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REACTION MECHANISMS IN ORGANIC CHEMISTRY A SERIES OF MONOGRAPHS EDITED BY E. D. HUGHES, F.R.S. ■ P rofessor o f C hem istry U n iversity College L ondon VOLUME I ELSEVIER PUBLISHING COMPANY AMSTERDAM / LONDON / NEW YORK NUCLEOPHILIC SUBSTITUTION AT A SATURATED CARBON ATOM BY C.A.BUNTON,Ph .D. R eader in C hem istry U niversity College L ondon ELSEVIER PUBLISHING COMPANY AMSTERDAM / LONDON / NEW YORK SOLE DISTRIBUTORS FOR THE UNITED STATES AND CANADA AMERICAN ELSEVIER PUBLISHING COMPANY, INC. 52 VANDERBILT AVENUE, NEW YORK 17, N.Y. SOLE DISTRIBUTORS FOR GREAT BRITAIN ELSEVIER PUBLISHING COMPANY LIMITED 12B, RIPPLESIDE COMMERCIAL ESTATE RIPPLE ROAD, BARKING, ESSEX LIBRARY OF CONGRESS CATALOG CARD NUMBER 63-9905 WITH 4 FIGURES AND 9 TABLES ALL RIGHTS RESERVED THIS BOOK OR ANY PART THEREOF MAY NOT BE REPRODUCED IN ANY FORM (INCLUDING PHOTOSTATIC OR MICROFILM FORM) WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS PREFACE In this monograph I have attempted to summarise my own views on one branch of Physical-Organic Chemistry, and to discuss some limited aspects of the subject. Workers in this field have been much too energetic for any complete review to be possible. I have deliberately restricted the field under discussion to nucleo philic substitution at a saturated carbon atom in order to keep this volume to a reasonable size. The price of this is the omission of such related topics as substitution at formally unsaturated centres, and at atoms other than carbon. Rearrangements and eliminations are mentioned briefly because they throw considerable light upon the properties of carbonium ion intermediates. The experimental problems of determining reaction rate, and the related kinetic parameters, have been omitted; they are not specific to this subject, and are dealt with very adequately in existing works. Physical-Organic Chemistry is a descriptive subject, and plagued by the uncertainties and ambiguities of our terminology. This is a great weakness, but one which is inescapable until theoretical chemistry can treat adequately such an immensely complicated problem as a chemical reaction in solution. For 25 years or more it has been customary to place reactions into mechanistic categories, usually in terms of their molecularities. I have generally followed the original mechanistic classification of Hughes and Ingold, which is based upon the concept of the duality of mechanism, although I believe that we should use the terms “uni-” and “bi-molecular” with considerable caution, particularly for solvolytic reactions and for reactions in solvents of low dielectric constant. Thus a given reaction may' show much of the behaviour typical of either mechanistic model without it being possible to assign it un ambiguously to either category. To the extent that I have abused, or perhaps what is worse, ignored the views or nomenclatures of VI PREFACE other workers I make my apologies in advance. Progress in any field results from the efforts of many individuals, and I have no intention of trying to make distinctions between individual contri butions. The literature has been covered up to the end of 1961. A fascinating aspect of any study of reaction mechanism is that it inevitably brings together a wide range of experimental methods. Mechanistic studies of nucleophilic substitution have benefited considerably from the use of the newer instrumental methods, but much of the stimuli for the work came from observations on reactions of naturally occurring compounds, in particular in the sugar, terpene and steroid fields. One can hope that the stimuli are in both directions. I am particularly grateful to my old teachers. Professors Sir Christopher Ingold, F.R.S., and E. D. Hughes, F.R.S. for their stimulating influence.The latter and Drs. D. Banthorpe, A. Ledwith, A. Maccoll and R. E. Robertson have read much or the whole of the manuscript and their contributions have been invaluable. Much of the preparation of this manuscript was done during a most enjoyable visit to the Department of Chemistry, University of California, Los Angeles, and I am happy to acknowledge the generous hospitality of its members, and in particular many entertaining discussions with Professors S. Winstein and D. J. Cram. Discussion with Professor V. J. Shiner and R. W. Taft and Drs. G. Kohnstam and R. E. Robertson were most helpful, and I am grateful to Professor Taft and Drs, Kohnstam and Robertson for giving me useful information in advance of its publication. C. A. B. CONTENTS P r e f a c e . . . . . . . . . . . ..................................... v Chapter 1. N u c l e o ph il ic Su bs t it u t io n a n d t h e D u a l it y o f M echanism . . . . . . .......................................... \ 1. Duality of mechanism ...................................... 