Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0479 531

I. INTRODUCTION

A. The Scope of this Chapter

Previous articles by the present contributor in The Chemistry of Functional Groups series have dealt with the electronic effects of the sulphonio group1, of the sulphinyl and sulphonyl groups2, of SOOH and related groups3, of amidino, guanidino and related groups4, of ether and hydroxyl groups5, and of cyano, isocyano, acetylenic and diazonio groups6. In the first two cases1,2 there was copious information from which to draw, but fairly comprehensive surveys were practicable. In the third and fourth contributions3,4 the amount of information available was very restricted. In the fifth and sixth cases5,6 the amount of available material was enormous and the treatment was highly selective both in the topics covered and in the illustrative examples provided. This will be the situation a fortiori for the present chapter, because the nitro group and the amino group and closely related groups are extremely popular substituents. In the space available it is not possible to give detailed accounts of all the substituents of interest. The contributor has therefore decided to give a fairly thorough account of the nitro group and to deal with the other relevant substituents much more concisely.

It is appropriate that the present Introduction should contain a specifically historical section, particularly in relation to the nitro group, whose electronic effect played a distinctive role in organic chemistry long before it was recognized as such. In this section and in later sections references are often given to classical papers and texts, whose importance has been overlaid by more recent work.

The quantitative study of the electronic effects of these groups is naturally much concerned with the Hammett equation and its extensions. The next main section therefore contains a summary of the salient features of the Hammett equation and cognate linear free-energy relationships, along the general lines of corresponding sections in certain of the contributor’s previous articles in the series1,2,5,6. This prepares the ground for a discussion of the electronic effects of the nitro group on the strengths of carboxylic and other acids: alicyclic, aliphatic and aromatic systems are covered. The discussion of aromatic systems leads to a further main section on the ortho-effect of NO2, in which electronic effects are moderated by steric and other influences. The emphasis of much of the chapter is deliberately ‘chemical’, but in the next section the application of modern spectroscopic and theoretical techniques to the nitro group is explored. The following section deals with several important areas for the manifestation of the electronic effects of NO2: the formation and stabilization of carbanions, nucleophilic substitution (both aliphatic and aromatic) and electrophilic aromatic substitution. Most of the treatment thus far has concerned NO2 as a substituent directly attached to the molecular skeleton of interest. A further section now deals with various substituents containing one or more nitro groups.

In a short section the electronic effect of the nitroso group is discussed. In the following section the electronic effects of the amino group and related groups are examined. The topics include the inductive effect and the resonance effect of these groups, their influence on the strength of benzoic and other acids, the ortho-effect and substituent effects in highly electron-demanding reactions. One topic which is only mentioned briefly in passing is the electronic effects of unipolar substituents such as NMe3C . The corresponding topic was dealt with in considerable detail in some of the earlier contributions to the series3,5,6, and this was, of course, effectively the sole main topic in the article on the sulphonio group1. Because of the highly variable nature of the electronic effects of any given unipolar substituent and the difficulty of incorporating data for such substituents in Hammett and other linear free-energy relationships, appropriate treatment of the topic must inevitably be highly detailed. It was therefore decided to omit this topic in the present chapter.

Multiparameter treatments such as the Yukawa Tsuno equation and the dual substituentparameter equation have long been important and further treatments have been devised in recent years. A final section is devoted to some of these, with an indication of the place of NO2, NH2 and some other groups in these treatments.

B. Historical Introduction

Nitrobenzene was first prepared in 1834 by Mitscherlich7. Aniline was first obtained from the destructive distillation of indigo in 1826 by Unverdorben8, who named it krystallin. It was rediscovered in coal tar by Runge in 18349, and called by him cyanol. In 1842 it was obtained by Fritzsche10 through the distillation of indigo (from Indigofera anil) with potash and was then first called aniline. At about the same time, Zinin11 obtained a base by reducing nitrobenzene and this was named by him benzidam. Hofmann investigated these variously prepared substances during the early 1840s and showed them to be identical12. After a short time the compound became known generally as aniline or phenylamine (initially it was phenamide). The study of nitrobenzene and aniline and their derivatives was pursued energetically throughout the 19th century from the 1830s onwards. A great deal of information was accumulated13, much of which was difficult to understand before the theory of valency and the structural theory of organic chemistry were developed in the third quarter of the century.

