Homolytic Aromatic Substitution: International Series of Monographs on Organic Chemistry

By G. H. Williams

Homolytic Aromatic Substitution deals with the theoretical aspects of homolytic aromatic substitution reactions. The effect of various kinds of free radicals on the substitution of atoms or groups (usually hydrogen) attached to aromatic nuclei is examined, and the preparative use of homolytic substitution reactions is also considered. This book is comprised of seven chapters and begins with an introduction to the general characteristics of homolysis, along with homolytic and heterolytic aromatic substitution. The discussion then turns to the various theoretical approaches used to rationalize aromatic substitution, particularly those that are germane to a consideration of the problems of orientation and reactivity in homolytic substitution. The following chapters explore homolytic arylation reactions, including those between aryl radicals and aromatic substrates; relative rates of arylation and partial rate factors for phenylation; the reaction mechanism underlying intramolecular arylation; and homolytic alkylation reactions. The final chapter deals with hydroxylation and some other substitution reactions such as benzoyloxylation, acetyloxylation, halogenation, amination and amidation, and mercuration. This monograph will be of interest to organic chemists.

• Language: English
• Publisher: Elsevier Science
• Release date: Apr 8, 2014
• ISBN: 9781483151137

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PREFACE

THE branch of organic chemistry which is concerned with the reactions of free radicals, although fairly young, has grown, and continues to grow, with remarkable vigour, and at a prodigious rate. Such has been its growth that the production of a comprehensive treatise on the whole of the field would now be an extremely difficult, if not impossible task, and the stage has now been reached when its subdivision for the purposes of book-writing has become necessary. This book is therefore concerned with one group of free-radical reactions, namely those in which substitution of atoms or groups (usually hydrogen) attached to aromatic nuclei is effected by free radicals of various kinds. While the emphasis in this book is on the theoretical aspects of the homolytic substitution reactions discussed, their preparative use has also been considered, and ample references are included to the original literature and to review articles when these are available. It is hoped, therefore, that this book will serve as a useful source of information to the reader who is interested in the practical applications of these reactions.

After a brief introduction, I have devoted Chapter 2 to a general survey of the methods of theoretical approach to aromatic substitution in general and homolytic substitution in particular. In the following chapters these ideas are applied in discussion of the results of a number of homolytic substitution reactions. Reactions of arylation, both intermolecular and intramolecular (the Pschorr phenanthrene synthesis), alkylation with simple and substituted alkyl radicals, hydroxylation, acyloxylation, amination, amidation, halogenation and mercuration are considered in these chapters. I have attempted to cover the literature up to December 1958. However, since one cannot guarantee that such a survey is complete, I can only hope that authors to whom full justice has not been done will be patient with its shortcomings. I have not hesitated, wherever it seemed appropriate, to place my own interpretation on experimental data, to point out correlations and to draw theoretical inferences. I do not, of course, pretend that this is the final word on any subject, and some readers may disagree with the views I have expressed concerning controversial issues. This situation, if realised, will give me considerable pleasure, since if it serves in any small measure to stimulate thought, or further research into the topics discussed, then the main purpose of this book will have been served.

I must express my thanks to those of my colleagues who have helped me during the writing of this book. Firstly, to Professor D. H. Hey, who first excited my interest in this subject, for many hours of stimulating and fruitful discussion. I am also indebted to Dr. J. I. G. Cadogan and Dr. C. W. Rees, who have read sections of the book and given me the benefit of their views and criticism. I must also thank those good friends who have, as indicated in the text, made their results available to me in advance of publication. Finally, I should like to thank my wife, to whom I owe a very great debt of gratitude, not only for her encouragement and forbearance, but also in a more material sense, for her very able assistance at all stages in the production.

CHAPTER 1

GENERAL INTRODUCTION

Publisher Summary

This chapter discusses the general characteristics of homolytic reactions and homolytic and heterolytic aromatic substitution. The term homolysis was first introduced by Ingold (1938), who drew a formal distinction between the two possible modes of bond-fission—heterolysis and homolysis. Although the reactions of organic compounds are generally distinguished from those of inorganic compounds as being reactions of non-ionic substances, it is accepted that the course of the majority of organic reactions is determined by the electrical influences of polarization and polarizability. Thus, owing to the experimental circumstance that homolytic reactions are encountered less frequently than their heterolytic counterparts, the so-called normal laws of aromatic substitution, developed as the result of experiment, are laws governing the heterolytic reactions in which the substances take part. Heterolytic reagents are of two kinds: Those that react preferentially at the centers of high electron density, that is, electrophilic reagents, and those that react at electron-deficient positions, that is, nucleophilic reagents. Hence, in the majority of aromatic substitution reactions, such as nitration, halogenation, sulfonation, and diazo-coupling, an electrophilic reagent capable of accommodating a pair of electrons replaces a proton.

