 308 Shakirov, I. Kh., 301 Shao, M., 218, 305 Shaper, W., 232 Sharafieva, E. S., 10, 60 Sharifullin, A. Sh., 6 Sharma, 0. K., 194 Sharma, R. D., 269,282,307 Sharma, R. P., 17 Shatenshtein, A. I., 291, 311 Shatkin, A. J., 180, 181, 196 Shaw, B. L., 2,20 Shaw, J. C., 265 Shaw, R. A., 260, 263, 264, 266, 267, 272, 282, 294, 3 12 Shcherbaeva, M. M., 294 Shearer, H. M. M., 282 Sheldrick, B., 282 Sheldrick, G. M., 4, 305 Sheldrick, W. S., 34, 55, 308 Sheluchenko, 0. D., 124 Shen, F.,305 Shen, P., 313 Shen, Y., 310 Shengeliya, K. Ya., 311 Shepherd, T. M., 221 Shereshovets, V. V., 17 Sherman, W. R., 313 Shermergorn, I. M., 48, 81, 298, 311 Shermolovich, Yu. G., 44 Shestakova, T. G., 89 Shevchenko, I. V., 30 Shevchuk, M. I., 22 Sheves, M., 243 Shibayana, K., 27, 28, 29, 99, 102, 287, 304 Shida, T., 166,210 Shih, N., 153, 176 Shihada, A. F., 306 Shikhallev, Sh. M., 26 Shima, E., 287 Shima, I., 27, 29, 60, 102 Shimoji, K., 253 Shimomura, S., 149, 213 Shishido, K., 208 Shizuri, Y., 253 Shklover, V. E., 15, 306 Shkol'nikova, L. M., 306 Shokol, V. A., 116 Skiriver, J. W., 156

Shtepanek, A. S., 109 Shubina, J. N., 192 Shudo, K., 203 Shudo, T., 204 Shukla, K. K., 17 Shumakova, N. B., 274 Shurubura, A. K., 300 Shvets, A. A,, 66, 300 Sibolev, A. N., 306 Sicka, R. W., 274 Sidky, M. M., 49, 307 Sidorchuk, I. I., 20, 22 Sierakowski, A. F., 33, 63, 112 Sievers, R., 30 Sigel, H., 212 Sigman, D. S., 210 Sih, J. C., 252 Silberklang, M., 207 Silver, J., 20 Silver, M. S., 203 Simalty, M., 33, 287 Simon, H. E., 286 Simon Z., 271 Simoncsits, A., 205 Simoni, D., 112 Simons, G., 2 Sinclair, D. P., 275 Singaram, B., 218 Singer, B., 202, 203 Singh, M., 188, 213 Singler, R. E., 274, 278 Sinha, N. D., 94, 191 Sinitsa, A. D., 140, 290, 292, 296 Sinitsyna, N. I., 289 Sinyakov, A. N., 189 Sinyashin, 0.G., 49, 81 Sinyashina, T. N., 49, 81 Sirks, G., 9, 306 Sisler, H. H., 26 Sivolobova, G. F., 192 Sivriev, H., 26 Skorokhodov, 1. I., 314 Skowronska, A., 45, 290 Skrzypczykki, Z., 89, 105 Sleijfer, D. Th., 273 Smigel, M. D., 198 Smirnov, R. P., 263 Smirnova, E. I., 291 Smirnova, N. B., 274 Smit, C. N., 28, 99 Smith, A. B., 111,60 Smith, D. J., 67, 124, 309 Smith, D. J. H., 111, 240 Smith, G., 179, 212 Smith, H. W., 307 Smith, J. D., 3 Smith, J. G., 113,239 Smith, L. T., 146 Smith, M., 192 Smith, R. A., 18, 85, 156 Smith, R. L., 237 Smith, R. T., 9

