Topics in Stereochemistry, Volume 3

TOPICS IN STEREOCHEMISTRY VOLUME 3 AN INTERSCIENCE SERIES ADVISORY BOARD STEPHEN J. ANGYAL, University of New Sou...

Author: Norman L. Allinger | Ernest L. Eliel

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TOPICS IN

STEREOCHEMISTRY

VOLUME

3

AN INTERSCIENCE SERIES

ADVISORY BOARD

STEPHEN J. ANGYAL, University of New South Wales, Sydney, Australia JOHN C. BAILAR, Jr., University of Illinois, Urbana, Illinois OTTO BASTIANSEN, University of Oslo, Oslo, Norway GIANCARLO BERTI, University of Pisa, Pisa, Italy DAVID GINSBURG, Technion, Israel Institute of Technology, Haifa, Israel WILLIAM KLYNE, Westfield College, University of London, London, England KURT MISLOW, Princeton University, Princeton, New Jersey SAN-ICHIRO MIZUSHIMA, Japan Academy, Tokyo,Japan GUY OURISSON, University of Strasbourg, Strasbourg, France GERHARD QU INKERT, Techrrische Hochschule Braunschweig, Braunschweig, Germany VLADO PRELOG, Eidgenossische Technische Hochschule, Zurich, Switzerland

JlRl SICHER, Institute for Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague, Czechoslovakia HANS WYNBERG, Uniuersity of Gronirtgen, Groningen, The Netherlands

TOPICS IN 0

STEREOCHEMISTRY EDITORS

ERNEST L. ELIEL Professor of Chemistry University of Notre Dame Notre Dame, Indiana

NORMAN L. ALLINGER Professor of Chemistry Wayne State University Detroit, Michigan

VOLUME

3

INTERSCIENCE PUBLISHERS A DIVISION OF JOHN WILEY & SONS

New York

-

London

*

Sydney

-

Toronto

Copyright 8 1968 by John Wiley & Sons, Inc. All rights reserved. No part of this book may be reproduced in any form, nor transmitted, nor translated into a machine language without the written permission of the publisher. Library of Congress Catalog Card Number 67-13943 Printed in the United States of America SBN 470 237473

INTRODUCTION TO THE SERIES During the last six years several texts in the areas of stereochemistry and conformational analysis have been published, including Stereochemistry of Carbon Compounds (Eliel, McGraw-Hill, 1962) and Conformational Analysis (Eliel,Allinger, Angyal, and Morrison, Interscience, 1965). While the writing of these books was stimulated by the high level of research activity in the area of stereochemistry, it has, in turn, spurred further activity. As a result, many of the details found in these texts are already inadequate or out of date, although the student of stereochemistry and conformational analysis may still learn the basic concepts of the subject from them. For both human and economic reasons, standard textbooks can be revised only at infrequent intervals. Yet the spate of periodical publications in the field of stereochemistry is such that it is an almost hopeless task for anyone to update himself by reading all the original literature. The present series is designed to bridge the resulting gap. If that were its only purpose, this series would have been called “Advances (or “Recent Advances”) in Stereochemistry.” It must be remembered, however, that the above-mentioned texts were themselves not treatises and did not aim at an exhaustive treatment of the field. Thus the present series has a second purpose, namely to deal in greater detail with some of the topics summarized in the standard texts. It is for this reason that we have selected the title Topics in Stereochemistry. The series is intended for the advanced student, the teacher, and the active researcher. A background of the basic knowledge in the field of stereochemistry is assumed. Each chapter is written by an expert in the field and, hopefully, covers its subject in depth. We have tried to choose topics of fundamental import, aimed primarily at an audience of organic chemists but involved frequently with fundamental principles of physical chemistry and molecular physics, and dealing also with certain stereochemical aspects of inorganic chemistry and, hopefully, biochemistry. It is our intention to bring out future volumes at approximately annual intervals. The Editors will welcome suggestions as to suitable topics. V

vi

INTRODUCTION

We are fortunate in having been able to secure the help of an international board of Editorial Advisors who have been of great assistance by suggesting topics and authors for several articles and by helping us avoid duplication of topics appearing in other, related monograph series, We are grateful to the Editorial Advisors for this assistance, but the Editors and Authors alone assume the responsibility for any shortcomings of Topics in Stereochemistry. N . L. Allinger E. L. Eliel

PREFACE The response of potential authors to our new series has been so good that we have decided to publish three volumes within the first two years instead of the originally contemplated two. Volume 3, like the two previous volumes, contains four articles on topics of current interest in the field of stereochemistry. The first article, a comprehensive treatment of the stereochemistry of phosphorus by M. J. Gallagher and I. D. Jenkins, documents our intent of having the series extend to elements other than carbon. To be sure, most of the examples in this chapter are organo-phosphorus compounds and therefore the chapter should be of considerable appeal to chemists with a wide variety of different backgrounds and interests. Phosphorus stereochemistry illustrates the important new phenomenon of pseudorotation (the term “ligand reorganization” suggested to one of the Editors by Professor Andre Dreiding would appear to be more appropriate, since “ pseudorotation ” has already been preempted for the type of puckering motion found in cyclopentane) which will undoubtedly prove to be of significance in other areas of stereochemistry as well. The second chapter deals with the computation of rotational barriers from NMR data. This has become an important area of conformational analysis with which every chemist should be at least somewhat familiar. In this chapter G. Binsch combines a thorough theoretical introduction with an extensive but very critical consideration of the existing experimental data. An important message to the many chemists of diverse background who nowadays measure barriers by NMR is that while faulty methodology and inadequate mathematics have frequently been used in this field, there is little extra effort involved in using accurate methods and an adequate mathematical treatment. The third chapter, by G. L. Closs, deals with the stereochemistry of addition of methylenes, carbenes and carbenoid species to olefins. This is a topic which was covered in a few sentences only six years ago and in which recent research has shown that matters are not quite as simple as had been assumed in the early hypotheses. This chapter, like the following one, should be of special interest to the reader who wishes vii

viii

PREFACE

to gain an insight into the stereochemistry of an important fundamental organic reaction. The stereochemistry of electrophilic addition to double bonds is another topic which only six years ago was covered in most textbooks in a few pages, the gist of which was that such addition usually involves bridged ion intermediates and proceeds in arlri stereochemical fashion. R. C. Fahey’s extensive treatment of the subject in the last chapter clearly shows that this point of view represents a vast oversimplification. There are now recognized to be several mechanisms of electrophilic addition (just as there have long been known to exist several mechanisms of nucleophilic displacement), and the stereochemistry may vary from extensive SJW addition through a stereochemically indiscriminate process to nearly complete anti addition. This chapter should be of special value to the teacher who has to cope with the subject of electrophilic addition in both elementary and advanced courses in chemistry. N . L. Allinger E. L. Eliel

June 1968

CONTENTS STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY l y M . J. Gallagher and I . D. Jenkins, School of Chemistry, The Unicersity of New South Wales, Kensington, N S W , . . Australia

1

THE STUDY OF INTRAMOLECULAR RATE PROCESSES BY DYNAMIC NUCLEAR MAGNETIC RESONANCE by Gerhard Binsch, Department of Chemistry and the Radiation Laboratory, University of Notre Dame, Notre Dame, . Indiana

97

STRUCTURES OF CARBENES AND THE STEREOCHEMISTRY OF CARBENE ADDITIONS TO OLEFINS by Gerhard L. Closs, Department of Chemistry, The University of Chicago, Chicago, Illinois . . 193 THE STEREOCHEMISTRY OF ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES by Robert C. Fahey, Department of Chemistry, University of California (San Diego), La Jolla, California . . 237 Author Index

.

. 343

Subject Index

.

.

Cumulative Index

.

367

. 379 ix

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

Stereochemical Aspects of Phosphorus Chemistry M . J . GALLAGHER and I . D . JENKINS School of Chemistry. The University of New South Wales. Kensington. NS W. Australia I . Introduction

. . . . . . . . . . . . . . . . .

I1. Physical Methods for Determining Stereochemistry

. . . . .

I11. P(I1) Compounds . . . . . . . . . . . . . . . IV . P(II1) Compounds . . . . . . . . . . . . . . . A . Chiral Acyclic Compounds . . . . . . . . . . . B. Stability of P(II1) Structures and Steric Consequences of their Reactions . . . . . . . . . . . . . . . . C . Acyclic Symmetrical Compounds . . . . . . . . . D. Cyclic Compounds . . . . . . . . . . . . . V. P(1V) Compounds . . . . . . . . . . . . . . . A . Introduction . . . . . . . . . . . . . . . B. Optical Isomerism . . . . . . . . . . . . . 1. Types of Resolvable Compounds . Methods of Resolution and Stability . . . . . . . . . . . . . . 2 . Reactions of Phosphonium Salts . . . . . . . . 3. Reactions of Phosphoryl and Thiophosphoryl Compounds . 4 . The Wittig and Related Reactions . . . . . . . . C . Geometrical Isomerism . . . . . . . . . . . . 1. Cyclic Compounds . . . . . . . . . . . . 2. Acyclic Compounds . . . . . . . . . . . . D . Conformational and Rotational Isomerism . . . . . . E. Steric Effects . . . . . . . . . . . . . . . F. Neighboring Group Participation . . . . . . . . . VI. P(V) Compounds . . . . . . . . . . . . . . . A . Structure and General Properties . . . . . . . . . B . P(V) Structures as Reaction Intermediates . . . . . . . VII . P(V1) Compounds . . . . . . . . . . . . . . . VIII . Addendum Added in Proof . . . . . . . . . . . . A General . . . . . . . . . . . . . . . . 1. Spectroscopic Methods . . . . . . . . . . . B . P(II1) Compounds . . . . . . . . . . . . . C . P(1V) Compounds . . . . . . . . . . . . . D . P(V) Compounds . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

.

1

11 15 19 25 25 26

26 29 31 38 44 44 41 51 56 59 61 61 68 76 79 79 79 80 82 85 86

2

M. J. GALLAGHER AND I. D. JENKINS

I. INTRODUCTION Stereochemistry and its influence on reaction pathways in carbon compounds have been the subjects of fruitful study for over a century. Until very recently, investigations relating to other elements have been spasmodic and largely directed toward the resolution of selected compounds. Thus, though Meisenheimer first reported the resolution of a phosphine oxide, R1R2R3P0,in 1911 (l), only a handful of such studies was reported in the subsequent forty years. However, with the realization of the importance of phosphates in metabolic processes and the discovery of the extreme biological activity of certain classes of organophosphorus compounds, an immense upsurge occurred in work relating to the chemistry of phosphorus and its derivatives. Stereochemical studies have been less common but have increased considerably in the last few years following the development of a useful general method for the resolution of phosphonium salts. The stage has now been reached where it seems worthwhile to review the subject as a whole and to note in particular the difficulties and peculiarities arising from the presence of an element of the second row of the periodic table. In this chapter, an attempt will be made to survey all aspects of stereochemistry concerned with compounds of phosphorus with the exception of condensed phosphates and metal complexes. The literature has been surveyed until the end of 1966. A comprehensive coverage is not intended and some topics which have been extensively covered elsewhere will be dealt with only briefly. A number of other reviews have appeared dealing with general aspects and reaction mechanisms ( 2 4 ) and optically active compounds (5,6), and, very recently, there has been a comprehensive review on structural features (7). Important papers which have appeared in the first ten months of 1967 are covered in the Addendum (Sect. VIII). The most notable feature of the chemistry of phosphorus, which is shared by most elements other than those in the first row of the periodic table, is multiple valence. Thus, stable compounds are known carrying 2-6 substituents attached to a central phosphorus atom. This greatly increases the difficulty of interpreting the stereochemical consequences of a reaction. In unfavorable cases, it is not uncommon to have as many as three possible transition states (or intermediates) for a given reaction, each having a different geometry. [See, for example, the discussion on P(V) compounds in Sect. VI.] For convenience, this chapter

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY

3

TABLE I

Bond Lengths and Bond Angles in Phosphorus Compounds Bond length,

A

Bond angles, degrees

/\

2.22

P-P

P-P-P = 106 (6-membered P(IV) ring)

/\

P-P-P = 95 (6-membered P(II1) ring)

A

P-P-P = 94-107 (5-membered P(II1) ring)

P-c

1.84

P=C

1.71

P=C P-H P-F

P-Cl P-Br P-I P(I V)-N P(II1)-N

k N

/\

C-P(1V)-C

+ 106

c-P(II1)-c

=

/\

/\

P=C=C 1.65 (Ph,P=C=C=O) (8) 1.54 1.42 1.53 (Me2PF3;P-Fradlal = 1.55; P-Fapical = 1.64) (9) 1.98 2.14 2.47 1.77 (NaHNH2P03) 1.69 (Me2NPC12)(10) + 1.88 (PhzP-N(Et)-PPhzEt (1 1) 1.49

/\

1.59 1.56

P-0-C

P-o-(P)a

1.61

P-0-P 100

P-S-(P) P=S

=

145.5

=

120 rfr 6

=

128; 0-P-0

I-)

P-O-(C)* P-0-( H)a

P=O

99

From 1.46 (&PO) to 1.54 (Po: -) 2.10 1.91

/\

/\

=

4


will be divided into sections dealing with each of the possibilities, and compounds will be referred to as P(IV), P(VI), etc., without regard to the nature of the substituents or the type of bonding involved. Where convenient, these sections will be further subdivided along lines of acyclic and cyclic structures. A proper understanding of steric effects requires an accurate knowledge of bond lengths and bond angles. In Table I are recorded some average values of these parameters. For accurate data, the comprehensive review of Corbridge (7) should be consulted. Stereochemical effects deriving from the bulk of substituents (H. C. Brown’s F strain) will, in general, be less evident in phosphorus compounds than in the carbon or nitrogen analogs by virtue of the greater radius of the central atom and the greater length of the bonds. For these effects to become severe, it is usually necessary to have very bulky groups (e.g., t-butyl) present.

II. PHYSICAL METHODS FOR DETERMINING STEREOCHEMISTRY

1. 31P nuclear magnetic resonance ( N M R ) spectra. Although the chemical shifts of large numbers of P compounds of all types have been reported, very little use has been made of this information in the study of reaction mechanisms, and only a single assignment of the shifts in two stereoisomers has appeared. Katz et al. observed a difference of 65 ppm for two geometrical isomers of a P(II1) compound (see Sect. IV). This huge difference is probably atypical, since the structures involved are somewhat exceptional, but suggests that when sufficient data accumulate chemical shift differences may provide a valuable method for determining stereochemistry. Though peaks corresponding to diastereoisomers have been observed in a number of instances, no assignments have yet been made. 2. IH NMR spectra. A reasonable number of examples of olefins carrying P substituents has been examined, principally by Westheimer (12), Griffin (13,14), and their co-workers. Stereochemistry may be assigned with a fair degree of confidence on the basis of the large difference between the cis 3JpH(9-25cps) and trans 3JpH(30-50cps) coupsplitting across a double ling constants. This behavior parallels the 3JHH


5

bond but the splittings are of considerably greater magnitude. The correlation is reasonably well established for P(IV) compounds but an insufficient number of P(II1) compounds have been examined to confirm it, though the detailed analysis of trivinylphosphine (1 5 ) supports the same behavior for this class. Unfortunately, the proton spectra are often quite complex and the vinyl proton signals sometimes overlap into the aromatic region. This is a disadvantage since phenyl groups are common substituents on phosphorus. The useful correlation between the 13C-H coupling constant and the per cent s character of the bond (16) suggests that a similar relationship may exist with 31P-H coupling, thus providing direct information concerning stereochemistry at phosphorus, particularly since many compounds with P-H bonds are known. The relationship is not a good one, however (1 7); changes in hybridization at phosphorus produce considerable changes in JPHbut much more work is necessary before any but the most qualitative conclusions can be drawn. In general, P(II1) compounds have relatively low coupling constants (170-240 cps) and P(1V) compounds considerably higher ones (350-700), but structural or stereochemical assignments cannot yet be based on the magnitude of the splitting. X-ray crystallography, electron diffraction, and microwave spectroscopy have been used to determine the structures of a wide variety of phosphorus compounds; reference 7 should be referred to for an extensive collection. Of course, such methods cannot be used for routine stereochemical determinations. Of particular importance however is the recent determination (18) of the absolute configuration of the P(IV) salt ( +)benzylmethylphenylpropylphosphonium bromide, 1 as S,which has enabled many stereochemical correlations to be made. Pr

I

,,Pt Ph” 1 “CH, CH,Ph

Br-

cis-trans Isomers of olefins may often be distinguished on the basis of melting point, that of the trans isomer being higher. Though insufficient examples are known to indicate a useful general trend, the same relationship does not seem to hold for many phosphorus compounds.


6

Thus, cis- and trans-ethene-l,2-bisdiphenylphosphinehave the same melting point (19), and in the case of Iy2-diphenylethenediphenylphosphine, the cis isomer is solid and the trans isomer liquid (20). However, in those relatively few cases where assignments have been made to geometrical isomers the melting point of the trans oxides is higher than that of the cis (Table 11). If this relationship is general then it will be a useful one since oxides are readily obtained from phosphines and phosphonium salts by reactions of known stereochemistry.

TABLE I1

Melting points of Isomeric Phosphine Oxides (“C) Oxide PhZP(O)CH=CHP(O)Phz PhCH=CHP(O)PhZ PhCH=CPhP(O)Pha

PhZP(O)CH=CHCHa

Refs.

cis

trans

244 103 153

310 168 224

19 21,22 23

234

251

24

276

> 400

24

182

197

25

113-116

124-125

307

3. Optical Rotatory Dispersion. In a few instances this technique has been used for confirming the stereochemical consequence of reactions at phosphorus (26,27) and to support the assignment of absolute stereochemistry to phosphine oxides (28).


7

III. P(II) COMPOUNDS Very few compounds belonging to this class are known. Cyaninetype salts of general formula 2 may be obtained (29) as shown in eq. (1).

The molecule 2 is nearly planar, the dihedral angle between the two ring systems being 6" and the CPC angle 105". The structure has been determined by X-ray methods (30). A more interesting structure from the chemical viewpoint is 3 which is prepared in an analogous way (31) [eq. (211-

No details of the structure are available but the compound is monomeric and the NMR of the ring protons is in the region expected for aromatic protons. The chemistry and stereochemistry of this new class of compounds should prove most interesting. Reactive intermediates such as Ph,P- and Ph2P. have had their chemistry explored to a considerable extent but nothing is known of their stereochemistry. Nucleophilic displacement of halogen at unsaturated carbon by Ph2P- [eq. (3)] proceeds with retention of stereochemistry (19) and the radical, Ph2P., attacks alcohols [eq. (4)] without affecting the stereochemistry of the a-carbon atom (32). PhzP.

+ R*OH (+I

PhaPOR*

(+I

(4)

8


IV. P(III) COMPOUNDS

A. Chiral Acyclic Compounds Despite earlier predictions to the contrary [good surveys of this early work have been given in the reviews of Mann (2) and McEwen (4)], it is now well established that P(I1I) compounds have a configurationally stable, pyramidal structure. Much of the progress in this field is due to the elegant work of Horner and his collaborators (5) who first succeeded in obtaining optically active phosphines. The path to these compounds is beset with difficulties. P(1V) compounds had been resolved over fifty years ago but numerous attempts to reduce them had always led to failure. Part of the reason lay in the stability of P(1V) compounds and the necessity for the use of forcing conditions or powerful reagents to reduce them. Thus, reduction of optically active phosphine oxides (33) or phosphonium salts with sodium (34) or with lithium aluminum hydride (35,36) at 0" invariably afforded racemic products. The first P(II1) compound to be resolved was the cyclic compound 4 by Campbell and Way (37) but, as these workers point out, this example is ambiguous since the molecule is in fact a bridged biphenyl and could

N-P

HI

exhibit asymmetry even if the P(II1) group were planar. Since no evidence could be found of diastereoisomerism the question remained unresolved. In 1959, McEwen and his colleagues (38) introduced the (-)-dibenzoylhydrogentartrate anion as a resolving agent for phosphonium salts, and optically active phosphonium salts became relatively readily available. Horner resolved a number of salts in this fashion and, using the recently developed (39) method of electrolytic reduction


-

9

(cathodic fission), obtained a series of optically active phosphines (40) [eq. (511. RlR2R3kH2Ph ( + I or (-)

2.Z. Hf

+

RlR2R3P PhCH3 (+) or (-)

(5)

Earlier studies (39) had shown that the group removed in this process was that most stable as an anion, benzyl in the example. This made optically active phosphines accessible by a reasonably straightforward process since the appropriate benzylphosphonium salts are available conveniently by the method of Bailey et al. (41) [eq. (6)]. PCI3

+ PhCH,MgX

+ P(CH2Ph)3

I

R16(CH2Ph),XLiAlH,

+ R,X etc. RiR2RaPCHzPhX- t RlP(CH2Ph)a

(6)

Subsequently, McEwen and his collaborators (42) synthesized both enantiomers of benzylbutylmethylphosphine (5) by resolving the 2-cyanoethylphosphonium salt of this phosphine and decomposing it with sodium methoxide [eq. (7)] by the method of Grayson et al. (43). BuMePCH2Ph

CH,-CHCN NHICl

BuMePhCHakHzCH2CNC1-

I

1. Resolve 2. MeO-/MeOH

4,

BuMePCH2Ph

(+I and (-1 (5)

(7)

A less-clean method involves the reduction with trichlorosilane of optically active phosphine oxides (44). Optical purity of the product phosphine is not as high as by the methods using phosphonium salts but it usually exceeds 60%. If the reaction is carried out in the presence of triethylamine, the configuration of the resulting phosphine is inverted. The pathways shown in eqs. (8)-( 10) have been suggested.

M. J. GALLAGHER A N D I. D. JENKINS

10

In theory any reaction yielding a phosphine and not involving attack at the central phosphorus atom could be adapted to prepare optically active phosphines. Such reactions are not common, however, since phosphonium salts undergo elimination much less readily than their ammonium analogs. Horner has recently reported that allylarsonium salts are decomposed by cyanide ion to give arsine in high yield and with good optical purity (45). The reaction also works for phosphonium salts but its steric consequences have not been reported. It has been observed in these laboratories (46) that 2-cyanoethylphosphonium salts are decomposed smoothly to the corresponding phosphine in high yield by cyanide ion. Doubtless, other methods will be developed, but at the moment, the most general seems to be the cathodic fission of resolved benzyl- or allylphosphonium salts. An alternative synthesis for chiral phosphines involves the reaction of a phosphonous halide with a mixture of Grignard reagents [eq. (1 l)]. RiPCla

+ R2MgX + R3MgX

RiPRaRz

+ RiPR3R3 + RiRaR3P

(1 1)

The desired phosphine is formed in the highest yield and readily separated by distillation. The method seems simpler and less laborious than methods involving alternate quaternization and removal of preferred leaving groups. It should also provide easy access to chiral triarylphosphines not readily available by other methods [although one example has been reported (47)]. Table 111 records the optically active phosphines so far obtained.

TABLEI11

Optically Active Phosphines R1R2R3P RI Me Me Me Me 4-Methoxyphenyl Me

Rz Pr CHz=CHCHz Et PhCHz 1-Naphthyl Bu

R3 Ph Ph Ph Ph Ph PhCH2

+1.5 k 0.5

Ref. 40 40 40

f24 f 2

42

b I D

+ 18.4

-1Of

+ 45.8 + 2.9

1

5 47

Horner has also obtained an optically active diphosphine (8) and a

meso (9)diphosphine by cathodic fission of the bisphosphonium cations

6 (resolved) and 7 (meso),respectively, but no rotation of 8 was reported (48).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 11 CH,Ph

CH,Ph

I

I

.P+ H,C,"

1

\

Ph

H,C,"

CH,-H,C

I

/

CH,Ph

P.+

1

...

Ph CH, 2Br-

CH,Ph

I

Ph

I

I

,P;

CH,-H,C CH3

(7)

I CH,-H,C 1

I

(8)

(9)

,p\

Ph

P. / -. 'Ph CH,

/

P+ ,**. 'Ph CH, 2Br-

I

No examples of optically active P(II1) compounds other than phosphines (i.e,, compounds with three P-C bonds) have been reported.

B. Stability of P(II1) Structures and Steric Consequences of their Reactions

Optically active P(II1) compounds are relatively stable but they may be thermally racemized (49) with half-lives of 3-5 hr a t 130" and activation energies of ca. 30 kcal/mole (49). The mechanism of thermal racemization is unknown but is presumably analogous to the much more facile behavior of NR, compounds and involves oscillation of the P atom along an axis normal to the plane of the substituents. The process has been studied in another fashion using the diphosphine, PhMePPMePh, whose 31P NMR spectrum shows two peaks corresponding to the two expected diastereoisomers (50). These peaks coalesce at 180" and from a study of the rate (51) an EA of 26 f 2 kcal/mole was derived in fair agreement with the value obtained for monophosphines (49). This is reasonable, since only one inversion is required, but the possibility of a very rapid dissociation-recombination process cannot be excluded and must be given serious consideration in view of the labile nature of the P-P bond [eq. (12)]. RZPPR,

2RzP.

!12)

It should be noted that Fluck and Issleib (52) obtained no NMR evidence of stereoisomerism in the tetralkyldiphosphine EtBuPPBuEt. Thermal racemization also explains why Maier (50) always obtained the same 1 : 1 mixture of diastereoisomers when either meso or


12

racemic compounds RIRzP(S)P(S)RIRz were reduced to the corresponding diphosphine by tributylphosphine at 170". Many reactions of phosphines involve the lone pair of electrons on the P atom and proceed with an expansion of valence from three to four, e.g., quaternization. Reactions of this type follow second-order kinetics and are free of side reactions, at least in the case of primary aliphatic halides. Retention of configuration at the P atom would seem a reasonable assumption. If an optically active phosphine and a benzyl or allyl halide are used, then the product phosphonium salt may be converted back to the starting phosphine without loss of optical activity, by cathodic fission [eq. (13)]. R1RaR3P

PhCHaX 2-,H+

+

RiRaRsPCHaPh X -

Hence, both forward and back reactions have the same steric result, either retention or inversion,if the reasonable assumption is made that neither is a multistep process. From the sequence of reactions shown in Figure 1 Horner et al. (53) concluded that both quaternization and cathodic fission proceed with retention. However, since the replacement of allyl by propyl (bottom line) must in any case involve inversion, regardless of the steric course of quaternization and cathodic fission, the reaction sequence does not, in fact, establish the stereochemical pathway. Horner and Winkler subsequently noted (57) this fact; hence, though it is apriori probable that quaternizationproceeds with retention, all stereochemicalassignmentsstemming from this assumption still await a rigorous proof. CH2Ph

I

,P\ H&"' Ph

I

CH,Ph

I .P+

RdNi/Ho

H3C'"

CH2CH=CH2 I

2,

I

H3C" Ph CH,CH= CH2

PrBr

H2CH,CHS

Pr I

,.p

-70.5"

Et

I

( i ) EtONa (ii)EtBr

Et

S

RNH=C-v-P-OEt NHR I Et I\-

I

(9)

+41.95"

(R = cyclohexyl)

( i ) EtSNa ( i i ) HCI

Et(EtO)P(S)OH -13.42"

+ Et(EtO)P(O)SEt

-33.57" (48% optically pure)

Figure 7

intermediate 51, formed by nucleophilic attack of the amine at phosphorus. Thus the phosphoryl portion of the product 50 can have either configuration, depending on whether or not attack by the second mole of thiophosphonate occurs on the initially formed DCC adduct or the EtO 0 \p/

R,N:

-4

+

II I

NHR +R,N-P-OEt Et

L - C '

(-)

0

\"HR

(+I (51)

0

S

OEt

OEt

I1 II Et-P-0-P-Et I I


38

intermediate 51. With the sterically hindered 2,6-lutidine, formation of 51 is much less favorable. In contrast to phosphorylation, reaction with alkyl halides and phosgene appears to proceed by attack of the Et(EtO)P(O)S- anion and not Et(EtO)P(S)O-, i.e., S-alkylation occurs (144,145). Acetyl chloride gives the 0-acylation product and is thus analogous to phosphorylation. RX

+ COCl,

Et(EtO)P(S)SR f- Et(EtO)P(O)SNa (+)

Et(EtO)P(O)CI

(-1

(+)

The anomalous reaction with phosgene led to the suggestion (144) that this reaction proceeded by formation of the intermediate 52 followed by rearrangement, rather than by direct formation of the thermodynamically more stable 53. This seems unlikely however (4). EtO

EtO

S

\pH

\p/

Et

/-\

0-C-CI

I

Et

0

/-\

S-C-Cl

I

0 (52)

0 (53)

Phosphorylation, acylation, and alkylation of phosphonothioic acids can be interpreted in terms of Pearson’s concept of “hard” and “soft” acids and bases, the reactions being subject to kinetic control (120). For example, the alkylation reaction involves interaction of the soft acid (RX) with the soft sulfur atom (base). All three of these reactions lend support to the theme (160) that mutual polarizability of reactants is a very strong operative force in the reactions of phosphorus compounds. 4. The Wittig and Related Reactions

Most aspects of the Wittig reaction have been discussed at considerable length in recent review articles (161-165) and only a brief resume will be given here.

a. Stereochemistry at Phosphorus. The reaction is stereospecific and takes place with complete retention of configuration at phosphorus. Horner (26) has interrelated the Wittig olefination reaction with

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 39

-

cathodic reduction and oxidation as shown in eq. (41). This result was taken as good evidence for cis elimination in a four-membered ring + MeEtPh(PhCH,)PBr= -43.4"

Olefination with

67% MeEtPhP=O

benzaldehyde

(41)

I [a1546

= -19.1"

(i) Cathodic fission (retn) (ii) Oxidation with H.Oo (retn)

intermediate. A cis elimination was also proposed in the olefination reaction shown in eq. (42). MePhP(O)CH,Ph [a1646

+ PhCH=NPh

= +61.5"

(54)

KOBut

+MePhP(0)NHPh [ a ] 5 4 6=

-29.2'

+ PhCH=CHPh

+ MePhP(0)OH

(42)

(55)

Rotatory dispersion curves of 54 and 55 showed that both compounds belonged to the same steric series, i.e., the substitution of -NHPh for -CH,Ph occurred with retention of configuration, presumably via a cyclic intermediate of type 56 or 57. 0

II

TI

R,P-CHPh

R,P-CHPh

PhaCHPh

PhNd-CHPh

\I

(56)

I \I

(57)

The related, but more complex, reactions of optically active phosphorus ylids with styrene oxide (166) and benzonitrile (167) have been given adequate treatment by McEwen (4). Both of these reactions result in a phosphine oxide which is only partially optically active. This has been explained on the basis of competing pathways of different stereochemistry, some leading to inversion and others to retention of configuration. b. Stereochemistry of the Product Olefin. Stereospecific olefin formation is best discussed with reference to a mechanism. The mechanism (168,169) given in eq. (43) is fairly adaptable and allows a reasonable interpretation of the stereospecificity of the products obtained from more general reactions. Betaine formation has been shown to be reversible (169) and betaine dissociation occurs at a rate comparable to


40

that of elimination, hence allowing the formation of a predominant amount of the thermodynamically more stable trans olefin.