1

GENERAL CHARACTERISTICS OF HOMOLYTIC REACTIONS

THE term homolysis was first introduced by Ingold (1938), who drew a formal distinction between the two possible modes of bond-fission:

(1)

(2)

where A and B are atoms or groups of atoms. The latter reaction is characterised by the production of neutral fragments, each possessing an odd number of electrons, and hence, one unpaired electron. The term free radical is used with this connotation and hence may include some stable, more particularly inorganic, substances, which possess odd numbers of electrons, for example, nitric oxide. Such substances are free radicals according to the terms of this general definition.

Since the separation of the oppositely charged particles of equation (1) obviously requires more energy than that of the neutral fragments of equation (2) the latter reaction might be considered to be favoured energetically. Although in the gas phase this is probably true, for the majority of reactions in solution, particularly with solvents of high dielectric constant, fission by reaction (1) predominates because the solvation of the resulting ions results in the acquisition by this mode of fission of a certain energetic advantage over its competitor. Consequently, in solution, homolytic reaction is the exception, rather than the rule.

The first experimental demonstration of the existence of organic free radicals was the classic work of Gomberg (1900) on the dissociation of hexa-arylethanes into triarylmethyl radicals. The idea of an anomalous valency for carbon was not at that time a popular one, but the accumulation of data from many fields has resulted in the establishment of the concept. Organic free radicals may conveniently be divided into two classes:

(1) those of long life like the triarylmethyls, which are stabilised by resonance; and

(2) those of short life like phenyl and methyl which do not enjoy such stabilisation.

The radicals which are capable of effecting substitution in aromatic nuclei are generally of the second type. The inference that the short-lived radicals are intrinsically unstable is, however, erroneous; indeed, the contrary is true. The reason why they cannot be prepared in large quantity is not that they have any tendency to suffer molecular disruption, for a single radical completely isolated from all contact with other molecules would doubtless remain unchanged indefinitely. The reason is instead that these highly energetic substances are so extraordinarily reactive that each entity undergoes some sort of chemical change in an attempt to satisfy its normal valency requirements, before it has made a large number of collisions with other molecules.

Strictly, therefore, the term short-lived when applied in description of a free radical, is meaningless unless the environmental conditions are also stated. However, except in the most rigorous analysis the above classification into two clearly defined groups is valid and may conveniently be employed.

The physical demonstration of the existence of short-lived free radicals in solution is extremely difficult, since owing to the very small concentration in which such labile intermediates must occur, the techniques usually applied to the detection of radicals of the triarylmethyl type (for example, colour reactions and magnetic measurements) completely fail. The presence of radicals of short life is therefore inferred from their reactions, on account of the complex kinetics which they exhibit, and the nature of the chemical products that are obtained. Free radicals have been found to react mainly in three ways:

by dimerisation, or combination of radicals;

(3)

by disproportionation, involving mutual hydrogenation and dehydrogenation;

(4)

by radical transfer, which is expressed by the general equation;

(5)

In the last reaction the nature of the final products is also dependent upon the radical R’·. It may react as in equation (5) to give another radical R·, which may or may not be the same as R’·. If it is the same, then a chain reaction is set up, and the process repeats itself until the chain is somehow interrupted. If the radical R’·, or R·is relatively unreactive, then the transference [reaction (5)] results effectively in the termination of the reaction.

In many instances these reactions may occur simultaneously, and the total reaction may appear very complex. In other cases, however, certain of these reactions are favoured relative to the others and specific reaction paths which lead to specific products predominate. This may be illustrated by a comparison of the reaction medium of the gas phase with that of the liquid phase for, although the reactions may be initiated in the same way in both media, there are great differences in the types of reaction occurring. For example, in the photolysis of ketones, and the pyrolysis of certain organometallic compounds, in the gas phase, where collisions between radicals can readily occur, reactions (3) and (4) predominate, while in solution, where the radicals are surrounded by solvent molecules, reactions between radicals are unlikely unless the life of a radical is for some reason prolonged. With labile radicals in solution the radical-solvent interaction (5) is the most important reaction, and it is clear from this equation that the product is determined by both the radical and the solvent.

With aromatic solvents, alkyl radicals behave differently from aryl radicals. Thus alkyl radicals, in general, react with aromatic solvents by reactions other than that of direct substitution. They do, however, effect substitution in some cases, and this will be discussed at a later stage (Chapter 6). Similar considerations are valid in the comparison between the reactions of a given radical with aliphatic and aromatic solvents, since only the latter are susceptible to homolytic substitution.