Smith, S. J., 12 Smith, W. S., 23 Smithers, G. W., 150 Smolii, 0. B., 22 Smrt, J., 186 Snyder, D. L.,275 So, K. K., 43 Sobolev, A. N., 235 Socol, S. M., 19 Soeda, Y., 5 Soll, D., 181,202 Soifer, D., 198 Soifer, G. B., 302 Sokolov, M. P., 300 Sokoi'skaya, I. B., 278 Solomatina, A. I., 270 Solouki, B., 31, 303 Songstad, I., 306 Sorokina, S. F.,291 Sournies, F., 263, 273, 282, 307 Sowerby, D. B., 269, 271, 282 Spangler, C. W., 225 Spassky, A., 206 Spek, A. L., 9,306 Spenser, I. D., 148 Spero, D. M., 18 Spivack, J. D., 89 Springer, J. P., 294 Sproat, B. S., 174, 188 Spur, B., 247 Sridharan, K. R., 272 Srinivasan, C., 17 Srivastava, G., 23 Srivastava, P. C., 158, 196 Stallcup, L. D., 180 Stam, C. H., 9, 306 Stan, H. J., 311 Stappen, P. V., 234 Staub, A., 188 Stauchkov, Yu. T., 304 Stec, W. J., 110, 124, 164, 168, 302 Stegmann, H. B., 2,295 Steinhuebel, L., 89 Steinkamp, H., 16 Steinwand, M., 11, 288, 304 Stempfle, W., 234 Stepanov, B. I., 9, 287, 292 Stepanova, T. Ya., 7, 8, 66, 293, 308 Stephenson, T. A., 102 Stevenson, R., 259 Stewart, C. A., 9, 28, 30, 31, 99, 287 Stezowski, J. J., 308 Still, W. C., 17 Stobart, S. R., 4 Stoodley, R. J., 230, 245 Storzer, W., 313 Stoyanov, N. M., 137 Strelkova, E. N., 143, 301, 308, 309

Author Index

332 Strepikheev, Yu. A., 114 Stroh, E. G., 275 Struchkov, Yu. T., 2, 15, 34, 65, 305, 306, 307

Strzalko, T. B., 127 Stuart, A. L., 31 Stubbe, J., 178, 209 Stults, B. R., 306 Stumpe, A., 189 Sturm, B., 183 Sturm, P. A., 167 Su, C. N., 302 Subramanian, A. R., 206 Suchomel, H., 6 Sudakhara Babu, Y., 282 Suetake, M., 183 Suffolk, R. J., 31 Suganuma, H., 239 Sugawara, K., 273 Sugina, T., 273 Sugiyama, H., 205 Suhadolnik, R. J., 193, 196 Suhateanu, T., 273 Sukhorukov, Yu. I., 123,141 Sukhorukova, N. A., 141 Sukhova, L. M., 273 Sulkowski, W., 265, 277 Sullivan, C. E., 26 Summons, R. E., 215 Sun, I. Y. C., 198 Sundaram, P. M., 88, 262, 264

Sundquist, W. I., 190 Sung, M. T., 93, 190 Sung, W. L., 188 Suss, J., 248 Sussman, J., 296 Suszka, P. R., 266, 269 Suva, R. H., 167, 168 Suwa, K., 4 S u e , M., 261 Suzuki, D., 262 Suzuki, H., 81, 111 Suzuki, M., 9, 261 Suzuki, N., 5, 60 Svara, J., 308 Swepston, P. N., 261, 282 Sykes, B. D., 144, 156, 214 Symons, M. C. R., 299 Szabo, L., 150 Szabolcs, A., 194 Szamosi, J., 170 Szemzo, A., 194 Szewczyk, J., 152, 314 Szmuszkovicz, J., 306 Taber, A. M., 81 Tabushi, I., 169 Tachibana, S., 183 Taddei, F., 297 Taira, K., 122 Takagi, M., 149 Takaharu, E., 15 Takaku, H., 183,184