R,P=CHR'

+

(43)

R"CH0

(5W

(5W

From eq. (43) it can be seen that the cis olefin would be favored if the ratios kl/k3,k6/ks,and k6/klwere high. It might be expected therefore that a high percentage of cis olefin (i.e., approaching 50%) would be obtained by employing a very reactive (or nucleophilic) phosphorus ylid, provided betaine decomposition was fast (168). In general, this is found to be the case. Highly reactive Wittig reagents give mixtures of cis and trans isomers [very nucleophilic ylids and electrophilic aldehydes give high ratios, approaching unity, of cis-trans olefins (168,170)]. Stable ylids tend to give exclusively trans olefin, though many anomalies exist. For example, in the reaction of phthalic anhydride with acyl-ylids (Ph,P=CHCOR; R = NR2 or OR) the product 59 was cis, but for R = Me, the product was trans. R = Ph gave a 4:l trans:cis ratio (171).


Similarly, the phosphole 60 is a stable isolable ylid being less reactive (and less stereoselective) than the triphenylphosphorusethoxycarbonylmethine ylid. With acetaldehyde and 60, the olefin obtained was 26% cis; with the ylid (Ph,P=CHCOOEt) it was only 8% cis (172). Probably specific bonding effects (dipolar and n-cloud interactions) are present in these particular examples (171,172). It seems likely that the geometry of ylids may be an important factor governing the initial nucleophilic attack by the ylid (173). The X-ray structure determinations (174) of several stable phosphorus ylids has shown that the major contributing resonance structure is the dipolar betaine (61; X = halogen). As X is varied from C1 to Br to I, the system becomes less planar but more basic (due to decreased carbanion stabilization). The decreased planarity would make steric factors much Ph3P

0

II

PhSP=C-C-Ph

I

X

++

X

\ / c=c / \

0-

Ph

(61)

more important for the iodo compound than for the chloro compound, so that despite the increased nucleophilicity of the iodo compound, it may be more stereospecific. Evidence of hindered rotation in stable triphenylphosphine alkylenes has recently been obtained by NMR (175). The compound Ph,P=CMe-COOMe was found to exist in chloroform in a 65 :35 ratio of rotamers 62 and 63, respectively. The rate of rotation was solvent dependent. 8+

8-

Ph3P Me

0

/

\ (62)

OMe

8+

Ph3P Me

OMe

/- -\ (63)

0 8-

The importance of factors such as hindered rotation and geometry of ylids is difficult to gauge at the present time but these factors could well be important in conjunction with solvent and Lewis base effects which are little understood. Lewis bases and polar solvents are said (161,176179) to increase the proportion of cis isomer in nonstabilized phosphorus ylid olefinations. In fact relative yields of close to 90% cis isomer have been reported (164) for some reactions employing aldehydes and excess ylid in a highly polar solvent and in the presence of

42


iodide ions. It is considered likely that halide salt impurities in reactive ylids are partly responsible for non-trans selective olefination of aldehydes (164), although a recent paper (180) contradicts this by claiming that alkylidenetriphenylphosphorus ylids tend in general toward cis olefination, the proportion of cis olefin being highest when the ylid is prepared in “salt-free” form. Lithium salts were found to favor the formation of trans isomers, the more so the larger the radius of the anion. The Lewis base effect has been interpreted in terms of a decreased orientation in attack by the ylid-base complex on the carbonyl compound, and the polarity effect in terms of solvent stabilization of the erythro betaine 58a, i.e., more equal energies of both betaines, 5& and 58d, due to solvation (161,179). In connection with the Lewis base catalysis (of cis olefin formation) it has been suggested that lithium salts affect the course of the reaction by forming an organolithium compound so that the ylid is no longer the reacting species (120,163,179). A recent, rather novel selective transolefin synthesis has employed a carbon-lithium bond in the betaine An analogy itself to bring about a stereospecificreaction (181) [eq. (a)]. was made between this result and the rapid rates of racemization of optically active organolithium compounds (182). + Ph,$-CHR X- + R’CHO + Ph3P-CHR X-

I

I

LiO-CHR‘

Li

PhLi

(44)

I

I

-

I

KOt-Bu

pure trans Olefin

The literature is also in a confused state regarding the effect of solvent and Lewis bases on stabilized ylid reactions. Some authors claim no effect (161,164,172,176,183) while others claim marked influence (179). Acid catalysis by benzoic acid has been found in several instances, specific hydrogen bonding being proposed in one case (1 84) and protonation of the carbonyl group in another (185).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 43 Ph,P4o Ph \c-H

I HO/C;;;.H

I

Ph

(64)

(65)

i

/G-B"

PhLi

PhLi

(cis)-PhCH=CHPh

( / r a m )-PhCH=CHPh

The phosphonate modification of the Wittig reaction is usually much more stereospecific leading to the trans isomer, with only trace amounts of the cis (164,186). It has been claimed (164,187) that solvent and Lewis bases have no effect on the stereochemistry and that only minor changes are produced by sterically and electronically different starting materials. The following examples show, however, that bases do affect phosphoryl activated olefination. Dihydrotestosterone reacts with diethyl ethoxycarbonylmethylphosphonatein an aprotic solvent in the presence of sodium hydride to give exclusively trans-3-ethoxycarbonylmethylene5-a-androstane-l7p-01, whereas addition of potassium-t-butoxide as Lewis base led to a preponderance of the cis isomer (188). A related observation has been made by Horner (1 39). Treatment of benzaldehyde with diphenylbenzylphosphine oxide and one mole of phenyllithium gave 90% threo-p-hydroxyphosphineoxide (64)and 5% erythro isomer (65). Treatment of the erythro isomer with phenyllithium gave cisstilbene, but potassium-tert-butoxide resulted in trans-stilbene. It is clear that an exhaustive study of the factors influencing product stereochemistry in the W h i g and related reactions is required. R'R2CHP(O)(NMeZ),

BuLi

- 78"

RRaCP(0)(NMe&

I

Li

(66) I

ASi02

4

(i) R3R4CO (ii) HaO

R'R2C=CR3R4 a R'R'C-CR3R4 benzene

I

(Me2N),P0 (67)

1

OH


44

From the synthetic point of view, a recently developed variant of the phosphonate modification of the Wittig reaction should prove valuable. Corey and Kwiatkowski (189) have recently been able to obtain either pure cis olefin or pure trans olefin by employing a-lithio phosphonic acid bisamides of type 66. The stereospecificity of this reaction rests upon the isolation of the two diastereoisomers of 67 which, upon heating in benzene or toluene in the presence of silica gel undergo stereospecific (probably cis) elimination to give the respective olefin in high yield. The 8-hydroxyphosphondiamidates may also be synthesized by alternative means. Steric effects can affect the course of the Wittig reaction. Thus, although benzylidene groups a to the carbonyl in cyclohexanone do not prevent olefination (190), triphenylphosphine methylene will not attack acetomesitylene (191). Reaction does occur with benzalacetomesitylene, but conjugate addition takes place as shown in eq. (45). Conjugate addition is rare for phosphorus ylids and apparently only occurs when the carbonyl group is sterically hindered. PhCH=CHCOCeH11

+

4

+ PhaP=CHa

Ph3P-CH2-CH-CH-COCsHlI

I

Ph

-

A

+ CaH11CO-CH-CHPh

\/

(45)

CH2

C. Geometrical Isomerism Two types of geometrical isomerism are found in organophosphorus compounds : (a)that resulting from the configuration of phosphorus and (b) that arising from configuration of an atom attached either directly or indirectly to the phosphorus atom. The former type is restricted to cyclic and the latter to acyclic phosphorus compounds. Many examples of both of these types have appeared in recent years, mainly as a result of investigations using NMR. Since (a) and (b) involve quite different concepts, they will be treated separately. 1. Cyclic Compounds

From the point of view of phosphorus stereochemistry, cyclic compounds are much more important than the acyclic ones. The ring compounds provide information on the configurational stability of the


phosphorus atom not always obtainable using optically active P(1V) compounds. Denney and Denney (96)have separated cis and trans six-membered cyclic phosphates by gas chromatography. The phosphates were obtained by oxidation of the corresponding phosphites (see Sect. IV). No work was done however on the interconversion of the cis and trans isomers. Ramirez et al. (192,193) have observed a slow stereomutation at phosphorus, in chloroform solutions of the meso five-membered cyclic phosphate (68). Roughly equal amounts of the two isomers were formed. It was suggested that the stereomutation was catalyzed by traces of methanol but traces of acid may have been responsible as aged chloroform solutions were employed. A definite configurational assignment was not made in this case but on the basis of 31P-ring Me M e 0\

...:,””’

O””\

0

+ 0 ,O , ‘ COMe + M e 0P COMe

.--. COMe

(68) hydrogen coupling constants, Ramirez (193)suggests a smaller coupling constant for the cis isomer of ~~-4-acetyl-5-ethyl-2-methoxy-4-methyl-

2-oxo-l,3,2-dioxaphospholan(69).

COMe (69)

There is a surprisingly large difference between the coupling constants for the cis and trans isomers of 69 (4.4and 14 cps), as they appear to differ only in the configuration at phosphorus. Ramirez attributed this to a difference in the dihedral angle between phosphorus and the ring hydrogen, resulting from a strong dipole-dipole interaction in the cis isomer. This is not a completely convincing argument, for, although it

46


has recently been shown (194) that 3JpH depends on the dihedral angle between H-C and P-C, according to an approximate relation given by Karplus, a very large change in conformation would normally be required to bring about a difference in coupling constants of nearly 10 cps (see Sect. V-C-2). Possibly an equally important factor is the change in charge distribution with conformation (subsection D). A somewhat similar stereomutation has been observed for the cyclic phosphonate 70, but refluxing with dilute hydrochloric acid was necessary (88). The equilibration results in a 2 :1 mixture of trans :cis. The identical IR absorption frequencies for the phosphoryl groups in 70 and 72 are good evidence for a different configuration of groups about the 4 position.

ClCHa E t k a p / C H a P h

II

0 (72) ( / r a m )

The fact that the six-membered cyclic phosphonate (70) required refluxing with hydrochloric acid for stereomutation while the fivemembered cyclic phosphate (68) underwent stereomutation simply on standing, perhaps in the presence of trace amounts of acid, may be an important piece of information regarding the pentacoordinate transition state proposed for the acid hydrolysis of cyclic phosphate esters and also from the point of view of the stereochemical rigidity of cyclic P(V, compounds (see Sect. VI). Another more novel molecule which exhibits cis-trans isomerism is the phosphacyclobutane(73).Gas chromatography of this ester showed two peaks, but here again no work was done on the interconversion of


0 MeV,!-OMe

MeI

MMe

e

(73)

the two isomers ( I 95). This problem would be most interesting, as intermediates of type 71 in which both hydroxyls are apical, should be almost impossible to form because of the angular restrictions imposed by a four-membered ring. The acid from 73 is quite stable to boiling concentrated nitric acid and potassium hydroxide solutions. This stability was thought (1 17,118)to be indicative of freedom from internal strain in the molecule, but restricted rehybridization dependent upon the four-membered ring, or simple steric hindrance to attack would seem to be more likely explanations. Cyclic bisphosphine oxides and phosphonium salts also exhibit cis-trans isomerism as a result of configuration at phosphorus. These have already been dealt with (Sect. IV). 2. Acyclic Compounds Considerable data are now available on the characterization of various cis and trans alkenyl phosphorus compounds. There are in most cases quite distinct cis and trans phosphorus-proton coupling constants analogous to proton-proton couplings in alkenes. Table VII gives a number of examples of these. It can be seen that the trans couplings 3 J p H for vinylphosphorus compounds are in the range 30-50 cps whereas cis couplings are usually about 10-25 cps. In allylic compounds on the other hand, cis couplings are greater in magnitude than trans couplings. Unfortunately, little work has been done on the sign of the coupling constant in phosphorus compounds (17,197,200) so that the relative signs of these values are uncertain. Based upon the homoallylic compounds 74 and 75 (Table VII) and model compounds, such as y-dimethylallylphosphonate, it has been shown (198) that transoid 5 J p H coupling has a greater magnitude than cisoid 5JpH coupling in the system H-C--C-C-C-P. This is analogous to 5 J coupling ~ ~ (201). 8, y-Unsaturated phosphonates, such as 74 and 75, are obtained by a Stobbe-type condensation of diethyl 13-carbethoxyethylphosphonate

48


TABLE VII

cis-trans Coupling Constants in Unsaturated P Compounds

3JpHcis, cps

Compound PhCH=CHP(O)Pha CHa=CClP(O)(OEt)a ClCH=CHP(O)(OEt)a CH3CH=CPh-P03Ha CHa=CPh--POaHa CHBr=CPh-P03Ha CHCl=CPh--P03Ha PhCH = CPh-POaHa PhCH=CH-P03Hz

MeO-CeH4-CH=CHP(0)(OEt)2

Cl-Ce H,-CH=CHP(

0)(0Et)a

NOa-CeH*-CH=CHP(O)(OEt)a

CH3(CH2)3CH=CHP(O)(OEt)a CHa=CCH3P(O)(OEt)2 + Ph3P-CH=CHa Br+ Ph3P-C(CH3)=CHa Br-

3JpHtrans, cps

Ref.

19.5 13.6 13.6 20 22 15 13 16 16 23.7 23.8 23.5 23.1 23.5

40.3 35.9 40.3 38 45

50.3

22 13 13 12 12 12 12 12 12 14 14 14 14 14

25

50

196

22

48

196

19

12

23

194

23.5

194

50

17

194

12 (continued)


TABLEVII (continued) Compound

3JpHcis, cps

3JpH trans, cps

9

v

Ref. 12

48.8

12

‘OEt

P(CH = CH3,

13.6

30.2

197

*JPH cis (MeO),P(O)OCMe=CH-C00Me 1.8 ( Me0)2P(0)OCH=CCl-H ( T ) 1.7

4JpHtrans 0.9 (f11.6 (1.2 and 3.2)

199 199 198

(CH3)2C=CH--P(O)(OEt)a

sJpHcis

5JpH trans

(CH3)2C=C(COOEt)

I

H,CP(O)(OEt)OH

4.1

5.8

198

4.4

5.6

198

4.2

5.4

198

(74)

CH3PhC=C(COOEt)

I

H2CP(O)(OEt)OH (75)

(CH3)2C=CH-CH2P(0)(OMe)2

with ketones (198). Approximately a 1 :1 ratio of cis :trans products is obtained. No base catalyzed isomerization was observed in the compounds studied although this type of isomerization [eq. (46)] has been reported (202). C-C=C-C-p-

I I I

H O

OH-

&

C-CH-C=C-p-

I 1

0

(46)

Vinyl phosphonates on the other hand are apparently produced stereospecifically by the Wadsworth-Emmons procedure, i.e., reaction of the carbonyl compound with tetraethylmethylene-bisphosphonatein the presence of base. The trans isomer is obtained (14). cis-Vinylphosphonates can be prepared by catalytic (Lindlar) reduction of the corresponding ethynylphosphonates (14).


50

Isomerization of vinyl phosphorus compounds has received some attention. Unlike the bis-phosphines, cis-l,2-vinylene-bis-diphenylphosphine oxide and sulfide may be converted to the trans isomers by refluxing in THF with phosphorus trichloride (19). The mechanism and generality of this isomerization are unknown. Presumably the C-C bond must lose at least some of its double bond character in order to undergo rotation. One can postulate an intermediate such as in eq. (47), but this is purely speculative.

H

/"

%=C PhzPf \'PPh,

"

-

H\

/

H

Ph,P 4c-c\pph,

l

0 p

(47)

I

0-

<Pa,

The partial conversion of trans vinylphosphonates to the cis isomers has been achieved by photoisomerization (14). Thus photolysis of diethyl trans-8-styrylphosphonate for 12 hr gave a 40 :60 cis :trans mixture. The isomerism considered so far has been due to the presence in the molecule of a C=C double bond. Interesting NMR data should also be obtainable from a study of molecules in which cis-trans isomerism is not dependent on a C=C double bond, i.e., molecules such as 76-78. &p(owEth

(76)

&

A

P(O)(OEt)z

(77)

(78)

P(O)(OEt)z

Diethyl 2-methyl- and 3-methylcyclohexylphosphonates76 and 77 are obtained as mixtures of cis-trans isomers which are separated by gas chromatography (203), and gas chromatography and PMR showed the presence of presumably endo and exo isomers in the norbornene compound (78). Unfortunately, attempted separation of 78 resulted in partial decomposition and the structures of the two isomers could not be assigned. No phosphorus-ring hydrogen coupling constants were reported for 76-78 but a study of similar systems by Benezra and Ourisson (194) has

STEREOCHEMICAL ASPECTS O F PHOSPHORUS CHEMISTRY 5 1

revealed an angular dependence of the spin-spin coupling constant, 3Jp H . For example in the phosphonate derivative 79, 3JpH is 12 cps, in 80 it is 35 cps while in 81 3JpH is approximately 0. The dihedral angles in 79, 80, and 81 are probably about 60, 180, and 90" respectively. In

(80)

(82)

compound 82, 3JpHi = 7 cps while 3JpH26 0.5 cps. It should be noted here that a dihedral angle of 180" does not always result in a large 3 J p H value. Thus in acetylenic compounds, P-C-C-H, 3Jp H can be quite small ( < 0.5 cps), smaller in fact than the coupling across two triple bonds (204). D. Conformational and Rotational Isomerism

The study of conformation in phosphorus chemistry is still in its infancy. The little work that has been done is almost wholly concerned with very simple molecules and the most probable rotational isomer or isomers present in solution. Nevertheless the importance of conformation has increased considerably in the last few years especially in relation to the anomalous rates of reaction of cyclic phosphate esters (Sect. Vl). As a result of molecular orbital calculations carried out on aliphatic phosphate esters (205) it has been suggested that very little energy is required to bring about small changes in conformation. These changes are considered to alter the 2p-3d orbital interaction sufficiently to result in large changes in charge distribution, i.e., nucleophilic attack at phosphorus is sensitive to the conformation of the ester groups about phosphorus. The charge distribution in cyclic esters is proposed as a

52


possible explanation for their extremely rapid rates of hydrolysis (205). Some time ago Paddock (206) suggested similarly that a restricted P-0-C angle should not only cause direct ring strain but would also prevent back donation (by the ring oxygens) to phosphorus, thus causing it to become strongly electrophilic. Considering Jaffe's conclusion (207) that unequal radicals enter into effective competition for the d orbitals of the central atom, it is perhaps not unreasonable that small changes in conformation and alterations in bond angles should markedly influence electronic charge distribution. Useful information might be gained here from 13C NMR of certain phosphonate esters, owing to the dependence of 13C-H coupling constants on the electronegativity of attached groups (in this case 31P).Unfortunately, a correlation of the 31P chemical shift with electron density at phosphorus is not yet possible (17,208), although it has been reported (209) that five-membered cyclic phosphate esters show less electron shielding of the phosphorus nucleus than do sixmembered esters or acyclic phosphate triesters. This does offer some support for the above proposals of increased electrophilic character of the P atom in five-membered phosphates, and is consistent with decreased dZ-pnbonding in these esters. It is perhaps significant here that the recent structure determinations of methyl ethylene phosphate (210) and methyl pinacol phosphate (21 1) have shown that the cyclic P-0 bond lengths are equal to the exocyclic P-OMe bond length and these values do not differ significantly from those in triphenylphosphate (212). This in itself would seem to indicate no major difference in the n bonding involved in the cyclic or acyclic phosphates, but based on symmetry arguments it has been proposed (21 1) that in the cyclic case, only four d orbitals are available for n bonding whereas five are available in acyclic phosphates. The remaining d orbital in the cyclic phosphate is thought to facilitate nucleophilic attack at phosphorus. As pointed out in Section VI, other calculations (213) have placed more emphasis on angle bending and bond eclipsing as the important factors governing the total strain energy in cyclic phosphate esters. These calculations revealed that the actual value of the strain energy, and the variation of this value with changes in the ring OPO angle, were sensitive to the values of the force constants and bond eclipsing constants. For an OPO angle of 90" in the transition state, the energy of the ring strain was of the order of 10 kcal/mole lower than for an OPO angle of 120".


It is probably true to say that both (a) ring strain as a result of angle bending and bond eclipsing, and (b) the concept of configurationally and conformationally monitored electronic charge distribution, play a part in determining the hydrolysis rates of phosphate esters. (b) embraces d-orbital participation and stabilization as a function of hybridization and the arrangement of groups about the phosphorus atom. Rehybridization is an important factor affecting reactivity and is apparent in the observed difficulty of quaternization of certain bicyclic phosphines (Sect. IV). An attempt has been made to elucidate the conformations of phosphines, phosphine oxides, phosphates, and phosphites in benzene solution using dipole moments, molar Kerr constants, and refractivities (214,215). Results indicated that the phenyl rings in triphenylphosphine oxide and sulfide are rotated (in the same sense) through angles of 60" and 62" from a theoretical model in which the phenyl planes are parallel to the molecular symmetry axis. In triphenylphosphine itself, the groups are rotated through 62". These results compare favorably with those obtained by X-ray analysis of solid triphenylphosphine (216). There is evidence that rotation around P-C and P-0-C linkages is rapid, even in compounds such as tert-butylphenylphosphinyl chloride (217,218). Rotational isomerism has been observed in the NMR spectra of organophosphorus compounds as a doubling of the resonances (218). This doubling has been found to be essentially temperature invariant and has been interpreted (218) in terms of a very low energy difference (AH = 0), but a high energy barrier between, the two isomers (if in fact the doubling is actually due to two discrete rotational isomers). Thus, the observed (219) PMR spectrum of 0,O-diethylmethylphosphonothioate was found to agree with a calculated spectrum based on two sets of nonequivalent methylenic protons (the nonequivalence of the methylenic protons is due to their diastereoisomeric environments. For other examples and discussions of nonequivalence see ref. 220). In this particular case of the diethyl ester, an explanation based on unequal P-O(R) bond orders was offered rather than preferred ethoxy group orientiations about P-O(R) single bonds. A similar effect would be produced by employing the antibonding electrons of only one oxygen atom in "back-donation" type resonance stabilization (219). In view of the results obtained for monoesters and for compounds such as ButP(0)(F)NMe2 the argument based on unequal bond orders seems invalid.

54


A study of N,N-dimethyl-tert-butylphosphonamide fluoridate, Bu'P(O)(F)NMe, (221) gave some quite unusual results. NMR (31P, l0F, and lH) spectra indicate two, presumably rotational, isomers in an approximately 3 : I ratio at room temperature. At 300", the ratio is 1 : 1. One isomer gave two sets of doublets for the NMe, group but the other isomer showed essentially no P-H or F-H coupling. Thinlayer chromatography also showed two components in a 3 : 1 ratio. This is certainly remarkable, as one would not expect rotational isomers of this type to be separable by chromatography [although rotational isomers of 2,4,6-tri-tert-butylbenzoic acid amides have been isolated in this way (222)]. The doubling of the phosphoryl (and thiophosphoryl) bands in the infrared spectra of phosphates and phosphonates has also been attributed to rotational isomerism involving the P-0-R groups (223228). Thus, the P=O band for phosphonates of the type HP(O)(OR), is a doublet, the relative intensities of the components varying with solvent (223). The lower frequency band was less intense in the liquid and absent in the solid, but it reappeared again in the gaseous phase (226). Low temperature IR spectra of (MeO),PO, (MeO),PS, (MeO),P(S)Me, and MeOP(O)Cl, in the solid, liquid, and gas phases indicate the presence of rotational isomers in these compounds. Crystallization stops the rotation and results in elimination of one isomer (226). Isomerism as a result of rotation around P-C bonds has also been observed (229). Raman and IR spectra of chloromethyl phosphonic dichloride (liquid) confirm the presence of two isomers; I R ofthe crystal showed only one form. Experiments with solvents of different polarity showed that the symmetrical form was present in the crystal, but the unsymmetrical form prevailed in the liquid state. Dialkylphosphinic chlorides (except the dimethyl compound) have been shown (230) to exhibit two P-C1 absorption bands as a result of P-C rotational isomerism. Rotational isomerism has been given some theoretical treatment (231-233). For example, of the three likely conformations (Fig. 8) for the dimethylphosphate anion, calculations suggest that only the conformation with C, symmetry is involved in solutions or crystals of barium dimethylphosphate (23 1). Favored conformations of molecules can lead to important stereochemical consequences. Kenyon and Westheimer (234) have shown that

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 55 Me

Me

O \ 0.- / ‘P

o--+/

‘

0

‘\

‘ 0

0

/

0-Me

O \ O - - - p/

OcMe

0‘

Me

\o G

Ca,

\

Me

Figure 8

1,2-dibromo-1-phenylpropylphosphonicacids decompose stereospecifically in aqueous base to 1-bromo-1-propenylbenzene, bromide ion, and a phosphorus moiety which behaves as the hypothetical monomeric metaphosphate ion [eqs. (48) and (49)]. The erythro isomer 83 gives the cis olefin and the threo isomer 84 gives the trans olefin as expected for a trans-oriented elimination. Br

Br

Ph-C-

I

Ph

I

NaOH

\

I

HaO

/

\H

\

/H

C-CH3-

I

P03Hz H (83) Br H Ph-C-

I C-CHs I

I

I

Br

Br

Ph >-

/CH3

C=C

/c=c\ Br

+ Br- + H2P0,

(48)

+ Br- + HaPo;

(49)

CH3

(84)

Swan (235) has shown that this stereospecificity is pH dependent, as erythro- 1,2-dibromo-2-phenylethylphosphonicacid (85) decomposes at pH 7 to the cis olefin but at pH 3.4 a mixture of cis and trans isomers is obtained.