During recent years these homolytic aromatic substitution reactions have been studied in considerable detail, and the results have been discussed periodically. The most recent, and comprehensive reviews of different aspects of the subject have been those of Dermer and Edmison (1957) and Augood and Williams (1957).

2 HOMOLYTIC AND HETEROLYTIC AROMATIC SUBSTITUTION

Although the reactions of organic compounds are generally distinguished from those of inorganic compounds as being reactions of non-ionic substances, it is accepted that the course of the majority of organic reactions is determined by the electrical influences of polarisation and polarisability. Thus, owing to the experimental circumstance that homolytic reactions are encountered less frequently than their heterolytic counterparts, the so-called normal laws of aromatic substitution, developed as the result of experiment, are laws governing the heterolytic reactions in which the substances take part.

Heterolytic reagents are of two kinds: those which react preferentially at centres of high electron density, i.e. electrophilic reagents, and those which react at electron-deficient positions, i.e. nucleophilic reagents. Hence, in the majority of aromatic substitution reactions, such as nitration, halogenation, sulphonation and diazo-coupling, a proton is replaced by an electrophilic reagent capable of accommodating a pair of electrons, e.g. the nitronium ion NO2+, which is responsible for most aromatic nitrations. Many nucleophilic reactions of aromatic substitution are also known, in which atoms and groups other than hydrogen are commonly replaced, and these have been reviewed by Bunnett and Zahler (1951). The history of the development of the theories of heterolytic aromatic substitution is long, and has been reviewed by Badger (1954) and Remick (1949). The so-called normal laws of aromatic substitution have been established mainly as the result of studies of nitration. (Ingold, 1934; Bird and Ingold, 1938; Ingold and Smith, 1938; Ingold, Lapworth, Rothstein and Ward, 1939; Hughes, Ingold and Reed, 1950; Bennett, Brand and Williams, 1946; Bennett, Brand, James, Saunders and Williams, 1947; Roberts, Sandford, Sixma, Cerfontein and Zagt, 1954.) On both theoretical and experimental grounds a directing group (X) attached to the aromatic nucleus in the compound C6H5X, may be placed in one of two main categories. Thus, for this type of substitution, the following groups X are ortho–para directing, and activate the nucleus for reaction with the electrophilic substitutient, relatively to the unsubstituted nucleus of benzene:

whereas the following groups are meta-directing and deactivating:

The situation is a little more complex in that certain anomalies, which are accommodated by the general theory, occur. Thus, for example, the halogens are deactivating groups, but are ortho–para directing. For nucleophilic substitution these rules have been found to be approximately reversed (for reviews see Badger, 1954; Remick, 1949; Bunnett and Zahler, 1951; Ferguson, 1952).

The contributions made by Ingold and his collaborators in this field were of the highest importance in providing quantitive data to describe the phenomena. The work resolved itself into two parts:

i.e. the ratio of the total rate of nitration of the monosubstituted benzene derivative, C6H5X, to that of benzene, C6H6; and

(2) the determination of the proportions in which the three isomers r-XC6H4NO2(where r- = o-, m- or p-) were formed in the nitration of C6H5X alone.

. Each of these factors expresses the change in the specific rate of substitution at any point r in the nucleus due to the presence of the group X, that is, it is the ratio of the rate of reaction at the point r are pure numbers; they have no dimension in time. A selection of the results obtained in this work is given in Table 1-1.

TABLE 1-1

PARTIAL RATE FACTORS FOR NITRATION

*Approximate values only.

It may be seen by examination of the table that for toluene the figures are greater than unity and show that the methyl group activates all the positions r, implies that this is the order of reactivity of the nuclear positions. The carboxyethyl group, CO.OC2H5, shows general deactivation, with the mata-position least affected, and the halogens show themselves to be exceptions to the rule linking ortho–para direction with activation, and meta direction with deactivation (the so-called Holleman rule), as mentioned above. Details concerning other groups, e.g., tert.-butyl, are also available ((Condon, 1948, 1952; de la Mare and Vernon, 1951). The differences between these figures and those of Table 1-1 show the electron demands of the reagents to be different (cf. Braude, 1949; Waters, 1952) and illustrate that any set of partial rate factors applies only to the reaction for which they were determined.

Although at that time these laws were not as clearly defined as they now are, it was the separation of apparently anomalous products from certain substitution reactions that first indicated the possibility of another, non-ionic, type of substitution. These reactions were those whereby the preparation of diaryls was accomplished, and it was suggested by Hey (1934) that, in these reactions, homolytic processes were occurring. This suggestion was elaborated by Hey and Waters (1937). In essence, the existence of short-lived free radicals of the type of phenyl was postulated, and these entities, being electrically neutral, and therefore not subject to electrical effects in the same way as the heterolytic reagents, effected substitution in aromatic molecules without conforming to the normal laws of aromatic