Takashima, H., 188, 191 Takashima, K., 241 Takatsuka, Y., 166 Takeda, S., 272 Takenaka, S., 113, 229 Takeuchi, Y., 166 Tamagaki, S., 67 Tamaru, Y.,119 T a m , C., 186 Tamura, C., 241 Tanaka, H., 15, 132 Tanaka, K., 53, 169 Tanaka, N., 113 Tanaka, T., 19,43, 186 Tanchoco, M. L., 147 Tang, C., 307 Tang, K.-C., 178 Tang, Y., 218, 305 Tani, K., 4 Taniguchi, Y., 256 Tanokura, M., 286 Tansley, G., 147, 174 Tantasheva, F. R., 299 Tarasevich, A. S., 307 Tarasova, R. I., 301 Tarassoli, A., 12, 86, 304 Tarchini, C., 45 Taresova, R. I., 289 Tashma, Z., 83, 116,303,311 Tata, T., 107 Tate, D. P., 274, 278 Tautz, H., 55 Tawata, S., 106 Taylor, B. F., 21 Taylor, B. H., 199 Taylor, J. G., 9, 289 Taylor, J. S., 208 Taylor, M. W., 295 Tazawa, I., 166, 181 Tchen, P., 179 Tebbe, K. F., 305 Tebby, J. C., 22, 58, 296 Teitel’baum, A. B., 312 Tel’natanov, Yu. I., 309 Teoule, R., 182, 183 Terekhova, M. I., 291,311 Terent’eva, S. A., 39, 91,290 Texier-Boullet, F., 83, 112 Thamm, R., 11,288 Tharp, G. A,, 227 Thomas, A. J., 255 Thomas, B., 271,295 Thomas, G. A., 216, 217 Thomas, M., 19 Thompson, A. S., 60 Thompson, M. D., 253 Thomson, C., 311 Thorne, A. J., 304 Thorsen, M., 132 Thuong, N. T., 162 Thurlow, D. L., 199 Tichit, M., 197 Tich9, P., 197 Tickner, A. M., 237

Tiedge, H., 179 Tigani, M. C., 168 Tikhonina, N. A., 128, 292 Tilichenko, M. N., 7 Timokhin, B. V., 110, 290, 302

Timosheva, A. P., 66, 308 Tipney, D. C., 253 Titmas, R. C., 188, 189 Toch, P. L., 269 Todesco, P. E., 13 Toepelmann, W., 266 Torok, I., 205 Toh, H. T., 75 Tohyama, J., 180 Tolkunov, S. V., 20 Tollefson, N. M., 20, 270, 279, 306

Tolmacheva, N. A., 124 Toman, K., 5 Tomasselli, A. G., 176 Tomita, K., 207 Tomoi, M., 26 Tonnard, F., 34 Topal, M. D., 203 Torgasheva, N. A., 124 Torny, G. J., 10 Toropova, V. F., 131, 312 Torr, R. S.,71, 72 Torrence, P. F., 193, 194 Tossing, G., 293 Townsend, J. M., 3 Toyota, K., 29, 60, 102, 287 Tozuka, Z., 182 Tran-Thi, Q.-H., 194 Traut, T. W., 314 Trayer, I. P., 176 Trecoske, M. A., 113, 239 Trentham, D. R., 178 Trifonova, S. A., 299 Trigala, F., 150 Trinquier, G., 95,288,292 Trippett, S., 81, 111, 132, 240

Tromp, M., 190 Trotter, J., 269,282,307 Truchon, A., 26 Truckenbrodt, G., 20 Trusova, E. A., 309 Tsai, M. D., 150, 151 Tsakalidou, E. C., 256 Tsang, P., 215 Tsao, Y. Y., 5 Tsapkova, N. N., 301 Tsay, Y. H., 219 Tscharbunin, H., 298 Tseng, K. S., 51, 84 Tsivunina, I. V., 110, 301 Ts’o, P. 0.P., 166 Tsolis, A. K., 83, 106, 313 Tsoupras, G., 156, 166 Tsuboi, H., 106 Tsuchida, E., 276 Tsuchiya, R., 12

Author Index Tsuda, S., 207 Tsvetkov, E. N., 103, 291, 303, 308, 311

Tsvetkov, Y. E., 84 Tsymbal, I. F., 301 Tumlinson, J. H., 250 Tundo, P., 225 Tuong, H. B., 22,45,218,222 Tur, D. R., 275 Turano, A., 148, 307 Turcot, J., 26 Tyc, K., 196 Tyuleneva, V. V., 218 Tzschach, A., 3, 8, 33, 86, 293