- 0 H ‘7’ \’ -O\ / Ph

I/?

c

Br

>=./

Ph Cd,,NH2+

H

Br +

EtOP03-

(50)

‘H

B< ‘H

(85)

Swan has interpreted this to mean that the acid, which is present as the dianion at pH 7, exerts a sufficient dipolar repulsion toward the 2-bromine to hold the molecule in the conformation shown (85), which

56


is favorable for a trans elimination of bromide and metaphosphate ions [eq. (SO)]. At lower pH the acid is only monoionized and presumably the weakened dipolar repulsion allows the conformation of the molecule to be determined more by other factors. The solvent probably plays an important role in conjunction with pH, as it would be expected that dipolar repulsive forces would be more effective in nonpolar solvents. This pH-solvent determined stereospecificity has also been observed for the analogous carboxylic acids. Thus, erythro- 1,2-dibrom0-2-phenylpropionicacid decomposes stereospecifically in ethanol to the cis olefin but in the more acidic solvent water, a mixture of cis and trans isomers is obtained. E. Steric Effects Although it is very difficult to separate steric from electronic effects, steric hindrance does seem to be an important factor in the reactions of P(1V) compounds. It has even been suggested that phosphorylation of cholinesterase may be subject to steric hindrance so that steric control could prove valuable in modifying the reactivity of certain types of organophosphorus compounds of biological interest (236). Bulky groups attached directly to phosphorus markedly reduce the rates of hydrolysis of various P(IV) halides and esters (237-240). For example diisopropylphosphiny1 chloride is hydrolyzed in aqueous acetone nearly 700 times as slowly as dipropylphosphinylchloride (238). This, together with the fact that the diisopropyl compound exhibits a lower energy of activation than the dipropyl compound is probably indicative of steric hindrance (120). As might be expected the effect of bulky substituents on reactivity is, in general, much more marked in phosphinyl than in phosphonyl compounds. Thus isopropyl isopropylphosphonochloridate is only hydrolyzed about 25 times as slowly as propyl propylphosphonochloridate. In nucleophilic displacement reactions such as those just cited, care must be taken before declaring a particular effect a result of steric hindrance as it cannot be assumed a priori that the nucleophile will attack at phosphorus itself. Westheimer et al. have shown (241) that in the solvolysis of tetrabenzyl pyrophosphate, catalysis by imidazole or N-methylimidazole occurs by nucleophilic attack at phosphorus, but with pyridine as base, attack occurs at carbon (242). It is suggested (241) that the transition state for attack by imidazole at a phosphorus


atom is stabilized by d,-p, overlap and that the more available lone pair on imidazole, as compared with pyridine, favors attack of the former at phosphorus. Similarly, 2,6-lutidine increases the rate of hydrolysis of diethylphosphonochloridate [which reacts rapidly with less basic amines such as aniline (243)l. 2,6-Lutidine is too sterically hindered to attack the phosphorus atom (241,244) of either compound, but can abstract a proton from the nitrogen atom of the phosphorodiamidic chloride and hence accelerate hydrolysis via a metaphosphatetype intermediate (see Sect. IV). There have been many reports in the literature of sterically hindered organophosphorus compounds and many more proposals of steric interference in reactions involving P(IV) compounds. Only a few representative examples can be dealt with here; a number of others are listed under ref. 245. One of the early examples of a sterically hindered organophosphorus compound is “ Boyd’s chloride ” 86 formed from triphenylcarbinol and phosphorus trichloride (246,247). The structure originally assigned to the compound was 87 as alcohols normally form phosphites with phosphorus trichloride. 0

II

PhaC-PCIz

Ph3C-O-PCIz

(86)

(87)

Compound 86 is not attacked by boiling water or aqueous sodium hydroxide and can be recrystallized from ethanol with little loss. Alcoholic potassium hydroxide gives triphenylmethylphosphonicacid. Steric hindrance is also thought (248) to account for the sluggish reactivity toward nucleophiles of the somewhat similar phosphinic chloride 88. 0

II 1

Ph2C-P-CI

1

CI Ph (88)

In the synthesis of sterically hindered phosphorus compounds, it is almost impossible to attach more than two highly branched groups to the phosphorus atom. Thus highly branched Grignard reagents react with phosphorus trichloride to give only the disubstituted product, while the reaction of r-BuPOC1, with t-BuMgC1 is very sluggish (249).

M. J. GALLAGHER A N D I. D . JENKINS

58

Similarly, the phosphoroamidic dichloride 89 reacts with only one mole of Grignard reagent 90 to give the highly hindered acid chloride 91. This was reported (250) as being difficult to hydrolyze and, in fact, it was claimed that the partially hydrolyzed product 92 could be steam distilled out of aqueous hydroxide solution. A model of 92 indicates considerable steric crowding but it seems unlikely that this factor alone could account for essentially complete loss of acidity. In general, branched chain alkylphosphonic acids give a fairly linear Taft plot (251) although deviations are observed with phosphinic acids such as Bu:P(O)OH (249). Et2N-POCI2

+ Me2CH-CMe2-MgCI

d

(90)

(89)

I

MeaCH-CMe2-P(0)(C1)NEtz (91)

MezCH-CMe2-P(0)(NEtz)OH (92)

1. HCI/ROH/H.O, 23 hr 2. NaOH 3. Steam distil

+ MezCH-CMe2P(0)(OH)2 (93)

The proposed sterically inhibited acidity of acid 92 contrasts with the observed (252) sterically increased (or assisted) acidity of the methylene protons in the phosphonium salts 94 and 95. Both of these salts undergo trans-ylidation with triphenylphosphine methylene [eqs. (51) and (52)]. This is unexpected on the basis of inductive effects, and, in fact, triphenylphosphine methylene is less basic than the corresponding ethylidene, isopropylidene or isobutylidene. +

Ph3P-CH2-SiMe31(94)

Ph3$-CH2-CMe31(95)

+ Ph3P=CHz + Ph3P=CH2

-

t

-

+ Ph3P-CHSiMe3 Ph3$-eHCMe3

+ + Ph3PMeI(51)

+ Me3bMeI- (52)

It is suggested (252) that the methylene protons in 94 and 95 are subject to severe steric crowding and that this results in C-H bond elongation and hence increased acidity of these protons. Compounds in which both a chlorine and a hydrogen atom are attached to the one phosphorus atom are usually unstable and lose hydrogen chloride very readily. However, the phosphinic chloride 96


is extremely stable to both hydrolysis and oxidation (76). The corresponding phosphinic anhydride 97 is also very stable as opposed to the phenyl analog which decomposes facilely to tetraphenylcyclotetraphosphine, phenylphosphine, and phenylphosphonic acid simply on standing at room temperature (253).

I

OH-/Fe(CN),'- 80-100 iZ2hr

KM"O,,OH-1

HOOC t-Bu

H

r-Bu

H

(97)

t-Bu

(98)

Steric hindrance does appear to be the main factor here but inductive effects could play an important part. For example, the stability toward oxidizing agents of secondary phosphine oxides increases markedly with increasing methyl substitution in the ring (254): (2,4,6-Me3CsHz)zPH0is oxidized in 30 min by alkaline ferricyanide at 80-90" (2,3,5,6-Me4C,H),PH0 is oxidized in 2 hr by alkaline ferricyanide at 80-90" (,Me5C&PH0 is only 14% oxidized in 17 hr by alkaline ferricyanide at 80-90"

F. Neighboring Group Participation Relatively few cases of neighboring group participation in the reactions of phosphorus compounds have been reported in the literature. The following examples are intended merely to illustrate these effects.


60

In the hydrolysis of 2-hydroxy-2,2-dimethylethylcyclohexyl phosphate 98, the rate of formation of the'cyclohexyl phosphate is nearly 40 times the rate of formation of the glycol phosphate. For the isomeric 2-hydroxy-1,l-dimethylethyl cyclohexyl phosphate, glycol phosphate formation exceeds cyclohexylphosphate formation by a factor of nearly 3. This is explained by a mechanism for the hydrolysis of 98 involving epoxide formation (255). A somewhat different mechanism was invoked (256) to account for the alkaline hydrolysis rates of alkyl diethylphosphinates 99-101. Hydrogen bonding of the neighboring hydroxyl group to the phosphoryl oxygen was proposed to account for the increased rate in 100. 0

0

II

EtaPOCH2-CH3 (99)

k(mo1e -%ec - l) 0.573 x lo-'

0

I1

EtzP-O-CHa-CHa-OH (100)

4.42 x 10-4

II

Et~P-O-CHa-CH2-OMe (101)

2.25 x 10-4

It seems equally likely that participation by the neighboring oxygen atom as in 98 is responsible for these rate differences. p-Nitrophenyl phenacyl methylphosphonate(102) is hydrolyzed about 9O00 times as fast as ethyl p-nitrophenyl methylphosphonate (103). It has been suggested that the neighboring carbonyl group could enhance the rate in several ways, one possible intermediate being 104 (257). This intermediate should be considered in the light of results obtained with phosphoramidates. Hamer (258) found that the phosphoramidate 105 did not undergo an intramolecular rearrangement to phosphoramidate 106, although it did react with 1-naphthylamine to form the


N-1-naphthyl phosphoramidate. This was explained on the basis of entering and leaving groups being unable to occupy apical positions in a trigonal bipyramidal intermediate 107 for the compound 105.

'CH,-NHPh 105)

\I/

N+

0--P

I i0-

I\ 1

N+

OR

/I\

(107)

It is worth mentioning here that in the apparently analogous system 108, a (presumably) intramolecular rearrangement does occur in the nitrogen to oxygen phosphoryl migration (259). H

I

H

I

R-C-C-COOH

I

OH

I

NH

A,HCI/HzO

H

1

H

I

R-C-C-COOH

I

I

I

VI. P(V) COMPOUNDS A. Structure and General Properties This is the first class of compounds for which there is no accumulation of data obtained with other elements on which one may rely to provide analogies and working hypotheses. Compounds of this type have long been known (e.g., PX5; X = halogen) but only recently have they become available in sufficient variety to allow consideration of the stereochemical consequences of an atom carrying five substituents.

62

M. J. GALLAGHER A N D I. D . JENKINS

A P(V) molecule must utilize at least one of its 3d orbitals in bonding, and which of these is considered to hybridize with the 3s3p3 orbitals normally used determines the geometry of the resulting structure. The possible structures are shown in the diagrams 109-111. The stereo-

chemical consequences of each structure will differ in some respects from those of the other two and clearly, before any useful interpretation of reaction pathway is possible, the geometry of the reacting species must be known. Unfortunately, knowledge is at a very early stage in this complex field. The various possibilities have been the subject of a great deal of theoretical speculation particularly with regard to bond lengths and bond energies. Which result is obtained appears to depend on what approximations are made and on the relative importance attached to the various parameters involved in the calculations. A clear summary of the current state of this mild controversy has been given by Hudson (120). The principal fact which seems to emerge is that there is little energy difference between the possible structures but that the trigonal bipyramid formed from three sp2 bonds and two pd bonds is slightly favored. Indeed, all structure determinations made to date support this, but since many of these refer to the crystalline state it does not follow that the same structure is preserved in the liquid or gaseous phase. A good example is Pel, whose structure varies with solvent (260) and phase. Some electron diffraction studies of the vapor of PCI, and PF5 have given the same picture but here it may not be wise to extrapolate from structures involving strongly electronegative substituents to others forming weaker bonds. The discussion which follows must therefore be seen as liable to considerable revision in the future. Nevertheless, a recent review by Muetterties and Schunn (discussing pentacoordination in general) summarizes the structural work on these compounds and shows that, for monomeric species at least, the trigonal bipyramid is the structure most commonly found (261). Hence, we will adopt this structure as a working hypothesis. At present, insufficient data are available to allow an accurate assessment of the effects of substituents on stability. In general P(V)


’15.

Y

y b

X b

“/j

b ah z

x b

Y x.

Y

Fig. 9. Diastereomeric (+) forms of Pabxyz.

compounds seem to be reactive species, but since a considerable variety of them is now known and they are relatively stable, it no longer seems reasonable to consider them as transition states. This applies only to neutral species; the situation when a positive or negative charge is present is less clear. In the absence of evidence to the contrary it will be assumed that such compounds have appreciable lifetimes and cannot be considered as transition states. Optically active compounds have been used extensively in chemistry as powerful probes for the study of reaction mechanisms but it does not seem likely that they will be similarly useful for P(V) compounds. A trigonal bipyramidal structure Pabxyz, carrying five different substituents, is capable of existing in ten diastereoisomeric racemic forms (Fig. 9) presenting a synthetic problem of awe-inspiring complexity. Even a compound of the type Paabbx would have three symmetrical and one racemic forms. The situation is simplified somewhat by incorporating pairs of substituents in rings, which restricts the positions such substituents can take up to apical-radial and radial-radial. One such ring reduces the number of possibilities to nine, but two, which is the maximum, of course, brings it down to a manageable two (if the rings are identical) or three if they are nonidentical (Fig. 10).

C

& p p

6

-

C C Fig. 10. Isomeric forms of P(V) compounds with two cyclic substituents.

64


Wittig and his school have studied the synthesis of P(V) compounds carrying cyclic substituents but have been unable to detect any evidence of isomerism (262). This failure probably resides in a unique feature of these structures first suggested by Berry (263) and elaborated by Gillespie (264) and others (265). Since, in the radial plane, the substituents are separated by an angle of 120°, vibrations in this plane are accompanied by little interaction until the angle between any two substituents approaches go", when repulsive forces between the substituents and the bonds begin to assert themselves. Hence, the formation of a structure of the type 112a from a trigonal bipyramid 112 requires relatively little energy. The return vibration to the trigonal bipyramid can now occur in either of the planes defined by xyz or aby. Such a process,termed pseudorotation, may result in interconversion of diastereoisomers (112 + 113) and, in fact, all ten diastereoisomers shown in Figure 9 may be so interconverted. The rate of interconversion, while dependent on steric and electronic factors, is normally very rapid. An additional important stereochemical consequence is that an optically active species may racemize without bond breaking, a process never observed for tetrahedral or octahedral molecules. Five successive pseudorotations are required (112 .+ 113 .+ 114 + 115 + 116 + enantio 112) in each of which the uninvolved substituent (pivot) is different.

The process is also possible for cyclic substituents provided that the structure of the ring can accommodate the angular variations involved. In this case it should be slower since the energy barriers to the necessary

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 65 CH2 R

CHa

CHa

‘CH2 (117)

(118)

vibrations will be considerably higher. If both rings were four membered, vibrations of this type should be impossible and hence isomerism should be observable, e.g., in a compound such as 117. The difficulties attendant on the synthesis of such a structure are, however, formidable, although the structure of a trigonal bipyramidal P(V) compound 118 containing a four-membered ring has been reported (266). The experimental evidence on which the above hypothesis of interconvertible isomers rests is due almost entirely to NMR studies. A trigonal bipyramidal molecule, PR5, should have two magnetic environments corresponding to apical and radial substitution. In consequence, if such a species is configurationally stable, two peaks should be observed for the group R and they should be in the ratio of 3: 2. Since PH5 has not been prepared and is believed too unstable to exist [though R4PH compounds are known (151,267)], much of this work has been done with P-F compounds; it has been reviewed by Schmutzler (268). Structures PF5, RPF4, and R3PF2show only single fluorine resonances a t room temperature in accord with the concept of a very rapid positional averaging process. Intermolecular exchange is unlikely since splitting of the laFsignal by 31Pis observed. On the other hand, some structures of the type R2PF3show two kinds of lSFresonance in a 1 : 2 ratio. In the case of the amino compound, Et2NPF4, nonidentity of fluorine atoms is observed at low temperature and the activation energy for interchange of fluorines in this molecule has been estimated at ca. 13 kcal/mole. This should be compared with the value of ca. 7 kcal/mole calculated for PF3C12and PF3Br2(269). Diamino compounds (R2N)2PF3 show two different leFenvironments at room temperature (270). It is difficult to see why only the structures R2PF3should show apical and radial fluorines and not, for example, RPF4, although significant differences are found even between apparently analogous R2PF3 compounds. Thus the cyclic compound 119 shows two lgFresonances

66


(119)

(120)

only at low temperatures in contrast to 120 which shows no sign of coalescence of its 'OF spectrum even at 100". This behavior has been attributed to steric effects and will be discussed below. A recent spectral study of PH2F3and PHFl (306) has led to similar conclusions: a trigonal bipyramidal structure with radial hydrogen atoms and undergoing rapid positional exchange without bond breaking. In structures where the substituents are less strongly electronegative a similar situation is found. A considerable number of pentaoxyphosphoranes (121,122) have been prepared and examined by Ramirez (271). No evidence has been reported of any differentiation between the

R

0,

/o

0, o ,

RO/p\I OR OR

RO/p\I OR OR

(121)

(122)

OR groups and though no results of low-temperature studies have appeared, the X-ray study (272) of the phosphorane from triisopropyl phosphite and phenanthrenequinone has yielded structure 123. Penta-p-tolylphosphorane shows only a single methyl peak in its

(123)

NMR spectrum down to -60". Other cyclic phosphoranes with five P-C bonds show some evidence of apical-radial substituents dependent on the bulk of the attached groups (273). Thus phosphoranes of type 124 show sharp singlets for the methyl resonances when R = phenyl or 2-naphthyl, a diffuse band for R = 2-biphenylyl, and


CH3

CH, (124)

doublets when R = 1-naphthyl or 9-anthryl. This implies a mixture of isomers or, perhaps, a very much slower rate of exchange. None of the above evidence rigorously excludes tetragonal pyramidal structures, but no simplification occurs on invoking such a type. A compound, Pabxyz, of this geometry would have fifteen possible diastereoisomeric racemic forms. The exchange process formulated above can be thought of as proceeding via such structures, in which case, if their lifetimes were appreciable, the possibility of obtaining an optically active P(V) compound would become impossibly remote. It has been suggested by Hellwinkel (273) that the tetragonal pyramidal form has the character of a transition state but the energy difference is probably too small to allow such a sharp distinction. Despite the great difficulties of obtaining stereochemically pure P(V) compounds, Hellwinkel has recently (274b) succeeded in obtaining an optically active penta-aryl phosphorane. Reaction of the resolved octahedral anion 125 with acid results in the formation of a mixture of three phosphoranes, one of which 127 retains the asymmetry of the anion and has [a],,k 94 k 1". The P(V) compound 127 can of course undergo the isomerization discussed above, but because of the restriction imposed by the rings such a process does not result in inversion (Fig. 11). Racemization is possible when both rings in the product phosphorane are identical and in fact 126 and 128 were also isolated and shown to be inactive. The papers describing this elegant work (274) also provide a clear and detailed discussion of more aspects of P(V) and P(V1) stereochemistry than is possible here, and they are recommended to anyone with an interest in this problem. The above discussion of P(V) stereochemistry applies equally to

68


other atoms having five substituents. All will belong to that class of structures called by Muetterties (275) “stereochemically nonrigid.” B. P o Structures as Reaction Intermediates

Despite the stereochemical complexity of the P(V) system and the unlikelihood of obtaining stable isomeric forms useful in mechanistic studies, a knowledge of such structures has become of increasing importance in recent years in order to understand the reaction pathways of many P(II1) and P(1V) compounds. The first proposal concerning P(V) structures as reaction intermediates was made by Ingold and co-workers (276,277) over thirty years ago to account for the formation of an alkane and a phosphine oxide by pyrolysis of phosphonium hydroxides [eq. (53)], R,P+OH-

--f

RnPO

+ RH

(53)

which contrasted sharply with the almost exclusive elimination of the


corresponding ammonium salts to give an amine, olefin, and water [es. (5411. +

R3NCHzCHzR OH- ---+ R3N

+ RCH=CHz + HzO

(54)

The saponification of phosphonium salts has been the subject of considerable study; the departing group is that which is most stable as an anion (276); the kinetics are third order (278,279) (except where the departing group is a very good one, e.g., p-nitrobenzyl, when the kinetics are second order (280); and the reaction proceeds with 100% inversion at phosphorus (36). On this basis, McEwen has proposed the following mechanism (4): R,P+

OH-

R4POH (130)

OH-

R4PO(131)

-

R3P0

+ R-

(55)

There are, however, some objections to this. The intermediates 130 and 131 should spontaneously racemize on the basis of the arguments presented above unless their lifetimes were extremely short and there is no good ground for supposing this, at least in the case of 130. This difficulty may be overcome by supposing that the intermediate is P(V1) and not P(V) since in this case racemization would not be expected (see Sect. VII). The phosphorus atom in R4P+ is highly electrophilic and certainly strongly solvated in aqueous solution and hence attack at such a solvated cation could lead directly to an octahedral intermediate such as 132. Alternatively, the second molecule of hydroxide required by the kinetics could attack 130 to give [R4P(OH),]- as has been suggested by Wittig (262) and McEwen (278). This reaction can have the same steric result but it seems less likely since there is no reason why the P(V) center in 130 should be strongly electrophilic.

(132)

This reaction, because of its importance, would seem to merit further study.

70


Phosphonium salts also react with alkoxides to yield phosphine oxides. The reaction is much more sluggish and is probably complex (15 1,281). Significantly it results in nearly complete racemization. A symmetrical intermediate has been invoked to account for the racemization but this is unnecessary since an initially formed P(V) compound of appreciable lifetime could easily racemize prior to subsequent reaction. The Wittig reaction (Sect. V) also proceeds stereospecifically with retention of configuration at phosphorus. The proposed intermediate 133 has many of the characteristics of a P(V) structure, and the retention

R3p-r +

6-CHR (133)

of configuration is also compatible with this since the four-membered ring should effectively block the autoracemization process. Much of the current interest in transition states (or intermediates) of this type stems from the work of Westheimer and his school on the hydrolysis of ethylene phosphate and related structures. This hydrolysis attracted attention since the observed rates were some 106-108times as great as for the acyclic analogs such as dimethyl phosphate. The heat of hydrolysis of methyl ethylene phosphate (134) is 7-9 kcal/mole greater than its acyclic analog 135 indicating the presence of strain in

the cyclic ester (282). It seems reasonable that the acceleration in rate is due to relief of this strain in the transition state or intermediate, and Khorana et al. have shown that the rate of hydrolysis of the corresponding six-membered cyclic ester 136 is unexceptional (283). Acid hydrolysis of ethylene hydrogen phosphate proceeds very largely by P-0 cleavage and is accompanied by exchange of oxygen with the aqueous medium at about 207, of the rate of hydrolysis (284), supporting the strained ground-state hypothesis since it indicates that collapse of the intermediate in the exchange process is less favorable than hydrolysis. Alkaline hydrolysis likewise occurs at a much greater


rate but no exchange of oxygen with solvent occurs. Subsequently it was found (285) that the enhanced hydrolysis of methyl ethylene phosphate proceeded with both ring opening and loss of methanol under acid conditions, but with exclusive ring opening in the presence of alkali. Cyclic phosphonates behave similarly (286). Strong support for the strained five-membered ring hypothesis was advanced by Usher, Dennis, and Westheimer (21 3) by detailed calculations of bond angles in methyl ethylene phosphate, which agreed closely with the concurrent X-ray work of Steitz and Lipscomb (210). Both approaches showed a ring angle of 99" at phosphorus, and hence considerable angular distortion from the anticipated tetrahedral structure. From this the relief from strain in a trigonal bipyramidal intermediate with a ring angle at phosphorus of 90" was calculated to be 3-6 kcal/mole which is sufficient to account for the rate increase. An angle in the ring of 120"would, on the contrary, introduce strain into the intermediate relative to the ground state. A recent structure determination on a six-membered cyclic phosphate (137) has shown (287) that the ring angle at phosphorus is 105.5" confirming the unstrained nature of the ground state in such species. Finally, the X-ray analysis of a pentaoxyphosphorane by Hamilton, LaPlaca, and Ramirez (272) showed that, in the solid state, the five-membered ring did indeed occupy CH,Br

& -/o

(kP,O

I

Br (137)

a radial-apical position and the ring angle at phosphorus was 90".In view of these studies the assignment of the structure 138 to the intermediate of acid hydrolysis must now be considered compelling.

(1%)

(139)

(140)

Haake and Westheimer also considered the possibility of a tetragonal pyramidal structure and the stereochemical consequences of the

12


phosphorus atom being chiral. Since there is evidence that the intramolecular flipping previously discussed occurs also with cyclic substituents, it does not seem probable that useful information will be obtained from the latter. Similar rate accelerations were observed (288) with other fivemembered cyclic systems but not with esters of cyclic phosphinic acids (139). Also, the cyclic phosphonic diester 140 underwent hydrolysis with almost exclusive ring opening (289) whereas methyl ethylene phosphate, gave both ring retention and ring opening. To account for these facts Dennis and Westheimer modified the original theory to include two further points: (a) there is an energy barrier to the occupation of an apical position by a carbon atom, or conversely, electronegative substituents favor apical positions (this is in agreement with theoretical expectations and the proposed structures of the fluorophosphoranes) ; (b) in the transition state pseudorotation occurred analogous to the autoisomerization of P(V) compounds discussed in Section VI-A. These, together with the original suggestion that the departing group left from an apical position (284), provide a rationale for the apparent exceptions. A trigonal bipyramidal intermediate of the cyclic phosphinic acid must have an apical carbon atom and the energy required to place it there is sufficient to offset the release of strain achieved in such a transition state. Similarly, in the case of the cyclic phosphonate, in order for the methoxyl group to take up an apical position prior to its expulsion "pseudorotation " must occur which would once again force a carbon atom into an apical position. It should be pointed out however that in the latter case the methoxyl group could occupy the apical position in the initial transition state formed by attack of water on the protonated ester, since this depends on which face or edge of the tetrahedron is attacked by the water molecule (140-142).

(141)

(14)

(142)

The first of the two modifications put forward by Dennis and Westheimer had been previously proposed for P(V) structures on theoretical (290,291) and spectroscopic grounds (9,270,292). Since the 3s orbital of phosphorus is concentrated in the radial bonds these are


the preferred sites for binding of electropositive groups. Such reasoning is also used to account for the single leF environment observed for R3PF2though this may be an oversimplification. In this context, it has been suggested (269) that the relatively strainfree 119 very rapidly isomerizes and hence shows only one fluorine EPFS

c P F 3

(119)

(120)

environment in its NMR spectrum as compared with 120 which shows two fluorine environments even at 100". However, it is difficult to see why acyclic RzPFBalso show apical and radial fluorine environments since these also should be strain free. An unrelated example of a rate acceleration attributed to relief of strain in an intermediate has been reported. The heterocyclic bis-salts 144 and 145 are known (293,294) to be decomposed by an excess of alkali into the phosphine-phosphine oxide 143. When the salts are in excess, different products (146,147), are formed which, on subsequent reaction with an excess of alkali, do not yield 143. The rate of this reaction is substantially greater than for acyclic monophosphonium salts. This is unexpected since the intermediate (either trigonal bipyramidal or octahedral) should be strained as a result of the angular distortion introduced into the ring. In this case it is suggested that relief of the strain arising from electrostatic repulsion between the two phosphonium centers is sufficient to overcome this. That the intermediate once formed is strained is shown by the preferential

14


opening of the ring in the product, instead of the expected expulsion of a phenyl group (295). In sharp contrast to these results Aksnes and Berges have observed (296) that alkaline hydrolysis of the cyclic monophosphonium salts 148 proceeds with ring retention and expulsion of the phenyl group. The rate for the five-membered ring was 1300 times that for the six-membered one and the reaction obeyed third-order kinetics. Analysis of the data, however, showed that the difference occurred in the frequency factor and not in the activation energy as might be expected by analogy with Westheimer’s work on the cyclic phosphates.

(148)

A number of other reactions are known which very probably involve P(V) intermediates. Some of these have already been mentioned, e.g., the action of halogens or bromocyanogen with optically active P(II1) compounds (Sect. IV). The racemic phosphines obtained by reduction of P(IV) structures with lithium aluminum hydride suggests a P(V) complex such as 149.

‘\.PI -RB Ra ‘I AlH; Ri

H

(149)

In the case of phosphonium salts, racemization may occur in an initially formed RIPH compound which has been isolated in one instance (150). Optically active phosphine oxides are racemized by HBr or HC1 (140,141) in the presence or absence of water. It is interesting to note that HCl is more effective than HBr, suggesting that the more electronegative chlorine forms a more stable P(V) compound. Similarly, such oxides are rapidly racemized by acid anhydrides (141). Denney has reported that when (+)PhMePrP reacts with chloral and the product is hydrolyzed, racemic PhMePrPO is obtained, and he has attributed this behavior to a P(V) intermediate (297).


Unfortunately, too few precise data are available in this complex field, particularly as regards the stability of these P(V) structures. It cannot be doubted that neutral P(V) compounds are relatively stable, and if, as seems probable, positively charged P(V) compounds can exist for long enough to undergo pseudorotation or autoisomerization, then it would seem unwise to consider these as true transition states. On the other hand, P(V) species carrying a negative charge would seem to be much less stable. Thus alkaline hydrolysis of ethylene phosphate, though very rapid, proceeds without exchange of oxygen with the aqueous medium. Optically active phosphine oxides are not racemized by boiling aqueous alkali and many P(1V) compounds react with alkali without racemization. All this suggests that intermediates such as 150 are extremely short lived and should perhaps be considered as

(150)

true transition states. This extreme instability may lie in the fact that the occupation of an apical position by 0 - is energetically highly unfavorable, a not unreasonable supposition in the light of current concepts, some of which have been previously mentioned. If such species are truly transition states then the reaction of resolved P(1V) compounds with nucleophiles to give asymmetric products is not at variance with the trigonal bipyramidal intermediates suggested for such reactions (3). Aryl amines displace alkyl amines from P(IV) compounds [eq. (56)]. ArNHz

/OH /OH + AlkNHP=O + ArNHP=O ‘OR

(56)

‘OR

However suitably constructed molecules such as PhNHCH2CH2NHP(O)(OR)OH (105) give no evidence of intramolecular reaction though they should favor it. On this basis Hamer (258) has suggested that in the transition state both entering and leaving groups should be apical, this being the only simple requirement which forbids intramolecular reaction in 105. This

76


is not in agreement with Westheimer’s views on the acid-catalyzed hydrolysis, but it is doubtful if the comparison can be carried too far since one reaction is done under acidic and the other under basic conditions, and this may well have a profound effect on the stability of the intermediate species. The intermolecular reaction proceeds probably by inversion and hence possibly by a transition state rather than an intermediate, and this is not necessarily the case in acid-catalyzed reactions.