Aliphatic analogues of aniline and nitrobenzene were discovered somewhat later. Methylamine and ethylamine were first prepared by Wurtz in 184914, and thereafter many aliphatic amines were made and their properties studied13, particularly by Hofmann15.

Nitrite esters of aliphatic alcohols were discovered long before aliphatic nitro compounds were made. Indeed ethyl nitrite was obtained by the alchemist-chemist Johann Kunckel von Lowenstern¨ (Kunkel) in 168116. It was prepared and characterized more definitely by Liebig around 184017. Certainly by the middle of the century it was appreciated that the alkyl nitrites are esters, which may be hydrolysed by alkalis or acids into alcohols and nitrous acid and converted by reducing agents into alcohols and nitrogen. About 1872 it was realized by Victor Meyer that there should be another series of ‘alkyl nitrites’ with properties more analogous to those of nitrobenzene. By the action of silver nitrite on amyl iodide he obtained a compound of the same molecular formula as amyl nitrite, but quite different properties, to which he gave the name nitropentane18,19. His choice of silver nitrite as a reagent may well have been influenced by his knowledge of the peculiar behaviour of silver cyanide in its reactions with alkyl halides to give alkyl isocyanides rather than alkyl cyanides6. Also in 1872 Kolbe prepared nitromethane by the reaction of alkali metal nitrite with alkali metal chloroacetate20. During the next twenty years Meyer and his students carried out extensive investigations of aliphatic nitro compounds21.

It will be convenient to develop separately the relevant historical background for the nitro group and the amino group in aliphatic and in aromatic systems. We shall deal first with the nitro group in aliphatic systems. It would be appropriate to mention here that the activating and directing effects of the nitro group in aliphatic systems were surveyed in great detail in an earlier volume of this Series, including over five hundred references22. A review article of 1947 contains many early references to aliphatic nitro compounds23.

At an early stage it was found that the nitro group had the power of activating the hydrogen atom(s) on the carbon to which the NO2 is attached. Victor Meyer found that primary and secondary (but not tertiary) nitro compounds dissolve slowly in alkali and if alcohol is added an alkali metal salt of the nitro compound is precipitated. Thus the activation of CH by NO2 was associated with incipient acidity and the behaviour of the group in this way was similar to that of certain other groups such as CN, COMe and COOEt6. It was more than twenty years, however, before the incipient acidity of CH adjacent to NO2 was correctly formulated in terms of the tautomerism of nitro and isonitro or aci forms.

In 1896 Hantzsch and Schultze obtained the separate nitro and isonitro forms of phenylnitromethane and studied their properties and their interconversion24. Hantzsch introduced the term pseudo-acid to describe neutral compounds which form alkali metal salts corresponding to their aci forms.

Victor Meyer also discovered the reactions of aliphatic nitro compounds with nitrous acid, which likewise depend on the activation of CH by NO221. Primary nitro compounds give nitrolic acids RC(NO2):NOH, secondary nitro compounds give pseudo-nitroles R2C(NO)NO2 and tertiary nitro compounds, having no activated CH, do not react.

As in the case of other groups which activate adjacent CH6, the nitro group in aliphatic nitro compounds soon acquired importance in preparative organic chemistry, particularly for condensation reactions. The condensing agents are normally bases. Thus nitromethane will react with benzaldehyde to give first a nitro-alcohol and then a nitroolefin (Priebs, 188425):

PhCHO C CH3NO2 ! PhCH(OH)CH2NO2 ! PhCH:CHNO2 C H2O

In 1896 Henry26 found that nitromethane reacted with N-hydroxymethylpiperidine to form 2-nitro-1,3-di-N-piperidinopropane:

2C5H10NCH2OH C CH3NO2 ! NO2CH(CH2NC5H10 2 C 2H2O

In the 20th century many further reactions of aliphatic nitro compounds were discovered, as detailed in the review articles cited above22,23.