Uchiyama, M., 162 Uchiyama, T., 20 Ude, W., 276 Ueda, H., 109,155,207 Uehara, A,, 3, 12 Uei, M., 259 Uemura, H., 202 Uenishi, J., 259 Uesugi, S., 166, 210, 292 Uges, D. R. A., 273 Uguen, D., 33, 63, 112 Uhl, G., 30, 31, 303 Uhl, W., 287 Uhlenbeck, 0. C., 195,202 Uhlig, W., 293 Ukinskas, I., 245 Umerova, I. O., 303 Unemi, N., 272 Uramoto, M., 208 Usher, D. A., 195 Uskokovic, M. R., 75 Uss, I. I., 273, Ustynynk, Y. A., 235, 306, 309

Utley, J. H. P., 220, 309 Utracka, B., 110 Uziel, M., 200 Uznanski, B., 164 Vacek, A. T., 187 Vachkov, K. V., 134 Vafina, A. A., 299 Vafina, N. M., 311 Vahrenkamp, H., 29, 100 Valaitis, J. K., 277, 278 Valceanu, R., 300, 301 Valentin, R., 200 Valentine, D., jun., 3 Valenzuela, B. A., 66 Valerio, R. B., 144 Valetdinov, R. K., 6 Valitova, V. M., 132 Valko, K., 313 Valle, L., 66, 306 van Boeckel, C. A. A., 190 van Bolhuis, F., 267, 284 Van Boom, J. H., 120, 190, 194

333 Vancova, V., 17, 59 Van de Grampell, J. C., 260, 262, 263, 264, 266, 267, 271, 272,273,284,296 van der Berg, J. B., 150, 284 Van der Gen, A., 75 Van der Helm, D., 104,306 van der Huizen, A. A., 262, 272, 273 van der Knapp, Th. A., 28, 31, 99,291 Van der Locht; G., 237 Van der Marel, G. A., 120, 190

van der Meer-Kalverkamp, A. A., 272 Van Derveer, D., 227 Van Der Veken, B. J., 301 Van de Woestijne, R. P., 120 van Doorn, J. A., 9, 67 Van Dyke, D. A., 67, 124, 309

Van Dyke, M.W., 208 Vandyukova, I. I., 301 van Haastert, P. J. M., 168 Van Leeuwen, P. W. N. M., 9, 67

van 001, P. J. J. M., 38 Van Oort, A. B., 9, 67 Van Plothe, C., 97 Van Schaik, T. A. M., 75 van Zen, A., 10 Varenne, J., 93, 163 Varughese, K. I., 307 Vasil’ev, A. V., 80 Vasudeva, Murthy, A. R., 263,264,266,267,282

Vasyanina, M. A., 141 Vater, N., 4 Vaultier, M., 227 Vaughn, D. A., 151 Vdovenko, S. I., 300 Vderkova, H., 186 Vedejs, E., 45, 222, 290 Veiko, V. P., 189,215 Veits, Yu. A., 289 Vengel’nikova, V. N., 110 Venturello, P., 225 Veracini, C. A,, 4, 25, 221 Vereshchagin, A. W., 66,308 Vergoten, G., 271 Verheyden, J. P. H., 193 Verizhnikov, L. V., 312 Verkade, J. G., 19, 294 Vermeer, P., 10 Veselg, J., 171 Vidal, Y.,141 Viehe, H., 127 Vierwinden, G., 314 Vignais, P. V., 179 Vikhreva, L. A., 119 Vilceanu, R., 273 Vil’chevskaya, V. D., 15 Vilkov, L. V., 308

Villieras, J., 237, 240 Vincent, C., 179 Vinogradova, S. V., 270, 275,277,291, 303

Visalakshi, R., 307 Viswamitra, M. A., 307 Vitkovskii, V. Yu., 310 Vlad, V. L., 20 Vladimirov, S. N., 201 Vlassov, V. V., 206 Vogel, H. J., 144 Vollmer, H., 7 Volodin, A. A., 265 Volz, H., 292 Von Itzstein, M., 16, 44 Von Schnering, H. G., 6 Von Seyerl, J., 282 Voran, S.,236 Vorob’ev, Yu., N., 213 Vorob’eva, L. A., 291 Voronkov, M. G., 110, 123, 3 10