VII. P(V1) COMPOUNDS Compounds of this type have been known for a considerable time, e.g., PF; . According to the Gillespie-Nyholm theory they should have octahedral geometry and this is true within experimental error for PF; (298). The complex anion 151 obtained by Hellwinkel (299) by the action of 2,2’-dilithiobiphenyl on phosphorus pentachloride has been resolved into enantiomers, strongly supporting an octahedral structure. Hellwinkel has also resolved a number of other such anions (274). The anion 152 formed by the disproportionation reaction shown in eq. (57) has a lDFspectrum compatible with this structure (300).

(151) 2MePF3NMe2 ---f [MePF(NMe2)2] [MePFJ+

(57)

(152)

Brown and Bladon (301) have obtained the only neutral P(V1) compounds known (153) by the action of PF6 on /3-diketones. Spectral data support the octahedral structure here also. Apart from this handful of substances, little is known about the chemistry or stereochemistry of P(V1). Gillespie has pointed out (264)


that octahedral structures should be stereochemically rigid since all the angles at the central atom are 90"and any appreciable distortion would be energetically expensive. This is confirmed (274d) by the stability of the anion 151. The stereospecific cleavage of these anions by acid has been mentioned in Section VI-A. P(V1) structures as intermediates or transition states have received little attention. It would be expected that the bulk of substituents should exert important steric effects when so large a number of ligands is attached to the central atom. This is borne out by the studies of Muetterties et al., on the adducts of PF5 with ethers (302). With diethyl ether an unstable adduct is formed but with the less-hindered tetrahydrofuran a distillable product is obtained. This should be compared with the minor steric effect observed in the saponification of phosphonium salts where a P(V) intermediate is believed to be involved (303). It seems likely that P(V) compounds in general will possess some Lewis acid character since PF, is quite a strong electron acceptor. By far the largest group of P(V) compounds known are the pentaoxyphosphoranes (such as 121 and 122) studied in detail by Ramirez (271). P(V1) structures should be important in the reactions of these compounds since the presence of five electronegative substituents should confer considerable Lewis acid character on the phosphorus atom and make it the preferred site of nucleophilic attack. The systematic chemistry of these compounds is in its infancy but two reactions have been examined in some detail (Fig. 12). The reaction with water is puzzling since ring retention is unexpected (see Sect. VI-B) and implies a considerable driving force which results in collapse of the intermediate or transition state to the thermodynamically less stable (compared with the ring-opened product) cyclic ester. If the reaction is sterically directed it is difficult to account for on the basis of an octahedral geometry in the intermediate. Alternatively, it is difficult to see why attack at oxygen or carbon should occur, and use of 180-labeled water results in a P=l80 ester, supporting attack at phosphorus by the water (271).

18


The reaction of carbonyl compounds with the oxyphosphoranes

121 to afford saturated oxyphosphoranes has been suggested (304) to proceed as shown. A transition state (or intermediate) such as 154

Rl R2 R l C O W R ,

/o

P

\

(OR),

formed by initial coordination of the carbonyl oxygen with phosphorus would seem to be particularly favorable for such an electron shift. Nucleophilic ligand exchange by Ar,P [eq. (SS)] has also been observed (305). Ar6P

+ Ar'Li

-----, Ar,MP

+ ArLi

(58)

This reaction presumably proceeds via a P(V1) intermediate. It is considerably more sluggish than the reactions of the oxyphosphoranes, probably reflecting the lowered Lewis acid character of the phosphorus in this class of compound.


VIII. ADDENDUM ADDED IN PROOF This brief section has been written in order to incorporate the more important papers which have appeared in the first ten months of 1967.

A. General Horner has published an extensive review covering his work on optically active derivatives of the Group V elements (308) and Michalski has reviewed the work of the Polish school on optically active P(1V) compounds (309). The synthesis of olefins using phosphoryl activated reagents has also been reviewed (3 10). Muetterties has discussed relative stability toward intramolecular racemization in pentacoordinate species in general (31 1). The influence of d-orbital participation on structure and stereochemistry in phosphorus compounds-particularly on the transition state for SN2 displacement at P(1V)-has been considered (312). Methods of resolution have been reviewed (313). I. Spectroscopic Methods

Further work has been reported on the angular dependencies of various 31P-1H coupling constants, and these should prove invaluable in stereochemical assignments. Table VIII summarizes these values and

TABLE VIII Angular Dependence of 31P-1H Coupling Type P(II1)-0-C-H P(II1)-0-C-H P(IV)-0-C-H P( 1V)-0-C-H P(I V)-0-C-H P(IV)-0-C-H P( 1V)-C-C-H P(IV)-C-C-H P(IV)-C-C-H P(IV)-C-C-H

Approximate angle, degrees 30 180 60 60 180 180 30 60 90 180

J, CPS

Ref.

2.8 10.8 3 6.2 21 22.4

314 314 315 316 315 316 194 194 194 194

7 12 0 35

80


for convenience, incorporates the values already recorded in Section V-C-2. The marked dependence of J on the dihedral angle supports the proposals of Ramirez that conformational changes accompany stereomutation in the cyclic phosphate ester 69 discussed in Section V-C-I. Gagnaire et al. (317) have observed two different 3JpHcouplings (9-9.6 and 1.2-1.8 cps) in monosubstituted 1,3,2-dioxaphospholans of type 155 which they attribute to different orientations of the protons with respect to the lone pair of electrons on phosphorus. RCH-0

IF

RCH-O

(155)

A similar reason is advanced for the AABBX-type spectrum observed (318) in the phospholan 156. Here the aJP(III)H couplings (25 and 6 cps) differ both in magnitude and sign and lead to the suggestion that the low values observed in acyclic systems may be time-averaged values arising from rapid rotation about the P-C bond. This suggestion contrasts sharply with the interpretation that steric compression increases the s character of the C-P bond (17).

H3cvcH I

Ph (156)

B. P(1II) Compounds The crowded tri-t-butylphosphine has been c-tained by Hoffmann and Schellenbeck (319) by the action of BdLi on BubPC1. The direct action of ButMgCl with PC13 leads to reduction as well as substitution. BdMgC1

+ PCla

4

BuP~CI+ B u~PH

The hindered tertiary phosphine reacts normally with methyl iodide and with sulfur, but fails to give a colored adduct with carbon disulfide, a reaction normally characteristic of trialkylphosphines. Stepwise replacement of ethoxy groups in P(OEt)3 with bulky alkoxy groups (e.g., But) produces a steady increase in the chemical shift of the phosphorus atom for the first two such replacetnents.


Introduction of the third such group, however, results in a large (10 ppm) negative shift. Mark and Van Wazer (320)have interpreted this as a sterically induced alteration in bond polarity and degree of 7r bonding. The calculated angular variation in each bond is ca. 0.25". No such effect occurs with P(IV) compounds. A new method, particularly suited for the resolution of triarylphosphines, has been developed by Wittig et al. (321).This incorporates the method of half quantities of Pope and Gibson (322) and involves partial conversion of the chiral phosphine to its hydroxymethyl salt by reaction with formaldehyde and an optically active acid such as camphorsulfonic. The phosphine is regenerated by treatment of the salt with triethylamine. 2Ar,P+ CHzO

1

+ HA* d A r 3 k H z 0 H A* + (-)Ar,P EhN

(

The optical purity of the products is uncertain, but the magnitude of the rotations (+ 8.7 and - 5.2)compares favorably with that of the previously reported triarylphosphine ( +2.9) prepared by cathodic fission (47). The method fails with alkyl- or aralkylphosphines. Shook and Quinn have reported full details of their work on 1,4-disubstituted4-phosphorinanols, including tentative assignments of stereochemistry based on differences in proton chemical shift values (323). The 31P spectrum of 1,4-dimethy1-4-phosphorinanol shows two peaks separated by 5.7 ppm; no interconversion of isomers is observed on heating. From a discussion of bond angles and interactions, a chair form for rhe ring is considered most likely. Tertiary acetylenic alcohols react readily with diphenylphosphinous chloride to give allenic phosphine oxides. A cyclic six-center transition state 157 has been proposed, and this is supported (324)by conversion of R( +)-phenylpropynol to an optically active product.

(157)

Stereospecificity in the reaction is also supported by a proton NMR study (325).

82


C. P(1V) Compounds

A valuable new route to resolved phosphine oxides has been described by Korpiun and Mislow (326). Phosphinic esters of optically active menthol are readily separated into diastereoisomers whose isomeric purity can be very conveniently checked by proton NMR. Reaction of the esters with Grignard reagents occurs stereospecifically to yield enantiomeric phosphine oxides in good yield and high optical purity. The Grignard reaction is believed to proceed with inversion since the chirality of one of the esters has been determined by X-ray diffraction and that of the oxide by correlation. This assignment is almost certainly correct; however, an absolute proof requires an X-ray structural determination on a known optically active phosphine oxide. This is very desirable as it would establish beyond doubt many correlations and proposed stereochemical pathways.

S

II

Ph-P-0-P-Ph I

NEt,

i I

NEt2

-t 109" 1 0 . -

i 'PN

> Ph-P-Nd

I

NEt,

NEt,

+ 7.9"

T NEt,

- 9.3"

NEt, Figure 13

4-71.5"

-


A careful study of the proton NMR spectra of diastereoisomeric menthyl phosphinates shows significant differences and allows assignment of chirality at phosphorus; similarly the ORD curves of the separated menthyl methylphenylphosphinates show enantiomeric positive and negative Cotton effects corresponding to R and S configurations at phosphorus, respectively (327). The salt 158 has been resolved as its camphorsulfonate (328). The dimethylimidazolium group is readily replaced by nucleophiles. The reaction with the anion from 2-methylimidazole proceeds with 100% inversion at phosphorus and the action of alkali yields an optically active P-0-P compound. These transformations are shown in Figure 13. Hydrolysis of ethyl ethylphosphonothiochloridate with water in dimethylformamide proceeds with inversion as in the case of alkaline hydrolysis. The stereospecificity is much reduced and this is believed to be due to the hydrogen chloride formed. In the presence of aqueous imidazole or pyridine almost complete racemization occurs (329). a-Phenylethylamine is reported to be a very convenient resolving agent for derivatives of phosphonothioic acids (330). Wadsworth (33 1) has presented a simple proof that nucleophilic attack on cyclic phosphates proceeds with inversion (159-162). The CH,CI

CH,CI

CH,CI

84


X-ray structure determination (332) of the cyclic phosphate 1-0x0-Iphenoxy-1,3,2-dioxaphosphorinanshows the molecule to be a somewhat flattened chair with the phosphoryl grouping equatorial. This distortion of the ring by phosphorus may be general since the previous study of a cyclic six-membered phosphate (287) also shows this feature. The effect is to lessen the distinction between axial and equatorial substituents at phosphorus. It should be compared with the considerable flattening observed in five-membered cyclic phosphates (210,211) which should also minimize confornational differences. It is interesting to note that the preferred orientation of the phosphoryl group is equatorial in both examples studied so far. Bartle, Edmundson, and Jones (316) have studied the NMR spectra of a considerable number of 1,3,2-dioxaphosphorinanderivatives and conclude on the basis of the chemical shift difference between axial and equatorial protons that the chair form is most likely. A detailed study of the factors influencing product stereochemistry in Wittig reactions has appeared (333). The Russian authors have examined the effect of varying solvent, substrate, ylid, time of reaction, and reactant ratio, as well as the influence of ions, on the steric course of the reaction and indicated the preferred conditions for obtaining a cis or trans olefin. The great variation in behavior between the unstabilized and semistabilized ylids, however, indicates that much more information must be acquired before any general guides to product stereochemistry in the Wittig reaction can be formulated. The bisWittig reagent 163, on the other hand, reacts nonstereospecificallyunder a wide range of conditions (334).

(163)

Benezra and Ourisson have studied the addition of the dimethyl phosphite anion to cholestan-3-one to give the a-hydroxyphosphonate (335). They conclude that the phosphonate group is equatorial on thermodynamic grounds since the reaction is reversible. Other ketosteroids react similarly, but no addition occurs when the keto group is in the 11, 17, or 20 position on the steroid nucleus. The contribution of the substituent (MeO),P(O) to the chemical shift of the C-19 methyl group is calculated to be zero in the a orientation and -2 cps in the 8.


A number of transformations of the hydroxy-phosphonates are described. The reaction of dimethyl phosphonate with monocylic ketones has also been studied (336). trans-Ethene- 1 ,Zdiphosphonic acid has been synthesized (337) and its Diels-Alder reactions have been studied. The Arbuzov reaction between triethyl phosphite and /3-chlorocrotonic and -isocrotonic esters affords the corresponding trans and cis phosphonates (338). Geometrical isomers of 1,2,2-dioxaphosphorinans have been separated and tentative assignments made on the basis of the modified Auwers-Skita rule (339).

D. P(V) Compounds Low temperature (- 76") NMR spectra of 164 show the presence of one apical and two radial methoxyl substituents. No separation is observed in a pentaoxyphosphorane even at - IOO", thus substantiating Westheimer's arguments concerning the preferred radial orientation of the carbon substituent in such structures (340).

o&cocH3 CHP.. \ CH30

;rCHPh OCH3

(164)

Though five-membered cyclic phosphinic acids normally show no great acceleration of their rates of hydrolysis, presumably for the reasons discussed in Section VI, they may be compelled to do so if the relief of strain in going to a trigonal-bipyramidal transition state is great enough. Westheimer's group has observed this in the highly strained tricyclic structures 165 and 166. The hydrolysis of one of the ester groups (believed to be P*) is some lo5 times as great as that for analogous monocyclic systems (341). The X-ray structure determination of l-methyl-l-phenylphospholanium iodide shows a ring angle at phosphorus of 94.8" (340). Since a P(V) intermediate is believed to be involved in the hydrolysis of phosphonium salts, relief of steric strain in such an intermediate may also explain the enhanced rate of hydrolysis of these compounds

86


(296). This enhanced rate is also observed with p-nitrobenzylphosphonium salts when the observed kinetics are second order rather than third (343). It seems reasonable that both reactions (i.e., with secondor third-order kinetics) proceed via a similar intermediate.

Acknowledgments The authors are indebted to many workers in. this field who informed them of work in progress at the time this review was written. I. D. Jenkins acknowledges financial support by the C.S.I.R.O. in the award of a Postgraduate Scholarship.

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STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 95 E. L. Muetterties, Inorg. Chem., 4, 769 (1965). G. W. Fenton and C. K. Ingold, J. Cheni. SOC.,1929, 2342. L. Hey and C. K. Ingold,J. Chem. SOC.,1933, 531. W. E. McEwen, G. Axelrad, M. Zanger, and C. A. Vander Werf, J. Am. Chem. SOC., 87, 3948 (1965). 279. H. Hoffmann, Ann. Chem., 634, 1 (1960). 280. G. Aksnes and J. Songstad, Acfa Chem. Scand., 16, 1426 (1962). 281. M. Grayson and P. T. Keough, J. Am. Chem. SOC., 82, 3919 (1960). 282. J. R. Cox, R. E. Wall, and F. H. Westheimer, Chem. Ind. (London), 1959,929. 283. H. G. Khorana, G. M. Tener, R. S. Wright, and J. G. Moffatt, J . Am. Cheni. SOC.,79, 430 (1957). 284. P. C. Haake and F. H. Westheimer, J . Am. Chem. SOC., 83, 1102 (1961). 285. F. Covitz and F. H. Westheimer, J . Am. Chem. SOC., 85, 1773 (1963). 87, 253 (1965). 286. A. Eberhard and F. H. Westheimer, J . Am. Chem. SOC., 287. T. A. Beineke, Chem. Comrnun., 1966, 860. 288. E. A. Dennis and F. H. Westheimer, J . Am. Chem. SOC.,88, 3431 (1966). 88, 3432 (1966). 289. E. A. Dennis and F. H. Westheimer, J . Am. Chem. SOC., 290. F. A. Cotton, J. Chem. Phys., 35, 228 (1961). 291. P. C. Van Der Voorn and R. S. Drago, J. Am. Chem. SOC.,88, 3255 (1965). 292. J. E. Griffiths, R. P. Carter, and R. R. Holmes, J. Chem. Phys., 41, 863 (1 964). 87, 671 (1965). 293. A. M. Aguiar, H. Aguiar, and D. Daigle, J. Am. Chem. SOC., 294. A. M. Aguiar and H. Aguiar, J . Am. Chem. Soc., 88,4090 (1966). 295. J. J. Brophy and M. J. Gallagher, Chem. Commun., 1967, 344. 296. G. Aksnes and K. Bergesen, Acta Chem. Scand., 19, 931 (1965). 297. D. B. Denney and N. E. Gershman, Tetrahedron Letters, 1965, 3899. 298. R. F. Copeland, S. H. Conner, and E. A. Meyers, J. Phys. Chem., 70,1288, (1965). 299. D. Hellwinkel, Angew. Chem., 77, 378 (1965); Angew. Chem., Intern. Ed., 4, 356 (1965). 300. R. Schmutzler, J. Chem. SOC., 1965, 5630. 301. N. M. D. Brown and P. Bladon, Chem. Commun., 1966, 304. 302. E. L. Muetterties, T. A. Bither, M. W. Farlow, and D. D. Coffman, J. Inorg. Nucl. Chem., 16, 52 (1960). 303. R. U. Pagilagan and W. E. McEwen, Chem. Commun., 1966, 652. 304. (a) F. Ramirez, A. V. Patwardhan, N. Ramanathan, N. B. Desai, C. V. Greco, and S. R. Heller, J . Am. Chem. SOC., 87, 543 (1965); (b) F. Ramirez, A. V. Patwardhan, and C. P. Smith, J. Org. Chem., 31, 3159 (1966). 305. M. Schlosser, T. Kadibelban, and G. Steinhoff, Angew Chem., 78, 1018 (1966); Angew. Chem., Intern. Ed., 5 , 968 (1966). 306. R. R. Holmes and R. N. Storey, Inorg. Chem., 5, 2146 (1966). 307. F. J. Welch and H. J. Paxton, J. Polymer Sci. A , 3, 3439 (1965). 308. L. Horner, Helv. Chem. Acta, AIfred Werner Commemoration Volume, 93 (1967). 309. J. Michalski, Bull. SOC.Chim. France, 1967, 1109. 310. A. V. Dombrovskii and V. A. Dombrovskii, Usp. Khim., 35, 1771 (1966); Russ. Chem. Rev., 35, 733 (1966). 275. 276. 277. 278.

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311. E. L. Muetterties, Inorg. Chem., 6, 635 (1967). 312. M. Mikolajczyk, Wiadomosci Chem., 21, 67 (1967); through Chem. Abstr., 67, 32080 (1967). 313. M. Mikolajczyk, Wiadomosci Chem., 21, 205 (1967); through Chem. Absrr., 67, 53172 (1967). 314. D. Gagnaire and J. B. Robert, Bull. SOC. Chim. France, 1967, 2240. 315. L. D. Hall and R. B. Malcolm, private communication. 316. K. D. Bartle, R. S. Edmundson, and D. W. Jones, Tetrahedron, 23, 1701 (1967). 317. D. Gagnaire, J. B. Robert, J. Verrier, and R. Wolf, Bull. SOC.Chim. France, 1966, 3719. 318. D. Gagnaire, J. B. Robert, and J. Verrier, Chem. Commun., 1967, 819. 319. H. Hoffmann and P. Schellenbeck, Chem. Ber., 100, 692 (1967). 320. V. Mark and J. R. Van Wazer, J. Org. Chem., 32, 1187 (1967). 321. G. Wittig, H. J. Cristeau, and H. Braun, Angew. Chem., 79, 721 (1967); Angew. Chem. Intern. Ed (Engl.), 6, 701 (1967). 322. W. J. Pope and C. S. Gibson, J. Chem. SOC.,101, 939 (1912). 323. H. E. Shook and L. D. Quin, J. Am. Chem. SOC.,89, 1841 (1967). 324. P. Cadiot, W. Chodkiewicz, B. Borecka, C. Charrier, and M. P. Simonnin, Composes Organiques du Phosphore, Editions du Centre National de la Recherche Scientifique, 1966, p. 99. 325. A. Seven and W.Chodkiewicz, Tetrahedron Letters, 1967, 2975. 326. 0. Korpiun and K. Mislow, J . Am. Chem. SOC.,89,4784 (1967). 327. R. A. Lewis, 0. Korpiun, and K. Mislow, J. Am. Chem. Soc., 89,4786 (1967). 328. J. N. Seiber and H. Tolkmith, Tetrahedron Letters, 1967, 3333. 329. M. Mikolajczyk, Tetrahedron, 23, 1543 (1967). 330. H. L. Boter and D. H. J. M. Platenburg, Rec. Trau. Chim., 86, 399 (1967). 331. W. S. Wadsworth, J. Org. Chem., 32, 1603 (1967). 332. H. J. Geise, Rec. Trau. Chim., 86, 362 (1967). 333. L. D. Bergelson, L. I. Barsukov, and M. M. Shemyakin, Tetrahedron, 23, 2709 (1967). 334. L. V. Shubina, L. Y.Malkes, V. N. Dimitrieva, and V. D. Bezugliji, Z h . Obshch. Khim., 37, 437 (1967); through Chem. Abstr., 67, 43251 (1967). 335. C. Benezra and G. Ourisson, Bull. SOC. Chim. France, 1967, 624. 336. C. Benezra, S. Nseic, and G. Ourisson, Bull. SOC.Chim. France, 1967, 1140. 337. P. Tavs, Chem. Ber., 100, 1571 (1967). 338. V. A. Kukhtin, Y. Y. Samitov, and K. M. Kerillova, Izu. Akad. Nauk. SSSR Ser. Khim., 1967, 356; through Chem. Abstr., 67, 21361 (1967). 339. K. Bergesen, Acta Chem. Scand., 21, 578 (1967). 340. D. G. Gorestein and F. H. Westheimer, J. Am. Chem. SOC.,89,2763 (1967). 341. R. Kluger, F. Kerst, D. G. Lee, and F. H. Westheimer, J. Am. Chem. Soc., 89, 3918 (1967). 342. E. Alver and B. H. Hottedahl, Acta Chem. Scand., 21, 359 (1967). 343. G. Aksnes and L. J. Brudvik, Acta Chem. Scand., 21, 745 (1967).


The Study of Intramolecular Rate Processes by Dynamic Nuclear Magnetic Resonance GERHARD BINSCH Department of Chemistry and the Radiation Laboratory* University of Notre Dame. Notre Dame. Indiana

I . Introduction . . . . . . . . . . . II . Scope . . . . . . . . . . . . . 111 Theory . . . . . . . . . . . . . A . Line-Shape Theories . . . . . . . 1 . Classical Line-Shape Theory . . . . 2. Quantum-Mechanical Line-Shape Theory B . Transient Techniques . . . . . . . C . Multiple Resonance Method . . . . . I V . Processing of the Data . . . . . . . . A . Experimental Procedures . . . . . . B. Determination of Rate Constants . . . . C . Calculation of Activation Parameters . . . D . Sources of Errors . . . . . . . . V Hindered Rotation . . . . . . . . . A . Substituted Ethanes . . . . . . . . B . Sterically Crowded Bonds . . . . . . C Amides. Thioamides. and Carbamates . D . Nitrosamines and Nitrites . . . . . . E . Aldehydes and Ketones . . . . . . F. Miscellaneous Hindered Rotations . . . VI . Inversion of Lone Electron Pairs . . . . . A . Open-Chain Derivatives of Ammonia . . . B. Cyclic Derivatives of Ammonia . . . . C . Derivatives of Imines . . . . . . . D Other Elements . . . . . . . . .

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*The Radiation Laboratory is operated by the University of Notre Dame under contract with the U.S. Atomic Energy Commission This is AEC Document N o C00.38.575

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G. BINSCH

VII. Ring Inversions . . . . . . . . . . . . . A. Cyclohexanes and Cyclohexenes . . . . . . . B. Six-Membered Heterocycles . . . . . . . . C. Seven-Membered Rings . . . . . . . . . D. Eight-Membered Rings . . . . . . . . . . E. Miscellaneous Ring Systems . . . . . . . . VIII. Valence Isomerizations and Intramolecular Rearrangements IX. Conclusion. . . . . . . . . . . . . . . X. Appendix . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .

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I. INTRODUCTION In the past two decades high-resolution nuclear magnetic resonance (NMR) has developed from an ancillary technique of the nuclear physicist into one of the chemist’s most valuable tools for probing the structure and stereochemistry of molecules. The positions of the resonance signals and their fine structure give detailed information about the bonding situation of magnetic nuclei and their spatial relationships. Since the energetics of pure spin problems can be treated exactly by quantum theory, NMR spectra can be fully analyzed in terms of resonance frequencies and intensities. The final aim is to obtain a set of parameters: the chemical shifts 6, and coupling constants Jlj. These parameters completely determine the energy levels of the nuclear spins in the external magnetic field H,, and therefore comprise the static information that can be extracted from an NMR experiment. In this review we will assume that the reader is familiar, at least in principle, with these static aspects of nuclear magnetic resonance. In addition to chemical shifts and coupling constants, NMR spectra are a function of certain time-dependent phenomena. There is, of course, the trivial case where a compound undergoes an irreversible chemical reaction while its NMR spectrum is being observed. By measuring the gradual disappearance of certain lines of the reactants and the appearance of the product spectra as a function of time, one may be able to calculate the rate constant for such a reaction. We shall not be concerned with this straightforward, though very useful, application of NMR; rather we shall be interested in those rate processes that occur in systems that already have reached a state of thermodynamic equilibrium, where, in other words, no net macroscopic change can be detected. If these processes are characterized by rate constants of a similar order of

STUDY OF INTRAMOLECULAR RATE PROCESSES

99

magnitude as the total spread (in cycles per second) of the NMR spectra of a certain magnetic isotope (typically 10-1 to lo5 sec-l), they may cause profound changes of the shape of NMR signals. It is common practice to speak of a characteristic “ NMR time scale,” inversely related to these rate constants. If the average lifetimes of a number of species in equilibrium exceed an upper limit, the NMR spectrum will show them as individual entities. Conversely, if the lifetimes are short with respect to the NMR time scale, one will obtain a single spectrum, in which the chemical shifts and, for intramolecular processes, also the coupling constants are statistically weighted averages of the corresponding values in the exchanging species, a feature which is especially valuable for conformational analysis. The characteristic phenomena that can be observed during the transition from one to the other extreme and their analysis constitute the realm of the method that we have chosen to call “dynamic nuclear magnetic resonance” (DNM R) . Following a number of early studies in the late 19503, DNMR has experienced a great upsurge of activity. The theory of this method has been refined, new experimental techniques have become available, and an ever-increasing number of publications deal with applications of DNMR, especially to problems in organic chemistry. The barrier heights of dynamic processes amenable to this technique conveniently extend just from the borderline (20-25 kcal/mole), where compounds become too unstable to be isolated chemically, down to activation energies of about 5-6 kcal/mole, below which another powerful tool, microwave spectroscopy, can be applied. Many rate processes of fundamental importance in chemistry happen to fall into this formerly almost inaccessible gap between the realm of rotational spectra and conventional kinetic techniques. Rate processes involving reversible intermolecular proton transfer, rotations around sterically crowded single bonds and single bonds with partial double character, inversion of lone electron pairs on nitrogen and phosphorus, inversion of carbocyclic and heterocyclic rings, and degenerate valence isomerizations and intramolecular rearrangements are among the more common examples. Many important qualitative conclusions can be drawn from the characteristic changes in the NMR spectra brought about by the variation of pH, magnetic field, or temperature. DNMR even led to the discovery of a new class of compounds, molecules with fluxional structures, of which bullvalene is perhaps the most striking example.