The mechanisms of the condensation and many other reactions of nitroalkanes are formulated nowadays in terms of carbanions, as in the case of reactions involving CH activated by other groups6. The ion generated from a nitroalkane by the action of base is regarded as a resonance hybrid; e.g. for nitromethane:

CH2:NO2 ! CH2NO2

with the negative charge residing mainly on the nitro group. In entering into reaction as a nucleophile, the ion is considered to be polarized to concentrate the negative charge on the ˛-carbon atom. The essential features of the mechanisms of reactions involving molecules with activated CH were put forward by Lapworth early in the 20th century27. For a long time authors seem to have been reluctant to accept mechanisms involving carbanions. However, in the early nineteen-thirties formulations involving carbanions became more widely used, although the actual term carbanion was not rapidly adopted. Hammett’s book (1940)28 appears to have been one of the first texts to use the term freely. By the nineteenthirties a fair number of ‘stable’ carbanions, as opposed to highly reactive intermediates, were recognized, and this no doubt helped to make the idea of carbanionic intermediates more acceptable. Thus it was known that dinitromethane in water was a slightly stronger acid than acetic acid, while nitroform HC(NO2)3 was a moderately strong acid.

There is not much historical background which it is necessary to explore for the amino group in aliphatic systems. The amino group, and substituted amino groups, are of interest as reaction centres rather than as substituents influencing reactivity elsewhere in the molecule; cf the situation in aromatic systems, dealt with below. However, one matter which should be mentioned, since it has been known for a long time, is the peculiar behaviour of amino acids.

It has been known for well over a century that amino acids, such as glycine (aminoacetic acid) and alanine (˛-aminopropionic acid), give neutral solutions in water and are somewhat reluctant to form metallic salts13. It was recognized that these peculiarities were due to the presence of both an acidic centre and a basic centre in the same molecule, and their neutrality was attributed to self-saturation. The interaction between the amino and carboxyl groups was expressed by writing ring structures for amino acids, either as monomers or dimers, e.g. 1 or 2, respectively. The correct formulation in terms of zwitter-ions, e.g. 3, was not possible until the theory of electrolytic dissociation was well established. The concept of zwitter-ions appears to have been originated as early as 1894 by Bredig29 and was well applied to the amino acids by Bjerrum in 192330,31. In connection with the effect of substituents on the acidity of aliphatic carboxylic acids, it is important to remember that potentiometric titration of amino acids indicates the effect of the pole NH3C , and not of NH2, on the dissociation constant of the carboxyl group.

We turn now to the historical background to the effects of nitro and amino groups in aromatic systems. It would be appropriate to mention here that there have been several articles pertinent to these topics in earlier volumes of the Series. In 1968 Chuchani contributed a chapter on the directing and activating effects of the amino group and related groups32, with over 340 references. In 1970 Urbanski´ reviewed the directing effects of

the nitro group in electrophilic and radical aromatic substitutions33, with over ninety references. In Part 1 of the same volume published a year earlier, de Boer and Dirx had contributed a chapter on the activating effects of the nitro group in aromatic (nucleophilic) substitutions34, with almost six hundred references.

Soon after the structural relationships between the ortho-, meta- and para-disubstituted derivatives of benzene had been established, attempts to formulate orientation rules began. It was recognized early on that the substituent already present tended to direct further substitution either to the ortho- and para-positions or to the meta-position. The problem of formulating orientation rules was thus essentially to classify substituents as ortho/para or meta directing and then to correlate the two classes with chemical character. The earliest attempts at this were by Hubner¨35 in 1875 and Noelting36 in 1876. The latter actually suggested that meta directing groups were of a ‘strongly acid character’, which showed remarkable insight in view of the rudimentary ideas as to the nature of acidity that were prevalent at that time. Empirical orientation rules were gradually refined, notably by Armstrong (1887)37, Crum Brown and Gibson (1892)38, Vorlander¨ (1902)39 and Hammick and Illingworth (1930)40. By the time of the last-mentioned it was well recognized that the factor underlying the mode of action of a substituent was its electronic structure, as we shall see below. However, it should be mentioned in passing that prior to the development of the electronic theory of organic chemistry, Flurscheim¨ had treated the ‘alternation’ characteristic of directing effects in terms of an electrical (but not ‘electronic’) concept of ‘alternating chemical affinity’ (1902 and later41).