3 (a) Molecularity of the reaction 3 / (b) Driving forces for substitution 4 t (c) Carbonium ions as reaction inter mediates 5 2. Simple kinetic evidence for the duality of mechanism . . . 6 (a) Kinetic form of an SnI solvolysis 8 / (b) The Sn2C+ mechanism 9 3. Alternative classifications of nucleophilic substitutions .... 10 (a) Charge-type classification 11 4. Side reactions : .......................... 12 (a) Rearrangements 12 /(b) Elimination 13 5. The nature of a substitution process. ................................... 15 Chapter 2. 25 St r u c t u r a l E f f e c t s u po n R a t e o f Su bst it u t io n 1. Introduction. . . . . . . . . . . . . . . . . . . . 25 2. Bimolecular substitution. Alkyl groups . . . . . . . . . 27 (a) Steric and electronic effects 27 /(b) Cycloalkyl groups 31 3. Bimolecular substitution. Substituents other than alkyl . . 33 (a) Aryl groups 33 / (b) Allyl and ethynyl groups 34 / (c) a-Carbonyl substituents 35 / (d) Other groups 38 4. a-Elimination . . . . \ . . .................................. 39 5. Unimolecular substitution. Alkyl groups. . . . . . . 39 (a) Electronic effects 40 / (b) Steric acceleration 40 6. Unimolecular substitution. Cycloalkyl groups ................... 42 (a) Bridgehead systems 42 / (b) Effect of ring size 43 7. Unimolecular substitution. Aryl groups . . . . . . . . . 45 (a) Baker-Nathan effect 47 / (b) Ortho-Alkyl groups and steric inhibition of resonance 48 8. Unimolecular substitution. Allyl and ethynyl groups . . . 49 9. Unimolecular substitution. Halogeno ethers and thioethers . 50 10. Neighbouring group effect . . . . . . . . . . . . . . . 51 11. Non-classical carbonium ions . . . . . . . . . . . . . 59 (a) Homoallylic and homoaromatic conjugation 65 VIII CONTENTS 12. Secondary structural isotope effects............................ 67 13. Analysis of kinetic effects in terms of energies and entropies of activation. ................................ 70 14. The displaced group X . . ................... , 72 15. The nucleophile Y . . . . . . . . . . . . . . . . . . 75 16. Summary . . . . . . . . ........................ . . 76 Chapter 3. 85 St e r e o c h e m is t r y ............................................................ 1. The Walden Inversion . . ................................ 85 2. Stereochemistry of bimolecular nucleophilic substitution. , 86 3. Stereochemistry of unimolecular substitution ..................... 88 (a) Configuration-retaining groups absent 88 / (b) Solvent effects upon the steric course of an Sn I solvolysis 90 / (c) Nature of the carbonium ion 92 / (d) Effect of configuration- retaining substituents 93 4. Replacements of OH and NH2 . . . . . . . . . . . . * 100 (a) Reactions of alcohols with halides of sulphur and phos phorus 101 /(b) Reactions of alcohols with hydrogen halides 103 / (c) Deamination 103 i Chapter 4. So l vent Ef f ec t s . ..............................................................Ill 1. Qualitative solvent theory........................ . Ill (a) Specific interactions between solvent and reactants 113 2. Linear free energy relationships.................................................115 3. Correlation of rates with product composition in mixed solvents. .................................... 118 4. Spectral measurements of solvent polarity . . . . . . . . . 119 5. Deuterium solvent isotope effects.................... 120 6. Special features of some solvents ................................ . . . 121 Chapter 5. Sal t Ef f ec t s f ....................... . . . . . . . . . . . 126 1. Aqueous and mixed aqueous-organic solvents.........................126 (a) Ionic strength effect 126 / (b) Common-ion retardation 129 2. Solvents of low dielectric constant........................ 132 (a) Ion-pairing and the reactivity of nucleophilic anions 133 3. Ion-pairs as reaction intermediates in Sn I reactions. . . . 