100

G . BINSCH

II. SCOPE Basic information about the theory and applications of dynamic nuclear magnetic resonance can be found in practically every standard textbook on NMR (e.g., refs. I and 2). A number of review articles, covering more or less the whole area (3-5) or various aspects of it (6-8), have also been published. For the present review the literature was searched up to the end of 1966. It is hoped that not too many important contributions have been overlooked. References to papers appearingearly in 1967 have been included as they came to the attention of the author. Although the theory applies, with little modification, to intermolecular as well as intramolecular rate processes, only the latter will be discussed. Readers interested in the former will find a detailed account of such applications in the review by Loewenstein and Connor (3). As mentioned in the Introduction, characteristic changes in an NMR spectrum on variation of a parameter (in most cases the temperature) indicate the presence and nature of a rate process with an activation energy between 5 and 25 kcal/mole. The value of such qualitative information is undisputed. In principle, however, dynamic nuclear magnetic resonance is also capable of yielding quantitative data about rate constants and activation parameters. On the surface it would appear that such data are quite easily obtained. Without carrying out a detailed investigation, many workers have therefore been tempted to report values along with rather optimistic error limits. Unfortunately, this quantitative aspect of DNMR is fraught with difficultiesand pitfalls. Judging from the interesting case histories of the cyclohexane ring inversion and the hindered internal rotation in amides, it now appears that the vast majority of reported values may not stand up to careful scrutiny. It has been argued that accurate values are really not sufficiently interesting to warrant all the trouble of obtaining them. Whereas this may have been true some years back, we do not believe it to be a valid argument any more. In view of the present activity in this field, more and more numbers about related systems are becoming available. If there is to be any purpose in obtaining all these data, one eventually must be able to compare them and draw conclusions from such a comparison. With the quantitative unreliability of a rapidly accumulating body of data this is becoming an increasingly frustrating exercise. To explain the philosophy that was adopted in writing this review, it may suffice at this point to indicate the two main origins of difficulties


101

in DNMR. One is inherent in the method itself and is related to the fact that dynamic parameters are much more susceptible to spurious effects, such as field inhomogeneities or saturation, than are line positions and intensities. The other one is due to the inadequate theoretical treatment of the experimental data. Although complete theories have been available for some time for all practically important cases, the use of approximate formulas of dubious validity is still very common. It was decided at the outset to make full treatment based on appropriate theory a prerequisite for considering a reported value as reliable. This may well turn out to be unfair to some investigators for whose results a detailed analysis might show that the approximations have not introduced a significant error. However, in the absence of such an analysis and in view of the rather desolate general situation, it was felt that there was no other choice. No attempt will be made to give a complete review of the theoretical work pertinent to DNMR. Interested readers are referred to the articles by Loewenstein and Connor (3) and by Johnson (8) for details and references. Only those theories that, in the author’s opinion, have proved to be of practical use are outlined in some detail. The formulas suitable for direct programming are given [eqs. (15), (19), (31), and (33)]. With the availability of modern computers the full treatment is just as easy to apply as the approximate formulas. For this reason, we will spend little effort or space to discuss approximations.

III. THEORY A. Line-Shape Theories The majority of dynamic studies by nuclear magnetic resonance have employed the line-shape method. Since the necessary measurements can easily be performed with standard NMR equipment, the line-shape method will probably remain the most important technique of DNMR. We will therefore discuss the underlying theory in somewhat greater detail. 1. Classical Line-Shape Theory It is a well-known fact that the spin of elementary particles does not have a classical analog and that the existence of discrete spin states in a magnetic field can only be explained by quantum theory. Nevertheless,

G . BINSCH

102

one finds that the resonance condition of a bare nucleus,

(Y/2n)Ho (1) relating the resonance frequency yo to the external magnetic field Ho and the gyromagnetic ratio y , does not contain Planck's constant h. This observation suggests (9) that it might be feasible to describe the resonance phenomenon itself by a classical picture. This view has indeed been adopted by Bloch in a celebrated paper (10). yo

=

a. The Bloch Equations. Bloch considers a nucleus with spin 111 = (h/27r)dZ(Z 1) and magnetic moment p = 71as a tiny gyroscope.

+

The forces it experiences in an external constant magnetic field in the z direction, H = (0,0, Ho},cause it to move in such a way that the rate of change is given by the torque with components

* dt

=

y [ p x HI

dpz - - y b x H l l - plyHx]= 0

dt Eqs. (3) immediately tell us that the nuclear dipole p precesses about the z axis with an angular frequency wo = yHo in a clockwise fashion (assuming y > 0), that is the vector wo points in the negative z direction (Fig. 1). This angular frequency, wo, is called the Larmor frequency and is related to the resonance frequency of eq. (1) by wo = 27rv0. In a sample containing a large number of identical nuclear dipoles, all will precess with wo, but their phases will be randomly distributed over a cone about z (Fig. 1). The resultant macroscopic magnetization will therefore only have a component in the z direction, M o = (0,0, Mo}. If we now disturb the system by a second magnetic field rotating in the xy plane with an angular frequency w in the neighborhood of wo and in the same sense as the precessional motion of the nuclei, H1= { H l cos wt, - H I sin wt, 0}, the x and y components of M will become different from zero. The quantitative description is again d-M(4) dt - Y[M x HI

RATE PROCESSES

103

Fig. 1. Classical precessional motion of nuclear magnetic dipoles in a magnetic field.

with H = { H , cos wl, - H , sin wt, Ho}. Instead of giving the components of eq. (4) in the coordinate system of Figure I , it is advantageous to refer them to a set of axes rotating clockwise about z with angular frequency W. In this rotating frame H1 is stationary, causing the time dependence of the right-hand side of eq. (4) to disappear. With H, coinciding with the rotating x axis, the components become*

%

=

(Wo

-

w)My

*In Bloch’s paper (10) and in most subsequent papers that made use of Bloch’s equations, all signs on the right-hand sides of eqs. ( 5 ) are reversed. This discrepancy is without consequences for the calculation of line shapes, since it only causes a phase shift by n.

G. BINSCH

104

NMR spectrometers are built in such a way that one can detect changes in the macroscopic magnetization in the xy plane, either by a receiver coil mounted perp.endicular to the transmitter coil or by an unbalance in the transmitter circuit itself. Eq. (5c) shows that the y magnetization is responsible for a change in M , and thus in the net nuclear Zeeman energy of the system. The out-of-phase component M y therefore corresponds to the absorption mode and M , describes the dispersion. Both effects can be expressed in a single equation if one defines the complex xy magnetization G by G = M,

+ iM,

(6)

so that eqs. (5a) and (5b) can be combined to read

dG - -- - i(wo - w)G dt

+ iyH,M,

The description of eqs. (5) is still incomplete, since it only takes cognizance of Ho and H, and ignores all other factors that might influence M. The combined action of such factors is referred to as relaxation. Bloch assumes that, whenever the system is perturbed, there will be mechanisms by which M can eventually return to its equilibrium value Mo = (0,0, Mo) by a first-order rate process. The complete Bloch equations then take the form

dG - -- -i(wo - w ) G dt dMz =

dt

+ i y H I M , - -G1 T2

(74

1 - y H I M , - T,(M, - Mo)

The longitudinal relaxation time TI is inversely related to the average first-order rate constant of the processes by which the spins can exchange their nuclear Zeeman energy with other degrees of freedom of a thermal bath or “lattice.” The transverse relaxation time T2 characterizes the rate by which G returns to its equilibrium value of zero. Obviously such a process does not involve exchange of energy with a bath, since it can be accomplished simply by a dephasing of the individual nuclear spins in the xy plane. Consequently, Tamay aptly be called the “ phase-memory time.”

b. Exchange between Two Sites. All classical line-shape theories may be based on suitably modified Bloch equations. We shall illustrate the


105

principles by first treating the simplest possible case, the reversible exchange of a single uncoupled proton between two chemically shifted sites. The first detailed treatment of a similar problem was presented by Gutowsky, McCall, and Slichter (11) (GMS) and elaborated in later papers by Gutowsky and Saika (12) and Gutowsky and Holm (13). The equations and approximations derived in the last paper (13) are the most widely used in practical applications of DNMR. The GMS theory is, however, somewhat involved in that it uses a complicated averaging procedure. Fortunately, the same equations can be derived in a much simpler way that was first suggested by Hahn and Maxwell (14) and McConnell(l5) (HMM). The following derivation is closely akin to the HMM treatment. Consider a proton that can reside in two different environments A and B with chemical shifts vA = (WA/27r) and vB = (wB/27r) and that jumps back and forth between A and B. A jump from A to B results in a decrease of magnetization in site A and a jump from B to A results in an increase. A corresponding statement holds true for the change of magnetization in site B. HMM assume that both the forward and reverse reactions can be described by first-order rate laws with rate constants kA-. = ~ / T Aand kB,A = ~ / T B .The Bloch equations for the sites A and B may therefore be modified to read

dGA = dt

-[~(WA

dGB dt

-[i(Wg

_.-

-

W)

+ ~ / T ~ A ] G+AiyHlhf,$ - (~/TA)GA+ (I/TB)GB @a)

- W)

+ ~ / T ~ B ] G+BiyH1hft - (~/TB)GB+ (I/TA)GA (8b)

Since the system is supposed to be in equilibrium, the mean lifetimes in the sites A and B must have the same ratio as the corresponding fractional populations p TA/TB

= PA/PB

(9)

In addition it is convenient to introduce a new variable =

TAPB= TBPA

(10)

If one sweeps slowly enough through the resonance (“slow passage”), the magnetizations will manage to follow “isothermically,” that is, they

G . BINSCH

106

become stationary. It is also assumed that saturation is avoided by choosing a low Hl field. These experimental conditions imply

With eqs. (10) and (1 1) the modified Bloch equations become linear equations in GA and G B ~(wA- W)

"83

+ - + - GA + PA T2A

-GB

=

-ipAyHiM,

(12a)

and are easily solved. If one defines = -[2ri(vA - v) f l/T2A UB

=

-[2ri(YB - v) f l/TZB

+ pB/r]

+ PA/T]

C = yH1Mo

(134 (13b) (14)

where vA and vB are the chemical shifts in cps relative to some standard and where C may be taken as an arbitrary scaling factor, the total transverse magnetization G = GA + CB is given by

G = -iCT[2pApB - dPAaB f PB"A)l PAPB - r 2 a A a B

(1 5 )

Formula (15) [together with the definitions eqs. (13)] is directly suited for a complete line-shape calculation over the whole sweep range Y as a function of the parameters vA,Y ~ TaA, , TZB, pA,pB,and 7.TOobtain the computed spectrum in the absorption mode, it is only necessary to extract the imaginary part of the complex quantity G. This operation is performed automatically by modern computers. An example of a spectrum computed with eq. (15) is shown in Figure 2. In most practical applications, including those based on a complete line shape analysis, the GMS equations as given in the paper by Gutowsky and Holm (13) have been employed. Although these formulas look more formidable than our eq. (15), it is not difficult to show that they are in fact equivalent, except that in the GMS theory one usually makes the additional assumption of equal transverse relaxation times

STUDY OF INTRAMOLECULAR RATE PROGESSES

107

Fig. 2. Calculated line shapes [eq. (15)] for classical exchange between two sites with populations 0.3 and 0.7. The transverse relaxation times were taken to be the same in both sites.

for all sites (or one neglects the effects due to T2altogether). A great variety of approximate formulas has been derived from the GMS equations (1 1-1 3,16-24). These approximations have been of considerable importance in the past, but recent experience (25) shows that the errors introduced in them are much more serious than was thought

108

G . BINSCH

previously. A strong plea is therefore made to abandon their use. We will only mention one very approximate formula, not because we mean to encourage its use, but because it provides a rapid means to get a rough estimate of a rate constant at a single temperature, the so-called coalescence temperature, for classical exchange between two equally populated sites with a chemical shift difference Av. The coalescence temperature corresponds to the point at which the doublet lines just merge to a single broad line. kcosl = =Av/Z/Z

(16)

The prospective user should be warned, however, that this estimate may easily be inaccurate by several hundred per cent. c. Exchange between Many Sites. A particularly nice feature of the HMM equations is that they can easily be generalized for n sites. To see how this is done let us write eqs. (12) in a different way. Suppose the coefficients of the GIon the left-hand side of eqs. (12) are collected in a square matrix A, and the G,andp, are written as column vectors G and P, respectively. Also making use of eq. (14), eqs. (12) become

AG

=

-iCP

(17)

Multiplying from left with A-' gives G = -iCA-'P

(18)

Eventually, we will have to sum over all the GIto get the total magnetization G . This is easily accomplished by multiplying eq. (1 8) from the left with the transpose IT of an n-dimensional vector (i.e., a row vector) whose components are all equal to 1.

G

=

1TG

=

-jCITA-lp

(19)

Since computer routines for inverting complex matrices are available, the solution of eq. (19) presents no problems. In fact, Saunders (26) has written such a program based on a somewhat different but equivalent equation and applied it to the bullvalene valence isomerization. It remains to show how the A matrix is evaluated. By looking at eqs. (I 2) one verifies by inspection A = -2~i(W,3- vI) - T-'

+X

(20)


109

where Wo and T are diagonal matrices with the chemical shifts (in cycles per second) and the relaxation times (in sec), respectively, I is the unit matrix, and X has elements xlj = kji

The k t j are the rate constants (in sec-') for jumps from site i to sitej. Since detailed balancing requires Plkt, = Prka (22) the spectrum depends on only n(n - 1)/2 independent rate parameters for a given set of populations. For the two-site problem we already took account of this feature by introducing the single variable T by eq. (10). But even for a many-site exchange process all possible rate ratios may become fixed automatically by the very nature of the problem. Bullvalene (26) happens to be a case in point. Here the k l j are simply given by q { j / T where the qlj specify the probability that a jump out of site i will terminate in sitej. Historically, equivalent equations were first derived by Sack (27) from Anderson's (28) stochastic theory of random Markovian modulation. The somewhat intuitive arguments used by Hahn and Maxwell (14) and McConnell (15) thus receive their justification by the detailed quantum-mechanical theory of exchange effects as developed by Anderson (28), Kubo and Tomita (29), Kubo (30,31) and Powles and Strange (32).

d. Exchange Involving First-Order Coupling. The classical treatment of the nuclear resonance phenomenon can only be rigorously justified for an ensemble of independent spins. Whenever nuclei in different magnetic environments are interacting by indirect spin-spin coupling, a quantum-mechanical theory is indicated. We would therefore suspect that our line-shape theories based on the Bloch equations break down in such situations. This is especially true for the strong-coupling case as encountered, for instance, in the exchange between the sites of an AB spin system. It may be argued, however, that a classical theory should still be a good approximation in the weak-coupling case. At an early date the classical GMS paper (11) was concerned with such an example. The method has since been extended by a number of authors (16,17,20,33-35), especially to the well-known collapse of multiplets in amines and alcohols. The Israel school has compiled a

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G . BINSCH

catalog of exchange-broadened multiplets (36). Since essentially all these studies involve intermolecular reactions, we will not discuss them further. Complications due to first-order splittings may also arise in intramolecular exchange. An interesting case has been treated by Dahlqvist and Forsdn (37). If one modifies the chemical shifts by the appropriate combinations of coupling constants for the various spin states, or if one replaces the role of chemical shifts altogether by couplings and takes proper care of the intensity ratios in the multiplets, the methods discussed in Sections b and c can be applied in a straightforward manner. We shall not enter into details here, however, for the following reason. The excellent agreement between the experimental and computed spectra in the paper by Dahlqvist and Forsdn (37) certainly indicates that the classical model was a very good approximation in their case. But the conditions under which such a behavior may be expected with certainty have unfortunately not yet been subjected to a systematic scrutiny. In any event, there is reason to suspect (38,39) that the approximations will get progressively worse as exchange gets faster. For the general case, therefore, it seems safer to apply the quantummechanical treatment to be discussed in the next section. 2. Quantum-Mechanical Line-Shape Theory We start with a simple argument to show why a quantum-mechanical theory is really indispensable whenever exchange effects on line shapes are complicated by spin-spin coupling. To be specific, let us first consider an intramolecular exchange of two uncoupled protons 1 and 2. Immediately before exchange proton 1 shall have its spin in the CL orientation and proton 2 in the t9 orientation. We will label this “state” by a( I ) /3(2). Exchange permutes the nuclear coordinates and converts our system to the new and distinct state cr(2)/3(1). Each time such a change takes place it will alter the magnetization and we will be able to detect it by DNMR. Now, if there is spin-spin coupling between the nuclei, the two states discussed above lose part of their individuality due to a typical quantum-mechanical interaction. The degree of “mixing” increases with increasing ratio of the spin coupling constant J to the chemical shift difference Av, until finally, for Av = 0, the two states become completely indistinguishable. Consequently, there is a finite chance of finding the system in the same state after exchange as before. Exchanges of this type will therefore go undetected and the rate constant

111


calculated by a classical theory does not correspond to the true rate constant of the molecular process. For strong coupling, that is, high J / A v ratios, and slow exchange this error must become very serious. For weak coupling and slow exchange, the quantum-mechanical correction may be so small as to be safely neglected. However, as exchange gets faster, even a small mixing coefficient must eventually produce an important effect due to a phenomenon that may be visualized as a “feedback” mechanism. In view of this it seems somewhat strange that a classical calculation becomes valid again for very fast exchange in the strong-coupling case. Rather than stretching our qualitative interpretation too far in trying to explain this also, we will now proceed to the quantitative formulation of the theory. A quantum-mechanical treatment of exchange effects in DNMR was first given by Kaplan (39,40) and further developed by Alexander (41-44), Johnson (49, and Newmark and Sederholm (46). All these theories are based on the density-matrix formalism (47), which is also highly suited for a refined discussion of Bloch’s phenomenological equations (48-50). In the following presentation we will follow a slightly different course ( 5 1). Consider a system of p identical coupled nuclei with spins undergoing exchange between n different magnetic environments. Each environment k shall be characterized by the state function $k. We wish to calculate the total transverse magnetization G = x k pkCk,where p k is the population of the spin system in the magnetic environment k. In the language of quantum mechanics each Gk corresponds to the expectation I,’ = hy ( I ; f il;). Note that in value of the operator hyI* = fiy order to be consistent with common N M R conventions, we have used the I operators in their abbreviated form from which the true operators are obtained from multiplication by h. Without loss of generality we may either work with I + or I - , and we will choose the minus sign (corresponding to spin flips from CY to /3). For convenience, we will henceforth drop Planck’s constant h whenever it occurs, so that the energy is expressed in frequency units. Thus we have

+

x,,

xfl

Gk

=

y(I-)

=

d$kl

I-

I#k>

(23)

Expanding # k into a complete set of orthonormal stationary spin basis functions c$~ =

2

#!i

I

ckih

(24)

G. BINSCH

112

eq. (23) becomes =$

2 (kl I-

l$j)

CkjCk:

1j

(25)

where the time dependence of Gk is now exclusively contained in the complex coefficients c. If one defines a density matrix pk for the kth magnetic environment by PFt = c k j c z (26) Eq. (25) can be written as G k = y ~ h ~ =ytr(I-P'0 P % (27) 1j

where Z,j denotes the matrix elements (+,I I and tr the trace. The calculation of G k becomes particularly simple if one chooses the spin product wave functions as basis # (41). The I- matrix then has only elements 0 or 1 and its evaluation is well known from static NMR. For an AB spin system with the basis a(l)a(2), a(1)8(2), p(l)a(2), 8(1)8(2) one obtains for instance 0 0 0 0 1 0 0 0

0 O1 O1 O0) It remains then to compute those off-diagonal matrix elements of the pk matrix that are needed to obtain the trace in eq. (27). For our AB example these are G k = y(d2 + O p! + Pf4 + p k ) (29) In the absence of relaxation and exchange, each pk (here interpreted as an operator) obeys the equation of motion (47,52) dpk-- 2rri[pk,.ekl = 2ai(pk*k

- i~kpk) (30) dt In analogy to the procedure we used in the classical case, this equation can be modified to read for the off-diagonal elements of pk in the presence of relaxation and exchange dPk - = 2ni[pk,*kl + dPk

(z)

dt

relax

=

2ni[pk,*']

Pk + -T2k

+

l(#k)

(klkp' - kklpl')

where the klkare the first-order rate constants of the processes by which the system switches from the magnetic environment 1 to the magnetic


113

environment k . Under unsaturated steady-state conditions the left-hand sides of eq. (31) vanish, and one obtains a system of linear equations for the elements p&. These are the master equations for line shapes in DNMR and they can be programmed for a computer (51). For all J = 0 they automatically reduce to the classical equations. We briefly indicate how the commutator in eq. (31) is evaluated. In the frame rotating with angular frequency w = 2 r v the Hamiltonian (in sec-l) becomes where YE are the chemical shifts (cps) of the nuclei p in environment k , J,& the coupling constants (cps) between nuclei h and p in environment k , and H , is the strength of the rotating radiofrequency field. If one prefers not to use the completely general master equations [eqs. (31)], they can of course be broken down algebraically for special cases. For the convenience of the reader we will here reproduce the full line shape function for the case most frequently encountered in practice, the intramolecular exchange of an AB spin system. =

with

'{(A+

+

R, + F iF)(B, + iF) - Q,

+

(A-

+

+ +

1

RF iF)(B- iF) - Q-

(33)

- 2 ? 7 i ( v A ? 5/2) - 1/T2 - k ; V o = (YA + V g ) / 2 ; B , = - 2?7i(vg k J/2) - 1/T2 - k ; Q+ = ( + r i J + k)2; R , = - 27r(v0 k J ) + 2ik + i/T2; F = 2nv (34) A,

=

where k is the rate constant and C an adjustable scaling factor. An equivalent equation was derived by Alexander* (41), using a somewhat different approach, and a number of people (53-58) have written computer programs. The theoretical curves in Figure 3 show the general behavior of an A B system. A rough estimate of the rate constant at the coalescence point can be obtained (55) from

+

kcoal= V ~ / ( V A- Vg)' 6Jig/d? (35) Special equations for ABC spin systems exchanging between three different magnetic environments were derived and programmed by Newmark (46,59).

* Note, however, that eq. (57a) in Alexander's (41) paper contains two errors. The quantity 1 should be replaced by i in both denominators.

114

Fig. 3.

G. BINSCH

Calculated line shapes [eq. (33)] for intramolecular exchange between the sites of an AB spin system.

B. Transient Techniques The line-shape equations discussed in Section A only apply under unsaturated steady-state conditions, that is, for slow passage and low H I fields. If either of these requirements is not satisfied, the NMR spectra themselves become time dependent. These transient phenomena may sometimes also be exploited to obtain information about rate processes.


115

Rapid passage spectra have occasionally been used to extend line shape measurements slightly beyond the fast- and slow-exchange limits (19,60,61) or to draw inferences from nonequilibrium magnetization transfer (62,63). Because of their limited applicability and inherent inaccuracy we are only mentioning these techniques in passing. By far the most important transient NMR method for studying rate effects makes use of strong and short radiofrequency pulses. Suppose a strong rf field H,, whose frequency satisfies the resonance condition, is switched on (at t = 0) for t, sec so that yHlt, = v/2. t , is so short that the system will have no time to relax during this “90” pulse,’’ and the total macroscopic magnetization Mo will therefore end up in the y direction of the rotating reference frame (Fig. 4u). After the rf field is switched off at t = t,, the y magnetization will start to decay, since the individual spins gradually lose their phase memory and “fan out” (Fig. 4b). Field inhomogeneities within the sample are the main cause for this dephasing. If after a time t, a second pulse of duration 2t, (180” pulse) is applied, the directions of all individual spins become reversed (Fig. 4c). Instead of fanning out they now move together and refocus 2t, t, to produce a strong signal, the so-called at t = t, + t , “echo” (Fig. 4 4 . The reader who wishes to learn more about spin echoes will find a commendably lucid presentation in the paper by Carr and Purcell (64). Not all of the original magnetization will be recovered in the echo signal, however. A certain amount of it is irretrievably lost, and this loss increases as t, gets longer. In the absence of exchange the decrease of the echo amplitude is mainly governed by the transverse relaxation as characterized by T2. An additional irreversible loss ensues if magnetization is transferred to another site in an exchange process. A quantitative analysis of the echo decay is therefore expected to yield numbers for the rate constants. Following a few scattered publications up to 1963 dealing with the theory of spin-echo methods and their applications to the study of rate phenomena (14,38,65-67), this technique has now developed into an elaborate tool for kinetic measurements, especially as a result of the systematic investigations by Gutowsky and his group (68-74) and the contributions by a number of other workers (32,75-79). The experimental procedure now being employed exclusively consists of a single 90” pulse followed by a whole sequence of equally spaced 180” pulses, referred to as a Carr-Purcell spin-echo (CPSE) pulse train. As one of the

+

+

G . BINSCH

116 Y

t”

I-

.V

1” V

V

f

Fig. 4. Classical motion of nuclear magnetic dipoles to produce a spin echo.

advantages of this modification all losses of phase memory due to diffusion through an inhomogeneous magnetic field are effectively eliminated, provided the pulse repetition rate is only fast enough. The CPSE train may actually be viewed as a “double-focusing” device. One also obtains a whole sequence of echoes in one experiment. By drawing a smooth curve through the echo maxima one can construct an “echo envelope,” and it is this echo envelope that contains the essential information of a CPSE experiment.


117

Since the decay of the xy magnetization starts after the HI field has been switched off, we can describe it by a Bloch equation in which the driving term is omitted, provided, of course, that spin-spin coupling is absent . dG = [-2ni(v, - v) - - G dt T2

‘I

In the presence of exchange between two chemically shifted sites A and By we have to modify eq. (36) in the, by now, well-familiar way

‘1

1 5 = [-2ni(vB - V) - - - - GB + -GA dt T2B rB

TA

(37b)

These two coupled linear differential equations have to be integrated subject to the boundary conditions of the stepwise action of the 180” pulses. In other words, one has to choose the integration constants in such a way that the magnitude of the magnetization at the beginning of a pulse interval is just equal to the magnitude of the magnetization at the end of the preceding one. The only practical way to treat these equations is to solve them numerically by means of a computer. The generalization of eqs. (37) to n sites is obvious. In the presence of spinspin coupling one has to resort to the corresponding density matrix equations. It is even possible to treat the effects of finite pulse times 2t, numerically (76). Needless to say, the mathematics for the most general case gets rather involved. Nothing much would be gained for an understanding of the principles by going into all the details here, so we refer the interested reader to the original literature. It turns out that for zero coupling the echo envelope is independent of pulse separation in the absence of exchange, whereas this is no longer true if magnetization is lost due to transfer by a rate process. One can make use of this feature by plotting the decay constant versus pulse frequency. This not only gives the rate constants, but as an additional “ bonus” also gives the chemical-shift differences and “true” transverse relaxation times, a distinct advantage over the line shape method. We will discuss the respective merits and drawbacks of the various methods in more detail in Section IV. In closing we only want to mention that the decay envelope may become modulated in the presence of spin-spin coupling.