Voronkov, M. R., 308 Vos, A,, 282 Vos, M., 31 Voskanyan, M. G., 140 Voskresenskii, V. A., 6 Vostrowsky, O., 248 Vournakis, J. N., 207 Voznesensky, V. N., 309 Vul’fson, S. G., 66, 308 Vullo, A. L., 233 Wada, M., 4 Waddington, T. C., 289 Wadsworth, W. G., 122 Wadsworth, W. S., jun., 122 Wagner, C. T., 31 Wagner, F.E., 219 Wagner, H. U., 22, 303 Wagner, L. J., 270,282 Wagner, R., 206 Wakabayashi, T., 183, 191 Wakselman, M., 120 Walczyk, W., 26 Waldmeir, F., 186 Waldyke, M.J., 67, 124, 309 Walker, B. J., 83, 85, 92, 93, 98

Walker, P. A., 194 Walker, R., 214 Walkinshaw, M. D., 102 Wallace, T. W., 33, 63, 112 Walseth, J. F., 175 Walz, W., 269 Wamprecht, C., 231 Wang, A. L., 150 Wang, C., 313 Wang, C.-L. J., 252 Wang, J. C., 206 Wang, Q. S., 197 Wang, Y. P., 41, 89 Warren, C. D., 151 Warren, S., 71, 72, 75

Author Index

334 Warrens, C. P., 29, 100 Washington, L. D., 180 Wasielewski, C., 152 Wasylishen, R. E., 295 Watanabe, T., 27, 102, 179 Wataya, Y., 169 Waterhouse, J., 10 Watjen, F., 225 Watkins, B. E., 187 Waugh, J. S., 213 Wax, G., 2, 295 Webb, G . A., 295 Webb, R. L., 24, 237 Webb, T. R., 192 Weber, D., 6, 304 Weber, H., 267 Weber, J., 179 Weber, L. D., 207 Weerasinge, D. K., 237 Weerasooriya, U., 238 Weferling, N., 55 Wegner, G., 273 Weichmann, H., 294 Weis, C. C., 204 Welch, C., 185 Welch, M. J., 14 Weller, T. F., 290 Wellman, G . R., 24 Welsh, L. W., jun., 277 Wermuth, U., 37 Wessels, H., 314 Wessely, H. J., 287 West, C. R., 150 West, J., 183 Westerhaus, A., 15, 31, 218, 289, 303

Westheimer, F. H., 36, 121 Westhoff, P., 197 Westlake, S., 142 Westmijze, H., 10 Weyerstahl, P., 237 Wheaton, G. A., 231 Wheeler, C. J., 226, 257 White, R. L., 148 Whitener, M. A., 51 Whitesell, M. A., 132, 238 Whitesides, G. M., 84, 145 169

Whitham, G. H., 71 Whittle, R. R., 269,270,282,

Willetts, S. E., 296 Williams, A. P., 314 Williams, L. D., 36 Williams, R. F., 151 Williams, R. J. P., 292 Willmes, A., 231 Wills, N., 202 Wilson, A. C., 131 Wilson, J. W., 218 Wilson, S. H., 216 Wilson, S. R., 127 Wilson, W. D., 215 Winnacker, E.-L., 186 Winter, W., 19, 23, 230, 304, 306

Winterzith, M., 188 Winzenberg, K. W., 60 Wirkner, C., 30,99,287 Wisian-Neilson, P.,2,85, 88, 261

Withers, H. P., 11 Wogan, G. N., 204 Wojciechowska, J. K., 108 Wolf, R., 32, 98, 289, 290, 296,308

Wolmershaeuser, G., 292, 304

Wolter, A., 184, 189, 191 Wolters, D., 29, 100 Wong, C.-H., 145, 169 Wong, J. T.-F., 197 Wong-Ng, W., 307 Woods, M., 263, 264, 265, 266, 267, 271, 282, 294, 312 Worcel, A., 210 Wreesman, C. T. J., 120 Wright, A., 151 Wright, S. D., 277 Wu, C., 176 Wu, C. C., 273 WU, F. Y.-H., 214 Wu, G., 307 WU, G.-C., 45 Wu, J. C., 209 Wu, J. M., 196 Wuthrich, K., 214 Wykes, E. J., 93, 186 Wynne, N., 13 1 Wysocki, R., 26

Yamaguchi, K., 187 Yamakawa, M., 181 Yamamoto, H., 65, 297, 306 Yamamoto, K., 43, 65, 297, 306