135 (a) Reactions in aprotic solvents 136 / (b) Reactions in hydroxylic solvents 138 / (c) Evidence from oxygen equi libration studies 146 Chapter 6. ..................................................151 E l e c t r o ph il ic Ca t a l y s is 1. Catalysis by ions of silver and m ercury.................... 151 (a) Catalysis by silver ions 151 / (b) Catalysis by mercuric ions 153 CONTENTS IX 2. Catalysis by proton acids . . ...................................................156 (a) Acid-catalysed hydrolysis of epoxides 157 / (b) Acid- catalysed hydrolysis of alkyl fluorides 160 / (c) Acid catalysis in aprotic solvents 161 ......................................................................................... 164 A d d e n d u m 167 In d e x . Chapter 1 NUCLEOPHILIC SUBSTITUTION AND THE DUALITY OF MECHANISM Nucleophilic substitutions at a saturated carbon atom are hetero- lytic reactions in which a group X is displaced by a reagent Y with transfer of a pair of electrons from Y to the reaction centre, and from the reaction centre to X, e.g.,* Y + -^cj—X — ► Y—C^- + x In these reactions the reagent Y and the displaced ion or molecule are nucleophiles, or Lewis bases. The terms solvolytic* * and non- solvolytic reaction are used to differentiate between the situations in which Y is, or is not, a solvent molecule. This large class of substitution reactions, designated Sn, includes many reactions of preparative organic chemistry, e.g., alkylations by esters of strong acids, where the nucleophile may be a hydroxy- compound, an amine or sulphide, or a carbanion. The substitution may involve no net chemical change, e.g., we can observe the iso topic exchange: _ i3ii + It—I ^ 1S1I—R + I and its stereochemical consequences at an optically active centre. The reactant may be an unstable intermediate; one of the steps in the aqueous deamination of an aliphatic amine can be written as the alkylation of water by an aliphatic diazonium ion, or by a carbonium ion derived from it: RNH, + HONO + H RN, + 2H,0 ' RN, + HjO ROH + N, + H * The development of these mechanistic ideas is discussed in ref. [1], * * For a comprehensive review of solvolytic reactions see ref. [2aJ, and for a review of the chemistry of carbonium ions see ref. [2bJ. 2 1 NUCLEOPHILIC SUBSTITUTION Various pictures had long been formulated for substitutions at a saturated carbon atom, (cf., ref. [1]). Formation of an addition complex, followed by ejection of the displaced group was one sug gested model; another involved synchronous addition of the reagent and ejection of the displaced group. A somewhat different model postulated a prior dissociation to a reactive intermediate which was subsequently captured by the reagent. In general these earlier theories were mutually exclusive, and because no single one could be accommodated to all the results it became necessary to suppose that the molecularity of a nucleophilic substitution depended in a characteristic way upon the structures of the reactants and their environment. Various examples of displaced and entering groups are given below; the list is not intended to be exhaustive. Displaced groups: \ ' ■ •». + + + + Na, HRO, R-SOj-O, halide, R2S, R3N, (R0)aP0-0, RCOa Entering groups: R3C, H, CN, NOa, RO, RS, RCOa, SOa, ROH, R3N, RjjS, halide ions This formulation of these reactions tells us little about their mechanisms, and progress in this direction has followed intensive experimental effort devoted largely to those reactions which were amenable to kinetic study. For much of the early work the solvent was water, or mixtures of water and organic solvents; this choice of protic solvents of high dielectric constant simplified the in vestigation in many ways. Solvents of low dielectric constant are now being studied in detail, and more complicated behaviour, governed in part by powerful electrostatic forces, is being observed. This recent work is of great theoretical interest, and it also provides useful pointers in the choice of experimental conditions for pre parative reactions, e.g., dipolar aprotic solvents are proving to be excellent media for displacements involving nucleophilic anions (Chap. 4, sect. 6). The initial phase of this investigation led directly to the concept of the duality of mechanism, i.e., to the idea that it was possible.