118

G. BINSCH

C. Multiple Resonance Method An elegant yet simple multiple-resonance method was recently discovered by ForsCn and Hoffman (80-82), applicable to rates that are too slow to lend themselves to quantitative measurement by the line-shape technique. As usual we start the discussion with the Bloch equations, this time focusing our attention on the z components of the macroscopic magnetizations. Suppose an exchange process takes place between two uncoupled, chemically shifted sites A and B. In the absence of radiofrequency fields the modified Bloch equations for the z components take the form dMf M," M : -- _ - M,A-Mt -(384 dt Tl A rA rB dM,B M f - Mt -M," M," - = dt TlB rB rA Since the system is in equilibrium, the left-hand sides of eqs. (38) vanish and by definition M," = M t , M," = M t . If at t = 0 we suddenly and selectively start to irradiate the B resonance with a strong radiofrequency field, M," will be annihilated (presumably after a very short transient period). This will disturb the equilibrium and cause a change in M$ described by

+-

+-

dM$ M," - - - -M $ - M t - dt TIA TA which on integration yields

(39)

Conversely, if one selectively irradiates the A resonance with a strong H, field, the change in M,B is described by equations analogous to eqs. (39) and (40) except that the label B takes the place of label A. Equation (40) can be exploited in a straightforward fashion. For t = co, that is, after the system has reached a new state of equilibrium, one obtains @ ( a ) / M t = rA/(TiA + 7A) (41) Taking the logarithm of eq. (40) yields

In [M,"(t)- Mf(co)]

=

- TIA

+ rA t + C

Tl A rA


119

where the constant C is of no interest in this context. From the slope of a logarithmic plot [eq. (42)] and with eq. (41) both T A and T i A can be calculated. The “mirror-image” experiment affords T B and T i B in the same way. The results can be checked against the peak areas of an ordinary steady-state spectrum by means of eq. (9). Experimentally one uses the unsaturated slow-passage technique to record the spectrum of A while double-irradiating B and vice versa. Under these conditions the signal intensity is directly proportional to M,. To observe the gradual decrease from M : at t = 0 to M , as a function of time, ForsCn and Hoffman used a multiple-sweep recording device. If the spectrometer features a field-frequency lock system, it is easier to just “sit” on the A resonance while double-irradiating B (83). Several modifications of the basic procedure and an interesting application to a three-site problem are described in the papers by ForsCn and Hoffman (81,82). It should be evident that the method in this form is suitable only if the nuclei in the various sites show up as distinct, nonoverlapping signals. Although the density-matrix description of multiple resonance is highly developed (84,85), including relaxation phenomena (86), no applications to rate processes involving coupled spin systems or employing low-power levels have been reported as of this day. This area promises to become an active and exciting field of research in the near future. IV. PROCESSING OF THE DATA A. Experimental Procedures

As already mentioned, most DNMR rate determinations have been done by the line-shape method. The application of double-resonance and spin-echo techniques is limited to special cases (compare Sect. IV-D), and since pulse experiments furthermore require equipment which at present is available in only very few laboratories, we will merely point out a few facts that deserve to be kept in mind when recording slow-passage spectra. In virtually all cases the parameter to be varied is the temperature, and the necessary variable-temperature probe is now a standard accessory of commercial instruments. Curiously enough, the design of the inserts and the general procedure of achieving and measuring a certain

120

G. BINSCH

temperature in the sample have remained somewhat primitive until quite recently, and further improvements are still desirable. Since there will necessarily be temperature gradients within the probe (the more so the farther away from room temperature the measurement is to be performed) it is imperative to allow for complete equilibration before any readings are taken. Even so, the temperature one measures may not be the actual temperature in the sample, and the difference may itself be a function of the absolute temperature, thus introducing systematic errors. One should therefore frequently calibrate the readings under the actual conditions of the measurements, either against a second thermocouple in the interior of an NMR tube partially filled with a solvent or by making use of the peak separations in methanol or ethylene glycol as recommended by Varian (87). Since line shapes depend very critically on field inhomogeneities, the importance of high-quality spectra cannot be overemphasized. It is quite common for the magnetic field to deteriorate substantially each time the temperature is changed by an increment, but one may not become aware of this if one only looks at an exchange-broadened spectrum. It is necessary, therefore, to readjust the field-homogeneity controls of the spectrometer while observing a signal that is not affected by the exchange, for example, the peak of a standard. Under the slow-sweep conditions required to eliminate transient effects such as wiggles, the danger of saturation is also more pronounced than usual. Finally, excessive filtering of noise should be avoided since it may cause distortions also. With all these precautions the lines not broadened by exchange will be symmetrical, narrow, and very close to true Lorentzian lines. Otherwise the deviations from Lorentzian shape may be so significant as to render even the merits of a full line shape calculation illusory. The theory of exchange effects on NMR line shapes has now matured to such a stage that every spectrum can be calculated without major trouble provided the static parameters for all exchanging species are known. But there are of course many cases of such high complexity that the chemical shifts and coupling constants cannot be extracted. It is then necessary to simplify the problem experimentally. One of the most frequently employed methods consists in deuterating the molecule selectively so as to “insulate” a particularly simple proton spin system which still shows all the characteristic effects of the rate process of interest. The proton resonance is then observed while simultaneously


121

irradiating the deuterium nuclei. Another very elegant device is to introduce fluorine atoms at certain points in the molecule and make use of 19F resonance to analyze the motions at the molecular level. This technique has been employed extensively by Roberts and his collaborators. Its particular advantages have recently been reviewed by Roberts himself (88). B. Determination of Rate Constants

In Section 111-C we already indicated how the mean lifetimes 7, and hence the rate constants k , = I/., are obtained from a logarithmic plot in those cases where the multiple-resonance method can be applied. In all other instances a simple and safe procedure is to compare, visually, computer-calculated plots of line shapes or echo envelopes with the experimental curves. For line shapes this gives the rate constants directly; for spin-echo data one has to construct another plot of the apparent decay constants versus pulse frequency. All other precomputer treatments based on certain approximations have become obsolete by now. For very simple spin systems a time-saving variation of the above procedure is sometimes feasible. One extracts a single spectral parameter such as a line separation, linewidth, peak-to-peak ratio, or peak-tovalley ratio from the computed line shapes and plots this parameter versus the rate constant. By measuring the same parameter in the experimental spectra one can read the corresponding rate constants directly from the theoretical plot (21-23,89). It should be noted, however, that this method is more susceptible to spurious effects than a direct comparison of the full line shapes (88). The ideal method is, of course, to feed the experimental spectra point by point into a computer and let it find the theoretical curve that represents the best least-squares fit. Programs of this type have been written for an AB exchange by Jon$:, Allerhand, and Gutowsky (57) and for a classical two-site exchange by van der Werf, Olijnsma, and Engberts (90). It is even possible to take account of significant deviations from Lorentzian line shape due to field inhomogeneities by a numerical convolution integral technique that generates any desired shape in the absence of exchange broadening (91). If one is careful in obtaining highquality spectra, however, the incorporation of such a refinement may not be necessary (83). It is then feasible to work with an “apparent”

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G. BINSCH

transverse relaxation time T i which is related to the widths W(in cps) a t half-height of the peaks not broadened by exchange by the simple formula T ; = l/vW (43) In general T2will be found to be slightly different for the time-averaged peaks in the fast-exchange limit and for the separate lines of the individual species in the slow-exchange limit, and some function must be chosen to join these two extremes, since Ta is not available experimentally in the intermediate region. The simplest device is of course a linear relationship (92) and this should be entirely satisfactory, since the detailed functional form is not critical for high-quality spectra. Sometimes it is not possible to obtain exactly the same field homogeneity at all temperatures. In that case an appropriate correction, obtainable, for instance, from the linewidths of a standard, should be superimposed on the functional form of T;. For two-site exchange problems the spectra are usually calculated as functions of a single rate parameter, often expressed in terms of T as in our eq. (15). To get the separate first-order (or pseudo-first-order for intermolecular processes) rate constants for the forward and back reactions, one must use eq. (10). In particular, for equal populations k is given by 1/(27)! It is perhaps worthwhile to mention that in Alexander’s (41-44) original formulas the variable T is directly equal to the inverse of the rate constant. We have avoided this inconsistency of notation by writing eqs. (31), (33), and (34) in terms of k.

C. Calculation of Activation Parameters In many applications of DNMR only a single rate constant, at the coalescence temperature, has been calculated or, rather, estimated. By means of the well-known Eyring equation (93)

k = K(k,T/h) exp (- AG*/RT) (44) this number may be converted to the free energy of activation, AG*, a t this temperature. Since no meaningful standard deviation can be attached to this value, since the calculation makes use of an approximate formula, and since the measurement is performed at a rather ill-defined point, it is somewhat difficult to judge how far this quantity might be off the true value. Its significance for comparison purposes is further limited by the fact that its temperature dependence is not known.


123

If the rate constants have been obtained at a number of different temperatures, one may construct a linear Arrhenius plot Ink

=

- E , / R T -k In A

(45)

and extract the activation energy E, from the slope and the frequency factor A (commonly reported as log A ) from the intercept. An Arrhenius plot of course implies the tacit assumption that both E, and A are independent of temperature, which can only be an approximation. Experience has shown this approximation to be a good one. In general, it would mean taxing the accuracy of rate data beyond its limits to detect deviations from linearity with any degree of certainty. The modern literature seems to prefer enthalpies and entropies of activation in place of Arrhenius parameters. Substitution of AG*

=

AH* - TAS*

(46)

in eq. (44) gives k

=K

("J

exp ( - A H * / R T )exp ( A S * / R )

(47)

A H * and AS* could, in principle, be obtained from the Arrhenius parameters by A H * = E, - R T (48) AS*

=

R[ln

(eT) - 11

(49)

and this seems to be the method of calculation employed by many authors. However, with eqs. (48) and (49) one introduces a temperature dependence into A H * and AS*. This temperature dependence is really artificial, since it is based on the assumed temperature independence of E, and A . A more reasonable approach is to assume temperatureindependent A H * and AS* values and obtain them experimentally in a direct fashion. There are two ways to do this. One can make use of eq. (47) and plot In (k/T) versus I/T to give a straight line with the slope - A H * / R and the intercept In (Kk,/h) A S * / R , or one may calculate AC* from eq. (44) for each temperature and plot eq. (46). In the sections that follow it would have been desirable to convert all activation parameters to oneconsistent set of numbers, but the requiredinformation was unfortunately not available in many instances. Thus we have had to be content to report the numbers as they are given by the respective

+

G. BINSCH

124

authors, but we have decided to delete all references to specific temperatures. The question of what to do about the somewhat mysterious transmission coefficient K still remains to be answered. The simplest way is to set it equal to 1 and thus dispose of this problem. In fact, there hardly seems to be a reasonable alternative. In their study of the internal rotation in substituted ethanes, Newmark and Sederholm (46) provisionally tried another extreme value, but reported that this led to disagreement with experiment. If exchange takes place between two unequally populated sites, the activation parameters of the forward reaction are of course different from those of the reverse path. Figure 5 illustrates their interrelation. AG stands for the free energy difference of the ground states at the same temperature to which AG$ refers and is given by AG = - RT In (pB/pA)= - RT In K

(50)

For exchange between n sites there will be n(n - 1)/2 pairwise relationships of this kind. Analogous diagrams can also be drawn for A H * and AS*and their ground-state counterparts. Since the equilibrium constant K is itself a function of temperature, the corresponding changes in the populations must be taken into account in line-shape calculations. It is sometimes possible to determine the thermodynamic functions from peak-area measurements at a series of temperatures below the slow-

A

L Y

B

Fig. 5. Relation between thermodynamic and kinetic parameters for an exchange between two unequally populated sites.


125

exchange limit and extrapolate to the temperature region where broadened or collapsed spectra are obtained (94). Or one treats the populations as free parameters to be adjusted so as to give the correct line shape. Finally, it is clear that the NMR method for determining reaction rates will not be applicable at all when the ground-state energies differ vastly, because then one sees essentially only one species, and the line shapes do not respond to any exchange process that might still be going on.

D. Sources of Errors In this section we will restrict ourselves mainly to a discussion of the advantages and disadvantages of the various D N M R methods. Consistent with our policy not to treat approximate procedures at any length, we will not address ourselves to the complicated problem of evaluating in detail all the conceivable errors that have to be blamed on the use of approximate formulas. Allerhand, Gutowsky, Jondi, and Meinzer (25) published an excellent discussion of these aspects and we refer the interested reader to their paper. Here we only want to stress again their most important conclusion-that these errors have a tendency to be systematic in character. One may still obtain a satisfactory Arrhenius plot with small standard deviations, but such an agreement may be highly deceptive. The distinct advantages of the line-shape method are that it is the most versatile technique, applicable even to quite complicated cases, that the experiments are comparatively easy to perform with standard N M R equipment, and that the analysis of the data has by now become a rather straightforward task. Unfortunately, the significant information content of the measurements is limited to a rather narrow temperature range, usually between 20 and 60" in magnitude, and the sensitivity is not uniformly distributed over this range. The most pronounced changes in line shapes occur in the vicinity of the coalescence temperature. By applying a complete line-shape analysis to carefully measured spectra one may place a high degree of confidence on the calculated numbers in this region. The spectral changes diminish rapidly toward both extremes of the range, and unless the spectra are of high quality, errors will become appreciable. As long as they stay random and are taken with a lower weight in a least-squares analysis, this will only reduce the precision of the activation parameters. As already mentioned, approximate formulas are likely to make these errors systematic. It can

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G. BINSCH

be shown (70) that this feature most seriously affects the entropies of activation. It is therefore not surprising that ASt values have become a sore point in applications of DNMR. There is one further drawback that deserves comment. For line shape calculations one needs the chemical shifts (and possibly also the coupling constants) of the exchanging species. Naturally, these parameters can only be determined at the slow-exchange limit. If they change appreciably over the temperature range of the measurements but are assumed constant in the calculations, the rates calculated are incorrect. It seems that insufficient attention has been paid to this possibility in the literature. One can sometimes check and, if necessary, correct for such a temperature variation of the static parameters by recording the slow-exchange spectra at a number of different temperatures. With the spin-echo method it is not only possible to extend the measurements to faster rates than are accessible by the line shape method, but the total temperature range itself may cover as much as 100”. The chemical shifts and true transverse relaxation times are obtained simultaneously with the rate parameters, first-order couplings may frequently be safely neglected, and field inhomogeneities do not seem to be critical. All this sounds very promising. Nevertheless, as we shall explain in more detail in later sections, the practical results that have become known so far do not seem to live up to these expectations. This author does not feel competent enough to pinpoint really what might have gone wrong. There is also a serious limitation to the practical applicability of the spin-echo technique. The radiofrequency pulses are, at least at the present state of the art, “nonselective.” If the molecule, as is frequently the case, contains magnetic nuclei that do not take part in the exchanges, spin-echo rate measurements become difficult or even impossible to perform. Spin-echo experiments furthermore require special equipment, are quite a bit more tedious to carry out than lineshape measurements, and the mathematical analysis is considerably more involved. The multiple-resonance technique is particularly suited to extend line shape measurements to slower rates. Although the method is, at present, limited to these very slow rates and to rather simple spin systems, it is very simple to apply, both experimentally and theoretically, and has the appealing features of affording the rate constants for the forward and reverse exchange separately, even for more than two sites, and of being insensitive to field inhomogeneities.


127

In the tables of the succeeding sections we will make use of the following abbreviations A B C D E F SE DR

Complete line-shape calculation, using accurate theory Complete line-shape calculation, using approximate theory Peak separation approximation Linewidth approximation Other approximate treatment at more than one temperature Number based on coalescence temperature only Spin echo Double resonance V. HINDERED ROTATION

For many applications of DNMR to be discussed in the following sections, hindered rotation about bonds may be one aspect of a more complicated motion of a molecule. In this Section we will discuss those cases for which internal rotation is the essential part of a rate process. A. Substituted Ethanes A huge body of literature has accumulated about hindered internal rotation about single bonds (95,96). Most of the numbers were obtained by the microwave technique. Compared to this activity, NMR investigations are almost nonexistent. It is true that the barriers of ethane-type molecules in which only one or two hydrogen atoms are replaced by bulkier groups are still outside the accessible range, but the NMR method should be ideally suited for heavily and especially asymmetrically substituted ethanes, for which the difficulties of a microwave study become insurmountable. Following some early studies by Phillips (6) and by Roberts and his group (97), there is only the work by Sederholm and co-workers (46,98,99), but this happens to be one of the most advanced applications of DNMR known to this day, both experimentally and theoretically. Figure 6 shows a schematic representation of an energy profile to be expected for this type of problem and Table I lists the results. In spite of the complexities of the systems (or rather, one is tempted to say, because of them), it was possible in all cases to arrive at an unambiguous assignment of the slow-exchange spectra to the various “frozen” conformers.

G . BINSCH

128

F

C

F

E

C

C

EA&D

Fig. 6. Typical free energy profile for the internal rotation in asymmetrically substituted ethanes.

The meso- and d,l isomers 1and 2 could actually be studied as a mixture. Peak-area measurements gave the free energy differences and complete line shape calculations, based on the classical equations for the unsplit systems 2 and 5 and on quantum-mechanical equations derived from Alexander’s theory (Sect. 111-B)for the A2, AB, A2B, ABX, and ABC systems of the other molecules, yielded the free energies of activation. Since the interconversion between conformers 2 and 3 of 5 does not change the magnetic environments of the two fluorine nuclei, the corresponding barrier does not affect the NMR spectrum. The exchangebroadened spectra do not respond to all rate constants with equal sensitivity, so that for some AG*values only lower limits could be stated. After it was found that the spectra of 4 could not be reproduced theoretically with K ’cH \;/ 0

O2N+N/

NO2

CH, NO2

U3a)

CH

0

’.‘CH, NO2

03b)

E, = 21.0 k 0.3 kcal/mole and log A = 14.3 k 0.2 for the forward exchange (a+ b) and E, = 19.2 ~t:0.3 kcal/mole and log A = 13.5 f 0.2 for the reverse (b + a). These numbers are particularly trustworthy, since the analysis of the peaks due to the two aromatic protons and those of the N-methyl resonances in the perdeuteroacetyl compound led to good agreement. The other study has been reported by Neuman, Roark, and Jonas (125), and their numbers for N,N-dimethylcarbamoyl chloride are quoted in Table 111. Typically enough, both investigations


135

yielded “normal” frequency factors, that is activation entropies very close to zero. A spin-echo study (68), on the other hand, yielded a frequency factor of log A = 10.9 (TableIII),which appears to be too low. It may be that the spin-echo method, though in general more reliable than any approximate treatment of line shapes, still suffers from some small systematic error whose origin is not understood at this time. It is gratifying that these conclusions receive independent corroboration by a recent paper by Walter, Maerten, and Rose (129) who succeeded in actually isolating the rotational isomers of 14 (the more stable “trans” H-C

// N ‘’

S CH3

I

H-C

// N ‘’

S

CHaCeHs

I

CHaCeHs

CH3

(144

(14~

isomer 14a in pure form, the “cis” isomer 14b enriched to 75%). The kinetics of their interconversion could be studied by conventional techniques and yielded activation energies of 25.16 & 0.46 and 25.12 f 0.46 kcal/mole and normal frequency factors of log A = 14.16 and 14.33 for the forward and reverse reactions, respectively. This piece of work also seems to confirm the qualitative conclusion reached by a number of workers (1 11,125-127) that the barriers in thioamides are higher than those in amides, but at the same time shows that this difference has sometimes been grossly overestimated (1 11). Incidentally, stable amide conformers have also been isolated in pure form by Staab and Lauer (130) in a case (15) where a severe steric interaction raises the barrier by

136

G. BINSCH

an additional amount. A preliminary estimate of 30-32 kcal/mole for the free energy of activation is mentioned in this paper. Before proceeding, a general comment about these activation parameters is in order. It has been noticed by many authors that the free energies of activation found by different workers for the same compound are in much better agreement than the Arrhenius values, and that the numbers for AG* also do not show the sometimes completely unintelligible scatter encountered with E, and log A (or A H * and AS*). One may suspect that the errors in E, and log A partly cancel in AG*, and this is precisely what one concludes from an analysis of the systematic errors introduced by various approximations. Some authors have therefore advocated that only AG* values be used for purposes of comparison. This would mean, of course, that one is prepared to waive the potential capabilities of DNMR and that rate measurements a t more than one temperature become illusory. Furthermore, the conclusion that the AG* values are good enough for establishing general trends simply because they do not show a severe scatter does not in any way appear to be warranted. The typical amide barrier persists in vinylogous compounds such as 16 (131,132), but seems to become attenuated with increasing number of

(CH3)aN-CH=CH-CO-R

[

(R=H, CBHB) CH3-C <JQCF

intervening double bonds (133). Hindered rotation was also detected in acetamidinium chloride 17 (134). Barriers of heights similar to those in amides have been found in carbamates. The most clear-cut example seems to be 18 where the splitting of the methyl resonance into a doublet below -3" indicates hindered rotation around the carbon-nitrogen bond with a free energy of activation of about 16 kcal/mole (135). The same type of rate process causes the methylene hydrogens A and B in 19 to become nonequivalent at low temperatures (1 35). It was claimed that hindered rotation around the carbamate bond also accounts for the temperature dependence of the NMR spectra of compounds such as 20 (136), but there is evidence


137

c6HSCH2\N/C02C’2H5

I

C,H,CH,’

N

\CO,C,H,

(21) H5

c6

H,COzC H

Ci\C02CH3

C6H5

(137-139) that slow inversion at the two nitrogen atoms provides an

alternative and possibly preferable explanation (cf. Sect. VI). Even more ambiguities arise in 21 and 22 and similar systems. The low-temperature spectrum of 21 indicates the presence of at least four conformers (140), and the great number of possibilities has so far prevented a detailed identification of the various interconversions. Compound 22 is characterized by two distinct rate processes. The one with the higher barrier [AG* z 19 kcal/mole (141)] was attributed to ring inversion (141) (cf. Sect. VII), and this interpretation has survived (135,142-144) subsequent criticism (145). There is still disagreement, however, as to whether the other rate process with a AG* value of about 15 kcal/mole represents the restricted rotation in the carbamate structure (135,136,141,144) or a nitrogen inversion (143). A barrier ( E , = 16 kcal/mole) was discovered in 23 (90), but was attributed to hindered rotation in the ester function, based on the observation that only the 0-methyl and not the N-methyl group showed splitting at low temperature. Independent evidence for this highly surprising conclusion seems desirable. Restricted rotation has also been found in thiocarbamates (1 27).

G. BINSCH

138

D. Nitrosamines and Nitrites Hindered internal rotation in dimethylnitrosamine 24 was inferred from its NMR spectrum by Looney, Phillips, and Reilly (146) as early CH3

\ / / N-N /

0

++

CH3

CH3 0” \e / N=N

/

CH3

(Ma)

Wb)

as 1957 and has since been studied a number of times (Table IV). The origin of the barrier in this molecule can be explained in the same way as for amides, and its height seems to be of a similar magnitude to that in amides. The high-field peak was originally attributed to the methyl group trans to the nitrogen-oxygen bond (l46,147), but arguments were presented later (149) in favor of the reverse assignment. Replacement of the hydrogen atoms by fluorine results in a dramatic decrease of the barrier to about 5 kcal(150). Since the electron-attracting fluorines are

TABLE IV

Activation Parameters for the Internal Rotation in Dimethylnitrosamine. The Measurements Were Taken on Neat Samples Unless Stated Otherwise E,, kcal/mole 23 25 k 5 10

1 8-40 a 21.9 f 1.6 22.9 k 1.7

Log A 12.8 11.2

AG*,kcal/mole 23

Method C E C

12.0 12.8 21.1d

E SE SE F

Reference 146 147 147 147 78 78 148

‘These studies were done in ethylene glycol solution as a function of concentration. The lowest value for E, was found for a molar solute-solvent ratio of 0.2, the highest for a ratio of 0.5. Spin-echo measurements “on resonance.” Spin-echo measurements “off resonance.” dValue obtained from the coalescence temperature in a 1WMcps spectrum of a gaseous sample.


139

expected to destabilize the resonance contributor 24b, this observation can easily be rationalized. When the nitrosamine resonance is transmitted through a benzene nucleus as in 25,the rotation of the nitroso group is still restricted, but the barrier is substantially lowered. Approximate formulas derived from the classical theory of exchange were applied to the spin-coupled aromatic protons in 25a (151) to yield AH* = 11.2 i- 1.1 kcal/mole and A S = - 3 k 5 eu. A single-parameter method derived from Alexander’s equations was later used to analyze the AB system in 25b (89) and activation parameters AH* = 14.9 f 0.1 kcal/mole and AS* = 4.8 f 0.4 eu were obtained. K H

R

H

(25a) R (25b) R

=H .= D

The temperature dependence of the NMR spectra of alkyl nitrites is thought to arise from the conformational interconversion between the nonequivalent forms 26a and 26b (152). Various investigators (19,66, R-0

/N=o

(26a)

-7

/N=o

A

R

(26b)

153,154a) found barrier heights in the vicinity of 10 kcal/mole. As for the nitrosamines, the original assignments have had to be interchanged (149). Brown and Hollis (149) recently also questioned the intramolecular nature of the rate process observed in the NMR by pointing out that a dissociation-recombination mechanism may be operative. However, no definite proof for such an alternative has yet been reported.

E. Aldehydes and Ketones When a carbonyl group is attached to an aromatic nucleus, stabilization due to resonance between the constituent T systems can only become effective in a planar arrangement and must get lost by rotation

G. BINSCH

140

into a perpendicular conformation. The anisotropy of an aldehyde or acetyl group should make such systems suitable for an NMR study. This expectation was first verified by Anet and Ahmad (154b) for the compounds 27a, b, and c. From the coalescence temperatures they estimated free energies of activation of 7.9, 10.8, and 9.2 kcal/mole, respectively. The differences between these numbers are in qualitative agreement with the known electron-donating powers of the dimethylamino and methoxy substituents. These findings were later confirmed (155) for 27b and d and extended to 27e and f, the latter two compounds showing free energies of activation about 2 kcal lower than the corresponding aldehydes. R

R\'P

27a H 2713 (CH3)aN 2 7 ~ CH3O 27d CH30 27e (CH&N 27f CH30

: =y $& G . BINSCH

X

x

(116a)

(116b)

x

o

(117a)

o

X

(117b)

Recently, several groups of workers (325-329) have communicated interesting temperature effects on the NMR spectra of cyclooctatetraene metal carbonyl complexes. The original disagreement as to the interpretation of the observations has now been resolved (330-332) for the irontricarbonyl derivatives. Apparently the metal is complexed to two adjacent double bonds in the frozen structures and the temperature effects can be explained by stepwise migrations and bond shifts around the ring. Interesting DNMR studies have yielded rates for intramolecular hydride shifts in a number of carbonium ions, such as in the protonated form of hexamethylbenzene (333,334) and in the 2-norbornyl cation (335,336). In the latter molecule the 3,2-hydride shift is much slower than the 6,2-hydride shift. A quantitative analysis of the line shapes afforded E, = 10.8 +_ 0.6 kcal/mole and log A = 12.3 for the 3,2-process (334). Fast intramolecular rearrangements have also been inferred from temperature-dependent NMR spectra in the heptamethylbenzenonium ion (337,338) and in allylic Grignard reagents (339). IX. CONCLUSION

In this article we have attempted to convey an impression of the wide range of applicability of DNMR methods for the study of intramolecular rate processes in chemistry. Special emphasis has been attached to pointing out the various difficulties and their possible influence on the accuracy of the reported numbers. There will no doubt be many more cases in the future where qualitative DNMR information will prove extremely valuable. It is believed, however, that the importance of accurate rate determinations will become more generally recognized. If this article contributes to convincing prospective users that quantitative DNMR studies can actually be carried out and reliable values obtained without major difficulty, then it will have served its intended purpose.


X. APPENDIX

177

Here we reproduce two simple computer programs for the calculation of line shapes. Program CLATUX (pp. 178-179) applies to the classical exchange betweentwo uncoupled sites, programQUABEX (pp. 180-1 81) computes NMR line shapes for the intramolecular exchange between the sites of an AB spin system. The programs are written in FORTRAN IV and make use of the plotting routines available in the UNIVAC 1107 system equipped with a CALCOMP plotter. Users with a different computer configuration may have to substitute their own plotting routines. The input to the programs is explained in the comment statements. Line-shape computer programs for more complicated exchange problems have been mentioned on pp. 108, 110, 113, 128, and 174 and programs featuring direct least-squares fitting on p. 121. A general program based on the master equations [eqs. (31)] is available from the Quantum Chemistry Program Exchange, University of Indiana, Bloomington, Indiana.

Acknowledgments I am deeply indebted to Professor E. L. Eliel (University of Notre Dame), Dr. R. Knorr (Universitat Miinchen), Professor J. B. Lambert (Northwestern University), Dr. W. von Philipsborn (Universitat Zurich), Professor J. D. Roberts (California Institute of Technology), and Professor M. Saunders (Yale University) for their constructivecriticisms of the manuscript and to Mr. F. R. Harrell of the Notre Dame Chemistry and Physics Library for his cheerful cooperation in providing me with photostatic copies of close to four thousand journal pages. Acknowledgment is made to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research.