Yamamoto, M., 1 Yamamoto, Y., 23 Yamanaka, H., 15 Yamane, A., 186 Yamanouchi, T., 113,229 Yamashita, H., 5 Yamashita, M., 5,60,65,297, 306 Yamashita, Y., 9, 207 Yamshchikov, V. F., 189 Yang, J. C., 156 Yano, S., 261 Yanovskii, A. I., 2 Yarkova, E. G., 132, 300 Yaroshenko, G. F., 306 Ye, W., 313 Yemul, S. S., 106, 121, 151 Yergey, A. L., 310 Yeung Lam KO,Y. Y. C., 34 Yokoyama, K., 277 Yokoyama, S., 292 Yoronkov, M. G., 298 Yoshida, M., 183, 277 Yoshida, T., 299 Yoshida, Y., 81, 111 Yoshida, Z., 119 Yoshie, O., 199 Yoshifuji, M., 27, 28,29, 60, 99, 102,287,304

Yoshii, E., 113 Yoshioka, A., 169 Yoshioka, H., 119 Yost, D. A., 147 Young, S., 26 Younger, D., 289 Youngs, W. J., 20 Yu, H.-S., 263 Yuanyao Xu, 111 Yuen, C.,313 Yufit, D. S., 65, 304, 306, 307

Yugudaev, M. R., 293 Yui, S.,207 Yusman, T. A., 309 Yusupov, M. M., 53,293

306

Widener, R. K., 227 Wider, G., 214 Wieczorek, M., 108, 307 Wiegand, G. H., 18 Wiesenfeld, L., 289 Wife, R. L., 9, 67 Wightman, R. H., 291 Wild, J., 114 Wildbredt, D. A., 289 Wilhelm, E., 308 Wilk, H A . , 197 Wilke, G., 234 Wille, G., 190

Xin, Y., 310 Xu, Y., 310 Yafarova, R. L., 301 Yagasaki, T., 14 Yakobson, G. G., 292 Yamada, K., 107, 145, 253, 286

Yamada, M., 5 Yamada, T., 212 Yamada, Y., 119 Yamagata, T., 4 Yamagata, Y., 207

Zabirov, N. G., 118,131,312 Zabski, L., 26 Zahler, R., 108 Zaikin, V. G., 309 Zaitsev, N. B., 271 Zakharkin, L. I., 2,270 Zakharov, V. I., 50,296 Zalinyan, S. A., 25 Zama, Y., 202 Zamaletdinova, G. U., 103 Zambani, R., 245 Zambi, R., 247 Zamkova, V. V., 310

335

Author index Zanasi, R., 297 Zanetti, G., 147 Zang, Q.-Z., 273 Zanobini, F., 6 Zapuskalova, S. F., 273 Zarian, J., 271 Zaripova, R. M., 299 Zaripova, V. G., 301 Zarytova, V. F., 183 Zaslona, A. T., 72 Zaslonova, N. Yu., 10 Zasorina, V. D., 109 Zang, A. J., 196 Zavalishina, A. I., 291 Zavgorodnii, S. G,Jhn Zavlin, P. M., 127 Zayed, M. F., 307 Zbaida, S., 313

Zbiral, E., 117, 229 Zeiler, H-J., 255 Zeldin, M., 277, 278 Zemlyansky, N. N., 235,306 Zenati, N., 103, 301 Zhang, D., 289 Zhang, H. M., 31 Zhdanov, R. I., 299 Zheng, Q., 305, 307 Zhong Li, 111 Zhuravlev, L. T., 311 Ziegler, M. L., 31 Ziemnicka, B., 108 Zimin, M. G., 117, 118, 126, 131, 312

Zimmer, G., 199 Zimmer, H., 23 Zimmermann, R. A., 199

Zinovich, Z. K., 274 Zipkin, R. E., 259 Zolotoi, A. B., 26 Zon, G., 131, 313 Zontova, V. N., 118 Zorn, H., 294 Zschunke, A., 293 Zsolnai, Z., 306 Zuckerman, J. J., 23 Zuikova, A. N., 6 Zvezdkina, L. I., 10 Zwierzak, A., 128 Zyablikova, I., 1, 308 Zyablikova, T. A., 12, 297, 311

Zybill, C. E., 305 Zykova, T. V., 110,289

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