G . BINSCH

178

Program Clatux C C C C

C

C

C C

C

C C

C C C C

C C C

C C

c

C C C

PROGRAM CLATUX MMH LINESHAPES FOri CLASSICAL TWO-SITF

EXCHANGE

ORDERIN6 OF DATA DECK 1. NRUN ( 1 3 ) NRUN HUN NUYRER 2. TEXT (12A6) 3. N T A U , F R A ~ F K ~ I ~ T ~ A P T ~ H , P A , P( IRl ,~ e 4 F 1 0 . 0 ) NTAU NUMBER OF TAU VALUES CHEMSHIFT A (CPS) FRA FRO CHEMSHIFT Y (CPS) RELAX T I Y E A (SEC) T2A RELAX T I Y E R (SEC) T2H PA POPULATION A PR POPULATION R 4. F R l ~ F R 2 ~ S C A L E ~ H E I G H(T4 F 1 0 . 0 ) FR1 LEFT PLOT FREOUENCY (CPS) NIGHT PLOT FIqEBUENCY (CPS) FR2 SCALE HORIZONTAL SCALE (MM/CPS) HEIbHT HEIGHT OF HIGHEST PEAK (MY) 5 . NEXT SET OF CARDS EXCHANGE VARIABLE TAU ( F 1 0 . 0 ) ~ ONF PER C A I 4 0 6. NEXT PROBLEM FOLLOWS, REPEAT 1 THRU 5 7. AFTER LAST PROBLEM BLANK CARD

=

=

= =

= = = =

= =

=

COMPLEX IM,AA,AB,FREQeALPHAA~ALPHAB,~UM,DENOM,S DIMENSION Y(SOOO)eTEXT(12) PI=3.14159 DEl.1S=20b. IY=CMPLX(O.tl.)

xx=1 ./DEWS 1 READ ( 5 0 1 0 0 1 ) 4RUN 1 0 0 1 FORMAT (13) I F (FIRUN) 2e2e.3 2 STOP 3 READ ( 5 e 1 0 0 2 ) T E X T 1 0 0 2 FORYAT (12Ab) tIEAD (5e1003) NTPUe FHA, FRHe T2A 7 T2de PA, PH 1 0 0 3 FORYAT ( I l U e 6 F l U . U ) HEAS (5,1004) FRI,FR2,5CALE,HEIGHT 1 0 0 4 FORYAT ( 4 F l O . O ) WRITE ( 6 1 1 0 0 5 ) NRUNeTEXT 1uos FORYAT ( l H l I 3 e Z U X 1 2 A 6 / / / / ) rJi7ITE ( b e l U 0 6 ) F R A ~ F R H e T 2 A e T 2 R , P A ~ P H ~ F R l , F R 2 , S C I \ L E e H F I G t i T 1 U 0 6 FOHYAT ( 2 5 r i GENtRAL IIUPJT P A R A M E T E R S / / / / l O X 1 6 H C H ~ M I C ~ L S H I F T A l 4 X l lH=FH.3rbH CPS/lOXlbHCtiCYICAL SHIFT 914Xlkl=FA.3,4H CPS/lOX17HRELAXA LTIOV TIME A13XlH=FH*3e4H SEC/lOXl7H?ELAXATION TIME 913XlH=FR,3e4H 3ScC/lOX12HPOPULATIOrJ AlHX1H=F8.3/1OX12tiPOPULATION HlRXtH=FR.3/10#.1 49HLEFT PLOT F ~ E ( ~ U E N C Y l l X l H = F R . 3 e 4 t iCPS/lOX20HRIGHT PLOT FRFOUEPICYl MY/CPS/lOX~HHFItHT24Xl~=F 5UXlti=FM.3e4H Ct’S/lOX5HSCALE2SXlH=FR.3,7H 6 8 . 3 ~ 3 H MM////22H TAU VALUES I N SECONDS////) XYAX=SCALE*(FHZ-FH1)/25.4 IJPO I NT=DENS*XMAX S T t P = ( F H 2 - F H l )/NPOINT DO 5 1 K=lv,\ITAU READ ( S e l U O 7 ) TAU 1 0 0 7 FORYAT ( F 1 0 . 0 ) WRIrF (6,1008) TAU i o o a FOHYAT ( 2 u x ~ i 0 . 5 )


y=-xx FRZFH1-STEP A 1 / T 2 A -P / T A 11 A A =-2. P I I M F I< AB=-2.*PI*IM*FRH-I./T~~-~A/TAU UO 1 0 I = l ~ N P O I o I T FR=FR+STEP FHEO=2.*PI*IM*FR ALPHAA=AA+FREO ALPYAS=AR+FREO (PA*ALPtiAR+Pn*ALPHAA N U Y = - I l J l * T A U * ( ? a *PA*1'13-TAU* DEIIIOM=PA*PL3-TAU**2*ALPtiAb C A L P H A R G=NUM/DEVOY Y(I)=AIYAG(G) YYAXZY (1) Y Y I W Y (1) DO 11 I = 2 P J P O I I 4 T I F (YuAX.bT.Y(I)) b9 T O 1 2 YYAXZY ( I ) IF IYYIN.LT.Y(I)) L O TO 1 1 YYIl4=Y ( I I CONJTINUE F A C T O R = t I E I G H T / (25.4*( Y I ~ A X - Y Y I N ) 1 DO 1 3 I = l r f J P O I ' I T Y(I II ) - Y Y I I J ) * F A C T O H + O . 5 CALL PLGTS(nU~,010,XMAX,YYIO,O,MES) 30 1 4 1=1v I P O I i J T

* * *

1(1

12 11 15

x=x+xx

-

14 C A L L P L O T ( X v Y ( 1 ) r L ) CALL PLDT(Oe0,-4) 51 COFITINUE GO T O 1 END

.

n

11

179

180

G . BINSCH

Program Quabex C C C C C

C C C C C C C C C C C C C

C C

C C C

C

PROGRAM QUABEX NMH LINESHAPES FOR QUANTUM-YECHANICAL AB EXCHANGE

INTRAMOLECULAR

OHDERING O F DATA DECK 1. NRUN 1 1 3 ) NRUN HUN NUMBER 2. TEXT (12A6) 3. NRC,FRA,FRB,AJ,T2 (110,4F10.0) NRC NUMBER OF RATE CONSTANTS CHEMSHIFT A ICPS) FRA FHB CHEMSHIFT B (CPS) AJ COUPLING CONSTANT (CPS) T2 RELAX TIME ISEC) 4. FRl,FR2*SCALE,HEIGHT (4F10.0) FR1 LEFT PLOT FREQUENCY I C P S ) FR2 RIGHT PLOT FREQUENCY (CPS) HORIZONTAL SCALE (MMICPS) SCALE HEIGHT HEIGHT OF HIGHEST PEAK ( M M ) 5 . NEXT SET OF NRC CARDS RATE CONSTANT RC IFlO.O), ONE PER CARD 6. NEXT PROBLEM FOLLOWS, REPEAT 1 THRU 5 7. AFTER LAST PROBLEM BLANK CARD

=

= = = =

=

=

=

COMPLEX IMIG COMPLEX A l 2 ) ~ B l 2 ) ~ Q l 2 ) ~ R l 2 ) DIMENSION Y ( 5 0 0 0 ) , T E X T l 1 2 ) TUPI=2.+3.14159 DENS=200. IM=CMPLXlO.,l.) XX=l./DENS 1 HEAD 15,1001) NRUN 1 0 0 1 FOHMAT 1 1 3 ) I F INRUN) 2 ~ 2 ~ 3 2 STOP 3 READ 15,1002) TEXT 1 0 0 2 FORMAT 112A6) HEAD ( 5 , 1 0 0 3 ) NRCtFRA,FRB,AJ,TE 1 0 0 3 FORMAT (110,4FlO.U) READ 15,1001)) F R ~ P F R ~ , S C A L E , H E I G H T 1 0 0 4 FORMAT 11)FlO.O) WRITE ( 6 ~ 1 0 0 5 )NRUNPTEXT 1 0 0 5 FORMAT I l H l I 3 ~ 2 0 X 1 2 A b / / / / ) WRITE 16,1006) FRA,FHBtAJ*T2oFRloFRZ*SCALE,HEIGHT 1 0 0 b FOHMAT 12% GENERAL INPUT PARAMETERS////lOXl6HCHEMICAL S H I F T A14X1 lH=F8.3,1)H CPS/lOX16HCHEMICAL SHIFT BlYXlH=FB.J,4H CPS/lOX17HCOUPLI 2NG CONSTANTlJXlH=FB.St1)H CPS/10XlSHRELAXATION T I M E l 5 X l H = F 8 . 3 ~ 4 t i SE 3C/lOX19HLEFT PLOT FREQUENCYllXlH=FB.J,4H CPS/lOXEOHRIGHT PLOT FREQ 4UENCYlOXlH=F8.3,1)H CPS/lOX5HSCALE25XlH=F8.3,7H MM/CPS/10XbHHEIGHT2 S ~ X ~ H = F B . ~ VMM////2bH JH HATE CONSTANTS I N l l / S E C ) / / / / )

XHAX=SCALE*(FR2-FH1)/25.4

NPOINT=DENS*XMAX STEP=IFR2-FRl)/NPOINT FRO=IFRA+FHB)/Z. DO 5 1 K Z l t N R C READ 1 5 , 1 0 0 7 ) RC 1 0 0 7 FORMAT lF1O.U) WHITE 16,1008) RC


1 0 0 8 F O R M A T llOXF20.5)

x=-xx

V

FH=FRl-STEP DO 4 I = 1 ~ 2 AJ=-AJ A(I)=-IM*TUPI*lFRA+AJ/2.)-l./T2-RC BlI)=-IM*TUPI*lFRBtAJ/2.)-l./T2-RC QlII=lIM*TUPI*AJ/2.tRC)**2 R~I)=-TUPl*lFHOtAJ)+2.*IM*RCtIM/T2 DO 1 0 I = l # N P O I N T FH=FRtSTEP FREQ=TUPI*FR G=CMPLXlU.tO.) DO 5 J = 1 v 2

5 G~GtlRlJ~tFREQ~/llAlJ~+IM*FREQ~*l~

1 0 Y(I)=AIMAGlG) YMAXZY I1 1 YMIN=YIl) 00 11 I=2iNPOINT IF IYMAX.GT.Yl1)) GO T O 1 2 YMAXZY I I ) 1 2 IF I Y M I N ~ L T ~ Y I I )GO ) TO 1 1 YMINZY I I ) 11 CONTINUE FACTOR=HEIGHT/l25.9*lYMAX-YMIN)) DO 13 I=lvNPOINT 1 3 YlI)=(YlI)-YMIN)*FACTOR+O.5 CALL PLDTS(BUF~O#O#XMAXvYYIO,O,MES) DO 14 I = l # N P O I N T

x=x+xx

19 C A L L P L O T I X v Y l I ) # 2 )

CALL PLOTlOvO#-9) 51 CONTINUE G O TO 1 END

181

182

G. BINSCH

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Structures of Carbenes and the Stereochemistry of Carbene Additions to Olefins GERHARD L. CLOSS Department of Chemistry, The University of Chicago, Chicago, Illinois

I . Introduction . . . . . . . . . . . . . . . . . 193 Electron Configurations and Geometrical Structures of Carbenes. . 194 A. Methylene . . . . . . . . . . . . . . . . 194 B. Derivatives of Methylene . . . . . . . . . . . . 198 111. Stereochemistry of Carbene Additions to Olefins . . . . . . 203 A. Theoretical Considerations . . . . . . . . . . . 204 B. Methylene . . . . . . . . . . . . . . . . 210 C . Methylene Derivatives. . . . . . . . . . . . . 219 References . . . . . . . . . . . . . . . . . 231 11.

I. INTRODUCTION The last fifteen years have witnessed an ever-increasing level of research activity in carbene (methylene, divalent carbon compound) chemistry. Several excellent reviews have recently been published on the subject (1-6) and it should be stated at the outset that this chapter, as its title implies, is limited to the stereochemical aspects of the field. As in so many other areas of physical organic chemistry, however, the study of the stereochemical course of carbene reactions has served as a major tool to gain insight into the reaction mechanism. Consequently, it has been found advantageous to consider reaction mechanisms in greater detail than might appear necessary for the mere discussion of the stereochemical results. But only in this way has it been found possible to integrate the stereochemistry into a consistent framework of carbene chemistry. 193


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Considerable evidence has been accumulated over the last few years indicating that many of the reactions initially thought to proceed through divalent carbon compounds actually involve intermediates which may be called “complexed” carbenes and which have a valency greater than two ( 4 3 . Inasmuch as the observed chemistry of such “carbenoids” is in many aspects very similar to that of free divalent carbon compounds, a discussion of their stereochemical behavior will be included in this review. 11. ELECTRON CONFIGURATIONS AND GEOMETRICAL STRUCTURES OF CARBENES A. Methylene The symmetry of the simplest carbene, methylene, is represented by either point group C,, or Dm,,,depending on whether the molecule has a bent or a linear structure. Before discussing experimental evidence bearing on this question, it will be useful to give a qualitative description of the electron configurations associated with these geometries.

90

I35

H-C-H

Fig. 1.

I80

Bond Angle

Modified Walsh diagram of methylene (7-9).

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Orbital correlation diagrams, in which the one-electron energies of molecular orbitals are plotted as a function of geometrical parameters, have first been constructed by Walsh (7,8) and are helpful in predicting the most stable molecular geometry. Figure 1 is a modified (9) Walsh diagram for methylene. Neglecting the totally symmetric 1s orbital on carbon (la,), a linear combination of the valence atomic orbitals on carbon and hydrogen will yield for a bent structure three molecular orbitals of symmetry, a,, two of b2, and one of b,. Consideration of bonding and antibonding interactions leads to an ordering of the oneelectron energies of these orbitals as shown in the diagram. In the 90"-geometry two orbitals, 2al and lb2, are strongly C-H bonding, while orbital 3a, is weakly bonding and lb, is nonbonding. The orbitals 4a, and 2b2 have antibonding character. Figure 2 shows qualitatively the atomic orbitals contributing to the formation of molecular orbitals at this bond angle. Placing six valence electrons into the lowest orbitals gives the electron configuration for this geometry as 2 4 16; 3a: with a wavefunction symmetry of ,Al. Widening of the valence angle decreases the bonding character of 2a, slightly because of decreasing hybridization between the 2s and 2p, orbital on carbon. Symmetry considerations require that at 180" this orbital transform according to the fully symmetric representation 2ug, and only the 2s atomic orbital

Fig. 2. Symmetries of molecular orbitals of methylene in bent and linear configurations.

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on carbon has this symmetry. The bonding character of the 1b2 orbital will improve with greater bond angles because of better overlap between the hydrogen 1s and the carbon 2p, orbitals. In the linear configuration this orbital becomes la, and has reached its lowest oneelectron energy. The rise in energy of the 3al orbital with increasing bond angle can be attributed to decreasing s-p hybridization because it correlates with the doubly degenerate IT, orbital which has no s character at all. No change in energy is expected for the 16, orbital which remains a pure p orbital over all bond angles. Similar qualitative arguments can be advanced for the behavior of the less important antibonding orbitals, 4al and 2bz, as a function of valence angle. The electron configuration in the linear geometry will then be 2 4 la: lw:, and application of Hund's rule to the doubly degenerate orbital IT, leads to a molecular wavefunction of 3X;. While there can be little doubt that the linear geometry of methylene should have a triplet multiplicity in its lowest energy state and while it is highly likely that the bent configuration will be a singlet state, there is room for discussion of which multiplicity may be expected for the true ground state of the molecule. This question can be resolved theoretically only with quantitative calculations and many attempts to do this have been reported (9-1 5). Unfortunately, very often the necessary drastic assumptions inherent in these calculations make the quantitative results highly suspect. However, backed up by experimental data to be discussed below, a semiquantitative picture emerges as shown in Figure 3 (12,14). The energy of the lowest singlet state shows a minimum

Fig. 3.

Energies of electronic states of rnethylene as function of bond angle 4.

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197

not far from a bond angle of 100" with a continuous rise for larger angles. The triplet state energy has a minimum at or close to 180" but the curve is rather insensitive to angle changes between 180 and 150". Only at substantially smaller angles does the energy increase significantly. Furthermore, the triplet state should be the true ground state although the energy difference between the minima of the two curves is rather uncertain. Estimates range from 0.3 to 0.6 eV. These theoretical considerations should be compared with experimental evidence relating to the structure of methylene. The most convincing information was obtained by flash photolysis spectroscopy in the pioneering studies by Herzberg and collaborators (16-18). These authors were able to obtain the absorption spectrum of methylene on flash photolysis of diazomethane at low pressure using a high-resolution spectrograph. Isotopic substitution of both hydrogen and carbon established beyond a doubt that methylene was the carrier of the spectra. A detailed analysis of rotational and vibrational fine structure of the spectra yielded extensive structural information. In summary, the results show that there are two states of methylene, a metastable state absorbing fairly strongly in the red region of the visible spectrum and weakly in the near ultraviolet, and the true ground state of methylene giving rise to a spectrum in the vacuum ultraviolet region. It appears that the metastable state is produced first and then decays to the ground state. The decay process is accelerated on collision with inert molecules such as nitrogen. The stereochemical structure of the metastable state as deduced from the fine structure of the spectrum shows it to be highly bent with a bond angle of 102" and a C-H bond length of 1.1 A. In contrast, the ground state appears to be linear or nearly linear with a C-H bond length of 1 .O A. Although the triplet splitting in the spectrum of the ground state molecule was not observed, it seems a safe assumption that the molecule has the expected 3C; configuration while the metastable species almost certainly should be identified as the 'Al state of methylene. From the observed transitions it is possible to reach some conclusions on the energy and geometry of the upper states which are indicated in Figure 4. Included in the figure are correlations between the corresponding electron configurations for the linear and bent geometries. However, since no transitions with intersystem crossing were observed and since the Rydberg limit is known only for the triplet manifold, the interesting question of the energy difference between singlet and triplet states remains unanswered.

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bent

linear

Fig. 4. Observed transitions in the absorption spectrum of methylene (17,18).

B. Derivatives of Methylene The structures of substituted methylenes have been investigated in recent years by several techniques. Several mono- and dihalocarbenes were investigated by emission and absorption spectroscopy using electrical discharge or flash-photolysis techniques to generate the methylenes from polyhalomethane precursors. Halomethylenes for which spectra have been obtained so far are CF2 (19-21), CHCl(22), CHF(23). All appear to have highly bent structures with bond angles ranging from 102 to 110". The spectra are consistent with a l A electron configuration which most likely is the ground state for these molecules. Electronic excitation (24,27) and absorption spectra (2.5-27) have been obtained in the condensed phase for several arylmethylenes and for fluorenylidene ; however, little unambiguous structural information is available from these data. Most information on the structure of polyatomic methylene derivatives comes from electron spin resonance (ESR) studies. This technique is, of course, limited to methylenes with triplet ground states or at least to molecules in which the triplet state can be thermally populated. All ESR studies reported so far make use of the matrix isolation technique in which methylene derivatives are produced in low concentrations in an inert matrix usually at very low temperatures. The purpose of the matrix is to prevent the highly reactive molecules from reacting with

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199

themselves or with the methylene precursor. Furthermore, to obtain information on the dipole-dipole interaction of the unpaired electrons in the triplet state the molecules must be prevented from rapid rotation. Both crystalline (28,29) and glassy (30,3 1,33) matrices have been used leading to spectra from oriented and randomly distributed methylenes, respectively. In most cases the methylenes were generated from the corresponding diazo compounds by photolysis at liquid nitrogen temperature. Usually the methylenes were found to be stable under these conditions and spectra can be obtained many hours after irradiation has been ceased. Structural information can be deduced from the spectra in several complimentary ways. By fitting the experimental spectrum to the triplet state spin Hamiltonian, for S = 1, the zero-field splitting parameters D/hc and Ejhc can be extracted. These parameters describe the separation of the three energy levels when no external field is present. Each energy level corresponds to a principal magnetic axis in the molecule as its energy will not change with the external magnetic field when the field is parallel to that axis. D is defined as the difference between the z level and the mean of the other two. The separation of the latter pair is 2E. It follows that a molecule with three different axes should exhibit a finite E, while this quantity will vanish for molecules with two identical axes. For example, the E value for triplet methylene should be zero for the linear geometry, but should have a finite value for all other valence angles. Although the magnitudes of D and E depend on the electron distribution, it has been shown that there is a fairly good correlation between the ratio of the two parameters and the bond angle on the methylene carbon (32). Additional structural information is available from hyperfine splitting data which are a measure of the interaction of the electron spin with the nuclear magnetic moment either of the methylene carbon, when C-13 has been substituted at this position (28,29,34), or of suitably located protons (34). Most recently, electron nuclear double resonance (ENDOR) experiments have been carried out on methylene derivatives and have proven to constitute the most powerful technique for obtaining hyperfine interaction data (35,36). Since the isotropic component of the hyperfine interaction depends predictably on the hybridization of the atomic orbitals on carbon, information on the geometry of the molecule can be deduced from these parameters.

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The most thoroughly studied molecules are the arylmethylenes, such as diphenylmethylene (1) (28-3 1,33,34,36), phenylmethylene (2) (33,34), and fluorenylidene (3) (29,33-35), all of which have triplet ground states. The common feature of the structure of these methylene derivatives is the nonlinear bond angle on the methylenic carbon. Angles of 140-1 55 have been estimated for phenylmethylene and diphenylmethylene. This result is somewhat unexpected in view of the fact that triplet mcthylene is linear or very nearly linear. The results obtained for

fluorenylidene, indenylidene (4), and cyclopentadienylidene (5) (37) require the assumption of bent bonds on the methylenic carbon. In all three cases the analysis of fine structure and hyperfine structure data leads to interorbital angles much larger than the internuclear angles compatible with a five-membered ring structure. A study of perfluoroalkylmethylenes (38) gives some information on the dependence of the bond angle on alkyl substitution. If one extrapolates the angles measured for bis-trifluoromethylmethylene (6) (140' ) and trifluoromethylniethylene (7)(160 ) to the unsubstituted system, a linear geometry is indicated for methylene. Unfortunately, so far no simple alkyl-substituted methyle m have been reported, but it is likely that the bond angle for these derivatives does not deviate very much from linearity. A series of propargylene derivatives with the general structure .. R-(C-C),--CH[/? H, CH,; / I = 2, R = CH,. (CH;j),C] 1, R have been examined by ESR, and in all cases E,'/K-was found to be zero within the experimental error (39). Symmetry considerations lead t o linear structures as the only ones compatible with the experimental data.


201

Besides the central bond angle, another structural parameter of interest in the arylmethylenes is the dihedral angle between the plane defined by the bonds on the methylenic carbon and the aryl plane. Assuming a planar structure for fluorenylidene this angle is, of course, O", but it can have finite values in phenylmethylene and diphenylmethylene. Experimental evidence on this question, however, is still very sparse. The ESR spectra of I - and 2-naphthylmethylenes (8 and 9) gave evidence for the existence of two geometrical isomers in each system (40). The data have been interpreted in terms of syn and anti structures (8a and 8b; 9a and 9b) which can be expected to have different zero-

9

field splittings. Of course, if the observed spectral differences are caused by conformational differences, the dihedral angle may have any value except 90". Considerably more information has recently become available from ENDOR studies on diphenylmethylene in a I , I-diphenylethylene crystalline host (36). A complete analysis of the isotropic and anisotropic hyperfine interactions gave the geometry of the molecule. As Figure 5 shows diphenylmethylene has a C , symmetry with a central carbon bond angle of 151". The dihedral angles between the phenyl planes and the plane defined by the sigma bonds on the methylene carbon are 34".It should be pointed out that although these values are quite precise, they may not necessarily represent the potential energy minimum of the isolated molecule because the packing forces of the host crystal may have some distorting influence on the geometry. On the other hand, the fine structure parameters, D and E, obtained in this

202

G . L. CLOSS

Fig. 5. The structure of diphenylmethylene as determined by ENDOR in a 1,l-diphenylethylene host crystal. Bond angle Q = 151" and dihedral angle 0 = 34" (36).

host are very close to those determined for diphenylmethylene in a variety of glasses (34). This may be taken as an indication that the packing distortions are not very severe. Application of the ENDOR method to the conformational analysis of other methylenes, in particular, methylenes with hydrogen substituents on the divalent carbon, should be very rewarding. Electron delocalization in arylmethylenes will be a function of the molecular conformation. The two unpaired electrons in the triplet ground state are in two separate orbitals and will be delocalized to a different extent. For example, in planar fluorenylidine one electron moves in a 7r orbital which extends over the whole carbon skeleton, while the second unpaired electron is confined to an orbital lying in the u plane and which is essentially localized on the divalent carbon atom. Spin density measurements by ENDOR technique confirm this simple model (35). A planar diphenylmethylene would show a similar partition of the unpaired electrons into an essentially localized electron and a highly delocalized one. Rotation of the phenyl planes out of the molecular plane will have the effect of diminishing delocalization of the 7r electron while at the same time increasing that of the u electron. The experimentally found dihedral angle of the phenyl groups of 34" is large enough to cause an electron delocalization somewhat different from that of the planar model. However, delocalization in fluorenylidene and diphenylmethylene is different in one other important aspect-the 7r electron of the diphenylmethylene is part of an odd and alternant hydrocarbon T system, while fluorenylidene must be classified as a nonalternant hydrocarbon. This difference in electronic configurations may


203

be partly responsible for the rather different chemical behavior of the two species and should contribute to the notable differences in the electronic spectra (25). 111. STEREOCHEMISTRY OF CARBENE ADDITIONS TO OLEFINS

Ever since Doering and Hoffmann reported that dihalocarbenes add to olefins to give cyclopropanes in good yields (41), the reaction of carbenes with carbon-carbon multiple bonds has been the subject of intensive investigation. The study of the stereochemistry of this process has yielded valuable information on the structure and spin multiplicities of a variety of methylenes. Stereochemical observations on cyclopropane formation have been used to distinguish free carbenes from the complexed counterparts (carbenoids). Also, the study of the steric course of methylene additions to olefins in the gas phase has been a valuable tool in the chemistry of “hot” molecules and the associated problem of unimolecular reaction rate theory. Finally, the great synthetic value of the reaction is a stimulus to much additional research. The stereochemical problems associated with the addition of methylenes to double bonds fall into two categories. The first involves the degree of stereospeciJciry of the addition as exemplified in eq. (1).

b

I

/

Olefins lacking a symmetry axis along the carbon-carbon double bond can form two adducts with a symmetrical methylene. The reaction is called stereospecific if the geometrical relationships of the substituents in the cyclopropane correspond to those in the olefin reactant. This stereochemical course is also referred to as a cis addition. A trans

G . L. CLOSS

204

addition would then lead to a cyclopropane in which the relationships of the substituents relative to the ring plane are opposite to the configuration of the olefin. A nonstereospecijic addition is defined as a reaction in which both cis-addition and trans-addition products are formed. If the methylene derivative is unsymmetrical and the olefin also lacks a center of symmetry, a further stereochemical problem arises because the maximum number of diastereorners formed will now be four. As shown in eq. (2), two arise by a cis addition and two from trans addition. Of course, the maximum number of cyclopropanes formed

6

will be smaller in reactions with more symmetrical olefins. Sometimes, the ability of an unsymmetrical methylene to discriminate between the two possible cis-addition routes has been referred to as the stereoselectivity (42) of the methylene. A. Theoretical Considerations It is rather obvious that a one-step addition of a carbene to a double bond will give the stereospecific cis-addition product. Just as obvious is the fact that the trans-addition product is hard to visualize as arising from a one-step reaction. Therefore, the formation of products with the latter stereochemistry is usually attributed to the intermediacy of a species with more or less free rotation around the carbon-carbon bond corresponding to the double bond in the olefin reactant. An intermediate meeting this requirement is a trimethylene diradical as shown in eq. (3) or its dipolar counterparts. Unless the rotamer equilibrium in this intermediate is strongly displaced to one side, through the intervention of strong nonbonded interactions, such a reaction scheme may lead to a nonstereospecific addition. Therefore, in an operational sense,


205

stereospecific addition has become synonymous with a one-step mechanism, while lack of stereospecificity is usually taken as evidence for a reaction intermediate. This inference, however, may not always be correct in cases of stereospecific additions, because it is easily possible that conformational or stereoelectronic effects will lead to a stereospecific closure of a trimethylene intermediate. Nevertheless, it is advantageous first to examine some theoretical principles which may hopefully lead to a better understanding of the stereochemistry of carbene reactions with olefins. b

b

A puioui, different results may be expected for additions of methylenes with different spin multiplicities. Reactions of singlet state carbenes should be simpler and will be considered first. Cyclopropane formation can be viewed as a cycloaddition reaction and therefore may be examined in the light of orbital symmetry correlations which have been very successful in predicting stereochemical results in other cycloadditions (43-46). To construct an orbital correlation diagram it must be recalled that singlet methylene has C,, symmetry in its low-energy conformation with a bond angle of 102". The symmetry of the orbital wavefunction 'Al is the product of the symmetries of the occupied orbitals: 2 4 lbz 3 4 . Considering a concerted reaction with ethylene, the first two orbitals 2al and lb, may be neglected since they are essentially C-H bonding only and do not participate directly in the reaction. Similarly, it is permissible to neglect their antibonding counterparts 4al and 26,. The only orbitals of importance in the ethylene molecule are the bonding and the antibonding 7r orbitals. The reaction path with the highest symmetry is the one in which a C,, symmetry is assumed at all points of the reaction coordinate. Classification of the orbitals of reactants and product in this point group gives the correlation diagram of Figure 6, in which the low-energy l A l state correlates with an excited state of cyclopropane. Based on symmetry considerations, one should therefore expect a transition state of lower symmetry to be more favorable. For example, the conformation of the transition state shown by

G . L. CLOSS

206

HH

\I

C2H4

n!*bl--

__---- u /-

-b,

u.0,

Fig. 6. Orbital correlation diagram for the addition of methylene to ethylene.

C,, symmetry of the reactants is assumed along the entire reaction coordinate.

(For simplicity, the cyclopropane orbitals have been considered to transform with C,, symmetry although the proper point group for this molecule would be Dab. The diagram is not changed by this simplification.)

10 has as the only symmetry element a plane of symmetry, and all participating orbitals in reactants and products are symmetrical with reference to this plane, making this reaction symmetry allowed. It may

(10)

be pointed out here that a transition state as pictured by 10 has been postulated for many carbene additions, but that it has been derived from a totally different line of thought. It has been recognized very early in the study of carbene additions to olefins that the carbene reagent exhibits electrophilic character, meaning that electron density has been shifted from the olefin to the carbene carbon atom in the transition state. Since the only low-energy orbital able to accept additional electrons


207

is the 16, orbital, it was postulated that the most efficient overlap would occur in a transition state resembling 10 (42,47,48). Another interesting consequence of a transition state having lower symmetry than C, is that in a concerted reaction the two cyclopropane bonds must be made to a different extent i n the transition state. Clearly, the two bonds cannot be equivalent because there is no symmetry operation which will transform one into the other. This postulate is also supported experimentally by relative rate studies which show that an unsymmetrical transition state is required to explain the observation that carbenes usually react faster with isobutylene than with 2-butene (42,47-49). It is worth noting that a transition state with C,, symmetry can be expected for the reaction of an olefin with a hypothetical methylene in which the relative energies of the 3a1 and 16, orbitals are interchanged. The low-energy singlet state of such a carbene would have the electron configuration 2 4 162 16:. Reaction of this state with an olefin gives a correlation with the ground state of cyclopropane. However, no methylene with this electron configuration has as yet been reported. While the theoretical discussion of singlet methylene addition rules out a reaction path with CZvsymmetry, it places no other restrictions on the process and even leaves open the possibility of a two-step reaction. In contrast, two powerful arguments can be advanced to demonstrate that the addition of triplet methylene to double bonds is a two-step reaction with all its stereochemical consequences. The first, and more widely accepted, argument rests on the principle of conservation of spin angular momentum during the reactive collision. The second restriction arises from orbital considerations similar to those advanced for the addition of singlet methylene. As originally conceived by Skell and Woodworth (50) the prediction of a nonstereospecific, two-step addition of triplet methylene is summarized in eq. (4). Their mechanism has as its basic assumption the postulate that the transfer of spin angular momentum is much slower than any other molecular process. If this assumption is correct, triplet methylene will react with an olefin to give as the initial product a species with the spin of 1. The simplest molecule meeting this requirement is a trimethylene diradical in its triplet state. The second assumption involves the lifetime of this species relative to the lifetime of a specific conformation (rotamer). Again it is assumed that spin angular momentum transfer is slower than rotamer equilibration with the effect of an overall nonstereospecific cyclopropane formation. Before commenting

208

G. L. CLOSS

in detail on this hypothesis it should be stated that the principle of this argument has been experimentally confirmed and has provided a theoretical explanation of the stereochemistry of many methylene additions. Nevertheless, the chain of reasoning is open to criticism and perhaps needs some modification. The first assumption, postulating the initial formation of a molecule in a triplet state, is backed up by the fact that in most organic molecules spin angular momentum is only very weakly coupled with orbital momentum, and therefore spin relaxation is expected to be slow on the time scale of molecular collisions (51). This argument, however, is based on considerations of the ground state of organic molecules and cannot necessarily be extended to the activated complex in which the nature of bonding may be obscure. Identification of the initially formed triplet state as the trimethylene diradical is justifiable because it is hard to conceive of a triplet intermediate with a lower energy. For example, a triplet state of cyclopropane in which the three-membered ring is preserved and which would presumably show no free rotation, can be expected to be of much higher energy than the postulated intermediate. The weakest link in the chain of reasoning appears to be the postulate of slow spin relaxation in the trimethylene diradical compared to rotamer equilibration. It is generally accepted that the probability of


209

intersystem crossing increases with a decreasing energy gap between two states of different multiplicity. Clearly, the energy separation between the singlet and triplet states of the trimethylene diradical cannot be large because of a small electron exchange interaction. Therefore spin relaxation in this system should be fast, although it is admittedly difficult to place this event on the time scale of intramolecular rotation. On the other hand, there is some evidence that ring closure of a trimethylene diradical requires a finite activation energy (52) and that, although some steric preference may be expected (53), this step will not be completely stereospecific even for the singlet state of this intermediate. It is therefore an open question whether nonstereospecific addition should be attributed to slow intersystem crossing in the trimethylene diradical or whether the intermediacy of a diradical by itself leads to nonstereospecific addition regardless of its spin state. Recently, a second argument has been advanced for a two-step nonstereospecific addition of triplet methylene to olefins (53). Without taking recourse to the principle of conservation of spin angular momentum, consideration of the orbital component of the wavefunction alone predicts that an adiabatic one-step process cannot lead to a ground-state cyclopropane. The orbital wavefunction of a triplet methylene belongs to the irreducible representation B, or C;, depending on whether it has a bent or linear geometry, respectively. Combination of these states of low symmetry with the totally symmetric state of an olefin correlates with wavefunctions which are not totally symmetric. This rules out all ground-state molecules with closed shells as the initial reaction products. Again, the trimethylene diradical is a suitable intermediate and the stereochemical consequences are the same as discussed above. Naturally, an experiment deciding whether orbital or spin correlation is the deciding factor for nonstereospecific carbene additions will be hard, if not impossible, to design. Finally, still another mode of nonstereospecific carbene addition to olefins can be envisioned. This process involves the initial stereospecific addition to form a cyclopropane in its electronic ground state but carrying a large excess vibrational and rotational energy. If vibrational relaxation is slow because of a low collision frequency with other molecules, as may occur in the gas phase, it is possible that one of the carbon-carbon bonds will break and a trimethylene diradical might be formed as a secondary product. Scrambling of the stereochemistry can then occur by intramolecular rotation in the diradical before vibrational

210

G . L. CLOSS

relaxation will permit ring closure (54). A thermochemical consideration as shown in eq. ( 5 ) makes this process appear very likely because CH2 +80

+ H2C=CH2 + 12.5

-

CHz

/ \

H2C-CH2

+ 12.7

AH = -79.8 kcal/mole (5)

of the high heat of formation of methylene (- 80 kcal/mole). With most olefins the reaction will be exothermic by 80 kcal/mole, while the activation energy of cyclopropane isomerization is known to be only 64 kcal/mole. Unless vibrational relaxation is very fast, as in highpressure gas phase reactions or in reactions in the condensed phase, the addition of methylene to olefins should always be nonstereospecific. Of course, this mechanism depends on a large heat of formation of the methylene participating in the reaction and more stable carbenes may show stereospecific behavior in the gas phase even at low pressures. It is worth pointing out that the argument presented here is not affected by the recently discovered stereoselective ring closure of the trimethylene diradical in its singlet state (55). The reason for this is that the 64 kcal/ mole of cyclopropane isomerization energy must not only include the energy for bond breaking in cyclopropane, but also the rotational barrier in the diradical. B. Methylene

The first systematic study of the stereochemistry of the addition of methylene to olefins in the gas phase was carried out by Frey (56,57). When diazomethane was photolyzed in the presence of either cis- or trans-2-butene, cis- and trans- 1,2-dimethylcyclopropaneswere among the reaction products together with several isomeric pentenes. It was found that the product ratios were strongly dependent on the total pressure of the system and, to a minor extent, on the wavelength of the incident light. For mechanistic considerations two observations were of importance: (a) the yield of cyclopropanes increases with rising total pressure and (6) the cyclopropane formation is more stereospecific at higher pressures. For example, in the reaction with trans-Zbutene the yield of trans-dimethylcyclopropane rises from virtually zero to an asymptotic value of 50% at the high-pressure limit, while cis-dimethylcyclopropane goes through a maximum of approximately 7”/, at 10 mm and declines at higher pressure. The stereospecificity of the


211

0

:n: I 0

a tre $*

I

I

I

I

-

4358 A

95-

3660 A

-

a9

I

I

100

200

I 300

I 400

Pressure ( m m 1

Fig. 7. The stereospecificity of the addition of rnethylene to cis-2-butene as a function of total pressure.

reaction as expressed by the ratio of trans-dimethylcyclopropaneversus total cyclopropane products is shown in Figure 7. Similar results were obtained for the reaction with cis-2-butene. The observations were rationalized in terms of the reaction scheme 1 which assumes initial stereospecific addition to the olefinic double bond in competition with the two possible C-H insertion reactions. Because of the high exothermicity of the primary addition process, however, the initial cyclic adduct is vibrationally highly excited and contains enough energy to rearrange to the isomeric cyclopropane and to the thermodynamically more stable pentenes. Deactivating collisions with other molecules, in this case mostly 2-butenes, compete with rearrangements more favorably at higher pressures and are responsible for preserving the initial adducts. The reduced stereospecificity of the reactions induced by light with shorter wavelength (cf. Fig. 7) is attributed to excess vibrational energy of the methylene carried over to the initial adduct. Thus, at constant pressure comparison of stereospecificity of cyclopropane formation is a measure of the excess energy of the reacting methylene. A detailed kinetic analysis based on steady-state assumptions led to a ratio of 0.33 for k,/k - ,. This number represents the equilibrium constant of the excited cis- and trans-dimethylcyclopropanes and reflects the additional nonbonded interactions between the two methyl groups in the cis isomer. Because of this steric effect the reaction with cis-2-butene should be considerably less stereospecific than with the trans-Zbutene. Experimental observations in this and many other nonstereospecific addition reactions are in agreemept with this conclusion. Also, it is

G. L. CLOSS

212

/

CH3 1 k ,b

&+&

(178)

c1

c1

Br

(179)

(180)

Winstein (242) reports that norbornadiene gives a mixture of dibromides with bromine in nonpolar solvents. The products can be viewed as arising from the intermediate nonclassical ion (184); attack from the top at C-1 yields 181 while attack at the upper and lower side of C-5 gives 182 and 183, respectively. The products can, of

J & / . l & 3 r + B r &

- 25% (181)

+Br&

Cd -25% (182)

s + - - . .._* -....i s + *. aa*.....

'J,,,'

(184)

*

50% (183)

+

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

291

course, also be viewed as rising from classical ions. The possible toxicity of these dibromides should be noted (242). Farnum and Snyder (243) find that the tricyclic diene (185) and related compounds give varying yields of cis dibromides (186), along with other products, upon bromination in chloroform. Here, steric hindrance to trans addition forces the reaction to take a less favorable course. Br

B. Addition to Acetylenes Limited studies by Robertson and co-workers indicate that bromine additions to acetylenes (1 13a) in acetic acid follow kinetics similar to those found for olefins, but that acetylenes are 100- to 50,000-fold less reactive than the corresponding olefins. The bromination of symmetrically substituted stilbenes and tolanes in bromobenzene solution follows third-order kinetics, second order in bromine and first order in unsaturated substrate (244). Whereas electrondonating substituents accelerate and electron-withdrawing substituents retard the rate of addition to stilbene, both types of substituent accelerate addition to tolane. Here, bromine addition cannot be exclusively electrophilic in character. Bergel’son (245) has studied bromine addition to a variety of acetylenes under conditions for homolytic addition and also in polar media. He finds that both cis and trans adducts are formed in the radical process and that trans adducts appear to be favored in polar solvents. Acetylene dicarboxylic acid adds bromine in acetic acid to yield a mixture of adducts (246). Owing to the lack of definitive evidence for an electrophilic mechanism and the lack of quantitative stereochemical data under conditions of known kinetic control, very little can be concluded at the present time about the nature of electrophilic addition of bromine to acetylenes. Further studies in this area would obviously be of value.

292

R. C . FAHEY

VI. IODINE

Iodine and iodine chloride are known to form complexes with olefins and other unsaturated hydrocarbons (247-249) and iodination of olefins and acetylenes in solution can occur by either ionic or radical pathways (250-255). The addition of iodine to ethylene (256) or acetylene (257) is exothermic by only about 10 kcal. Since addition is accompanied by an unfavorable entropy change, AG for addition is usually small and equilibrium is established before complete conversion of the olefin or acetylene to diiodide (252,253,258).

\ / \ / C=C + I a e CI4I / \ / \ Kinetic studies indicate that iodine addition to olefins and acetylenes follows the rate law -4Ialldt = k3[El[Iala

+ kr[El[IaF

and limited studies of the rate of addition as a function of olefin structure suggest an electrophilic mechanism (259). The fourth-order kinetic term is most important in nonpolar solvents and has been interpreted in terms of iodine polymers. Iodination of olefinic alcohols, CH2=CH(CH2),0H, in aqueous solution leads to cyclic ethers. The rate of reaction is greatest for n = 3, suggesting that the reaction proceeds with neighboring-group participation via a transition state resembling 187 (260). Similar reactions with olefinic acids and their anions yield lactones (261,262).

(187) Tanner and Brownlee (263) have shown that addition of iodine to 188 in nonpolar media gives 190 as the sole product. The rearranged benzylic cation 189 is presumed to be the product-forming intermediate. The reaction of (- )-1,3-dimethylallene with iodine in methanol yields (- )-trans-3-iodo-4-methoxy-2-penteneby trans addition and as a minor product (228a). also gives cis-3-iodo-4-methoxy-2-pentene

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES 293

The stereochemistry of iodine addition to olefins has received little attention, but the addition of other iodine compounds has been shown by a number of workers to occur with trans stereospecificity. Heublein (264) has shown that iodine chloride adds to trans-stilbene in a stereospecific trans fashion and that the rate of reaction is first order in stilbene and first order in iodine chloride. Bowers et al. (265) find that iodine fluoride adds trans to cyclohexene and to various steroids (191).

1

(191)

The addition of iodine isocyanate to olefins has been investigated by Hassner and students (266) and by Drefahl et al. (267). Stereospecific trans addition is observed with a wide variety of arenes (266b,267a) and alkenes (266,267). Gebelein and Swern (268) have shown that the relative rates of INCO addition to various olefins follow a pattern similar to that for bromine addition. Fowler, Hassner, and Levy (269) have made a thorough survey of the addition of iodine azide to olefins and find that arenes, alkenes, and a,P-unsaturated carbonyl compounds all react smoothly to yield 1,2-trans-adducts. The simplest interpretation of these results is that addition occurs via an intermediate iodonium ion (192). Strong evidence for iodonium ions X-

as intermediates in organic reactions has been provided by studies of neighboring-group participation in displacement reactions (270), and

294

R. C. FAHEY

direct evidence for the existence and the bridged structure of these ions has been obtained from NMR studies (131). It is not entirely clear, however, whether the formation of 192 or some subsequent step is rate limiting (265). The iodination of acetylenes has been less thoroughly studied. The reaction of INCO with 3-hexyne is nearly 100-fold slower than with trans-3-hexene (268), showing that the iodonium ion (193) is less easily formed from the iodination of acetylenes than is the corresponding ion (192) from olefins. X(193)

Evidence has been obtained by Miller and Noyes (257) which indicates that iodine addition to acetylene in methanol occurs by an AdE3 trans addition mechanism. From studies of the rate and equilibrium of iodide-catalyzed elimination of 1,2-diiodoethylene, they could infer the mechanism of the addition reaction from the principle of microscopic reversibility. They conclude that the transition state for elimination, and therefore for addition, resembles 194. Since trans-l,2-diiodoethylene 8-

T

(194)

eliminates much faster than the less stable cis-l,2-diiodoethylene, it follows that trans addition must occur faster than cis addition. In accord with this conclusion, the addition of iodine to acetylene in aqueous potassium iodide has been observed to give a high yield of the trans diiodide (271). Iodine addition to olefins should, under appropriate conditions, also occur by an AdE3 trans addition mechanism, but evidence for this is lacking.

VII. PERACIDS Olefins react with peracids to form epoxides by an addition process which differs from the others considered in this review in that a single


295

atom becomes fixed across the double bond (272). The epoxide has the same configuration as the reacting olefin so that the stereochemistry of epoxidation involves a simple 1,Zcis-addition (272). 0

II

\

/

0

\ / \ / RCOOH+ C=C --+ C-C +RCOOH / \ / \ The rate of reaction is usually first order in both olefin and peracid (273) and is faster in polar than in nonpolar solvents (274). The variation of rate with structure follows the same trend as that for chlorination and bromination, but the magnitude of the variation is smaller. Thus, relative rates of epoxidation in the alkene series (275) are CH,=CH, 1

CH3CHzCHa 22

CHaCH=CHCH3 -500

(CH3)2CSHa -500

and correlation of epoxidation rates for ring-substituted styrenes (276) and stilbenes (277) with u + gives p values of about - 1.2. The reaction is considered to occur by a molecular cis addition involving a cyclic transition complex (195) as was first proposed by Bartlett (278). This is consistent with the view that peracids form

intramolecular hydrogen bonds (196) (279) and also with the fact that epoxidation is slower in ether solvent, which can form intermolecular hydrogen bonds with the peracid, than in hydrocarbon media, where intramolecular hydrogen bonding remains intact (274). An alternative mechanism has recently been proposed (280a), but subsequent studies (280b,280c) raise serious questions as to its validity. For certain cyclic alkenes, epoxidation can give stereoisomerically different products depending upon which side of the double bond undergoes attack. The effect of substituents upon the direction of attack has been the subject of considerable study by Henbest and co-workers

R. C. FAHEY

296

(28 1). In cyclohexene, a 3-methoxy or 3-acetoxy substituent directs attack trans, but in cyclohex-2-en01 hydrogen bonding stabilizes the

transition state (197) for cis epoxide formation and the cis epoxide is the major product (281a). A similar preference for cis epoxide formation

& &$ +

0 formation occurs in 201 (287), 202 (287), and 203 (288), but epoxidation

(201)

HO

(202)

(203)

(204)

of apobornylene (204) gives mainly endo epoxide (289). The endo hydrogens at C-5 and C-6 hinder endo attack in norbornene causing exo epoxide to form preferentially, but the C-7 gem dimethyl group in 204 provides an even greater steric hindrance to exo attack and here the endo epoxide predominates. Epoxides are readily opened by acids and, since epoxidations are 0

\ / + CX-COH \ / \

\ / \ / F I X

/

C-C

R. C. FAHEY

298

frequently carried out under acidic conditions, it often happens that the epoxide is not the isolated product. The stereochemistry of epoxide ring opening can be complicated (290); while the epoxides of most alkenes open in a stereospecific trans fashion, epoxides of arenes sometimes open nonstereospecifically or even with cis stereospecificity (290c,291). Rearranged products are sometimes found in epoxidations when the expected epoxide is highly strained. Thus, peracid reactions with methylenecycloalkanes often yield aldehydes (292), as does the oxidation

C

C=CH,

RCOiH

CH-CHO

of norbornadiene (293), but it is not clear if these are primary products or secondary products formed from an intermediate epoxide.

Acetylenes react with peracids at about 1/1OOO the rate of olefins (294). Oxirenes (205) are not isolated, but the products formed (207, 208, and related compounds) suggest that 205 is an unstable intermediate in the reaction (295,296). The formation of 1 ,Zdiketones has been RC-CR-

RCOIH

[

R--C-R

RzCO

] [

/O\

I

d

/O\ R-C-C-R

\o/

I

]

RCOCOR 0

II + RzCH-C-OH

interpreted (296) in terms of further oxidation of 205 to 206 followed by rearrangement,


299

VIII. SULFENYL HALIDES A. Addition to Olefins

A substantial amount is known about the addition of sulfenyl halides to olefins, largely through the studies of N. Kharasch and students, and the subject has been reviewed by Kharasch (297). Most of the sulfenyl halide additions studied have been found to occur by ionic mechanisms, but free-radical additions can occur and are especially favorable for sulfenyl halides with strong electron-withdrawing groups, e.g., CC1,SCl (297,298). It had been generally thought that addition of sulfenyl halides to olefins proceeds mainly according to Markownikov’s rule. Thus, Kharasch and Buess (299) found that 2,4-dinitrobenzenesulfenyl chloride reacted with propylene to give primarily the Markownikov product [eq. (12)]. However, more recent studies by Mueller and RSCl

+ CHaCHECHa

C1 --f

I

SR

I

CH3CH-CHa

SR

I

C1

+ CHaCH-CHaI

R = 2,4-di-NOa-Ph R = Ph: initial rearranged

65%

15%

32%

68% 15%

R = CH3: initial rearranged

15% 8870

85%

85%

(12)

12%

Butler (300) with benzenesulfenyl chloride and methanesulfenyl chloride show that the initial products are primarily those of antiMarkownikov addition and that rearrangement to a mixture rich in the Markownikov adduct occurs at ambient temperature. Addition to styrene was found to follow Markownikov’s rule in all cases studied (299,300a,301a). It is clear that the product distribution varies with the structure of the sulfenyl halide, as well as with the structure of the olefin; recent studies by Thaller, Butler, and Mueller serve to clarify the factors involved (300b-300d). While 1,Zadducts are normally obtained in high yield, substitution can be important in some cases. Traynham and Baird (292a) found that 2,4-dinitrobenzenesulfenylchloride reacts quantitatively with 209 to give 210 and substitution products have been found in the reaction of p-methoxystyrene (301b), phenyl vinyl ether (302), and 1,l-diphenylethylene (303) with sulfenyl halides.

300

c3"-(--J

R. C. FAHEY

CH,-SAr

Skeletal rearrangements are quite rare in these reactions. Under conditions of kinetic control, tert-butylethylene reacts with 2,4-dinitrobenzenesulfenyl chloride at 25" to give 1,Zadducts and no products involving methyl migration, although the latter were formed a t higher temperatures under conditions of thermodynamic control (304). Sulfenyl halides, like halogens, react with suitable olefinic acids to give lactones (305). The rate of sulfenyl chloride addition is first order in olefin and first order in sulfenyl halide (301b,306), but Campbell and Hogg (307) have shown that in nonpolar solvents the rate law can appear to be more complex owing to solvation phenomenon associated with the reactants and products. The rate is much faster in polar than in nonpolar solvents, as is illustrated by the relative rates of 2,4-dinitrobenzenesulfenyl chloride addition to cyclohexene (306b) Solvent Relative Rate

CCl4 1

CHCI, 600

(CH2CI)Z 1400

HOAC 140

PhNOa 3000

The variation in rate of addition with structure establishes the electrophilic character of the reaction. Correlation of log k2 with u for 2,4dinitrobenzenesulfenyl chloride addition to para-substituted styrenes gives p = -2.2 (301b). Kwart and Miller (308) have correlated the rates of 4-mOnO- and 4,5-disubstituted cyclohexenes with the inductive substituent constants, u,, and found P I = -2.88. The effect of alkyl substitution on the rate of addition to ethylene does not appear to have been studied. For addition of 4-substituted 2-nitrobenzenesulfenyl chlorides to cyclohexene, Brown and Hogg (309) find that log k2 correlates with U + and p + = -0.714. These results show that there is significantly more positive charge at both the sulfur and the olefinic carbon in the transition state than in the ground state. The reaction is considered to proceed by an AdE2 mechanism involving an episulfonium ion intermediate (211) (299). Strong support for this view comes from the studies of Pettitt and Helmkamp (310) who were able to prepare stable episulfonium salts (212) from the reaction of alkanesulfenyl 2,4,6-trinitrobenzenesulfonateswith cyclooctene


\ / C S / \

R S

+ RSCl + \C-C/ + \ /

(211)

/ C1\

*

\

301

/ \

CSR-CCI

/

in ether. As expected for reaction via a bridged ion (211), the additions show a high degree of trans stereospecificity.

L

R = Me,Et,n-Pr,n-Bu (212)

Arenes appear to add sulfenyl halides trans, although truly quantitative evidence for this is not yet available. Thus, Cram (311) has demonstrated that cis- and trans-2-phenyl-2-butene each add 2,4-dinitrobenzenesulfenyl chloride in fair yield to give the different Markownikov adducts resulting from trans addition. Addition of the same reagent to

Ph

SAr

wcH3 Y

AH CH3

H

ArSCI>

Ph

I c1

cis-stilbene gives an adduct in . V S O ~yield ~ which has a lower melting point than the adduct from trans-stilbene, suggesting that trans

302

R. C. FAHEY

addition occurred with both olefins (312). The adduct (213) of acenaphthylene with methanesulfenyl chloride has been shown by NMR to have the trans configuration (300d).

(213)

Havlik and Kharasch (313) have shown that sulfenyl halide addition to the 2-butenes and to cyclohexene occurs trans. A quantitative study of the reaction between the 2-butenes and p-chlorobenzenesulfenyl chloride has been made by Schmid and Csizmadia (314). Using 1,1,2,2tetrachloroethane as solvent, they demonstrated that the additions to cis- and trans-Zbutene are trans stereospecific to the extent of 2 99.95 and 2 99.5y0, respectively; no change with temperature occurred from - 30 to 146°C. This study leaves little doubt as to the stereospecificity of addition to symmetrical alkenes. The stereochemistry of sulfenyl halide additions to bicyclic systems has received substantial attention and the subject. has been reviewed by Brindell and Cristol (3 15). Addition of PhSCl(300d), p-Me-C,H,SCl (316,317), p-NO,-C,H,SCl (318), and o-NO,-C,H,SCl (318) to norbornene gives high yields of the 1,2-trans adducts (214) and little or no 215 or 216. With 2,4-dinitrobenzenesulfenylbromide and chloride,

,c1

however, up to 13% of 215 is formed, but again none of the rearranged product (216) was found (317). The failure of these reactions to yield significant amounts of rearranged product contrasts with the reactions of norbornene with acids and halogens, and is considered to result from the special stability of the cyclic sulfonium ion intermediate (217) which does not readily rearrange to the nonclassical ion (218).

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

303

In contrast to the finding by Brown (289) that apobornylene undergoes epoxidation by endo attack, benzenesulfenyl chloride with apobornylene yields 85% of the 1,2-truns adduct resulting from exo attack (300d). Cristol et al. have shown that norbornadiene also reacts with p Me-C6H4SCl to give primarily the 1,2-truns adduct derived from an exo episulfonium ion (3 16). Dibenzobicyclo[2,2,2]octatriene (220), on the other hand, gives mainly rearranged acetate (219) in acetic acid as solvent (319), but gives the unrearranged trans adduct (221) in carbon tetrachloride (316) or ethyl acetate (241) as solvent. Cristol and Jarvis

(241) consider that collapse of the intermediate ion pair 222 to 221 is rapid in aprotic media, but that solvation by acetic acid reduces the nucleophilicity of the chloride ion, allowing 222 to rearrange to the benzylic cation (223) which then collapses to 219. The reaction of 224

(222)

(223)

(224)

with benzenesulfenyl chloride is much slower than that of 220, and rearranged product is formed even in aprotic solvents (241). The presence of the chlorine at the olefinic carbon apparently destabilizes the intermediate episulfonium ion and facilitates the rearrangement process.

304

R. C . FAHEY

B. Addition to Acetylenes Sulfenyl halides form 1:1 adducts with acetylenes in much the same way as with olefins, but there are some complicating features in the reaction. Whereas styrene adds sulfenyl halides predominantly in the Markownikov sense, phenylacetylene gives a mixture of adducts which varies with solvent and 1-alkynes give predominantly the antiMarkownikov product (see Table VII). Addition to monosubstituted tolanes does give product compositions consistent with an electrophilic addition (Table VII). Kharasch and Yiannios (320) have established that the rate of addition of 2,4-dinitrobenzenesulfenylchloride to phenylacetylene and to 3hexyne in acetic acid is first order in both acetylene and sulfenyl halide. Phenylacetylene reacts at about 1/100 the rate of styrene and 3-hexyne at about 1/10 the rate of cyclohexene. The activation parameters for addition to phenylacetylene were found to be: E, = 24.3 f 1.3 kcal/ mole, AS* = -3.3 & 4 eu. Kharasch and Assong (326) found that 2,4-dinitrobenzenesulfenyl chloride reacts with acetylene only in the presence of aluminum chloride as catalyst, whereas 2-butyne reacts without catalysis and diethyl acetylene dicarboxylate does not react even with catalysis. These observations support an electrophilic mechanism for the addition. Additions in aprotic solvents are reported to follow a second-order rate law, but the reactions exhibit a number of unusual features (325). Addition of para-toluenesulfenyl chloride to tolane or 1-hexyne is faster in chloroform than in ethyl acetate. In chloroform as solvent, tolane and I-hexyne react at the same rate, but in ethyl acetate 1-hexyne reacts nearly 100 times as fast as tolane. Finally, for addition to tolane in chloroform as solvent, E, = 3.1 kcal/mol and AS* = -53 eu. These observations, plus the predominant anti-Markownikov addition in these solvents, are suggestive of a homolytic reaction, but other explanations are possible. The stereochemistry of the acetylene-sulfenyl halide adducts, although usually assumed to be trans, has been established in only a few cases. Truce and Boudakian (327) have shown that the adduct of paratoluenesulfenyl chloride with acetylene, obtained in ethyl acetate as solvent, has the trans configuration, and Montanari and Negrini (328a) have established the trans configuration for the adduct formed from benzenesulfenyl chloride and chloroacetylene in ethyl acetate.

HOAc PhH HOAc CHC13 EtOAc EtOAc CHC13 EtOAc EtOAc EtOAc

Solvent

R

-40

-80

Major Major

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