In 1910 Holleman published a remarkable book about the direct introduction of substituents into benzene, which brought together the then known information about aromatic substitution42. In this book there was for the first time an emphasis on the importance of quantitative measurements of the percentage yields of isomers in aromatic substitution and on the value of measurements of relative velocities of substitution under standard conditions. The latter led to the recognition that ortho/para orienting substituents tended to increase the rate of substitution compared with benzene, whereas meta orienting substituents decreased the reaction rate. Holleman was able to rank substituents in order of ‘relative directing power’, thus:

ortho/para directing groups:

OH > NH2 > NR2 > NHAcyl > Cl > Br > Me > I

meta directing groups (all more weakly directing than the ortho/para directing groups):

COOH > SO3H > NO2

least directive power

By World War I it was certainly well recognized that both NH2 and NR2 were strongly ortho/para directing and activating; indeed so activating that with some reagents and under some conditions, the reaction did not stop with the introduction of one further group but polysubstitution was prone to occur, e.g. aniline reacts with bromine water to give tribromoaniline. NHAcyl was known to be somewhat less activating. It was also well recognized that NO2 was meta directing and was strongly deactivating43.

In the nineteen-twenties the examination of the directing effects of nitro, amino and related groups was prominent in the work of various research groups, particularly those involved in the controversies regarding electronic theories of organic chemistry which raged from 1924 for several years44 46. Thus in 1926 27 Robert Robinson and his

associates published a series of papers on ‘The Relative Directing Powers of Groups of the Forms RO and RR0 N in Aromatic Substitution’. Part IV of the series by Allan, Oxford, Robinson and Smith47 in 1926 contains the earliest fairly comprehensive statement of the main features of the electronic theory which Robinson was developing, this being given as necessary background to a ‘A Discussion of the Observations Recorded in Parts I, II, and III’. (There were in all eight Parts in the series.) The ‘observations’ were the percentages of isomers formed in the nitration of appropriate substrates, which were made the basis of a numerical scale of ‘relative directing power’. This was mainly for alkoxy groups5. The results were shown by Robinson to be accommodated by his electronic theory of organic chemistry, in which alkoxy-, aminoand dialkylamino-benzenes were classified as ‘hetero-enoid’ or ‘crotenoid’ systems, favouring the ‘anionoid’ reactivity of benzene through conjugative polarization represented as 4 or 5. Robinson’s interest in heteroenoid systems was originally aroused by Collie’s observation in 188348 that when ethyl ˇ-aminocrotonate reacted with alkyl iodide some of the alkylation occurred on the ˛- carbon atom. Nitro-substituted benzenes were classified by Robinson as ‘katio-enoid’ or ‘crotonoid’ systems, favouring the ‘kationoid’ reactivity of benzene through conjugative polarization represented as 6. This accounted for the activating effect of a p-nitro group on the displacement of a chloro group by a basic reagent49.

At around the same time Ingold and his collaborators began a series of publications on ‘The Nature of the Alternating Effect in Carbon Chains’. Part I of the series appeared in 192550; the series ended with Part XXXII in 193051. Several of the earlier Parts were concerned with aspects of the controversy about electronic theories of organic chemistry which arose between Ingold and Robinson44 46. Ingold initially favoured the approach of Flurscheim¨41, but by Part V52 of the series was formulating reactivity in terms of electrons46. Part I50 of the series concerned the directing influence of the nitroso group in aromatic substitution. The ortho/para directing nature found for this group was considered by Ingold to constitute a test case in favour of Flurscheim’s¨ treatment, but Robinson was able to show that it could easily be accommodated by his electronic theory46,53. Parts III54, V52 and VI55 of Ingold’s series were much concerned with the ‘relative directive efficiencies’ of oxygen, nitrogen and fluorine, and the studies involved determining the percentages of the various isomers formed in the nitration of such substrates as 7 to 9. Part III reported a study of the mononitration of teritary benzylamines and their salts. On the basis of Flurscheim’s¨ theory Ingold had predicted that the free amine would be nitrated in the meta-position and the salt in the ortho- and/or para-position. The experimental results in Part III appeared to confirm this prediction. Robinson admitted that he would have expected the opposite orientation and undertook a re-examination of the systems. He found that the free amine was nitrated at ortho- and para-positions and the

486 John Shorter

salt at a meta-position, in accordance with his electronic theory56. Ingold later carried out much useful work on the directing effects of NMe3C and of other positive poles, as well as on the damping influence of interposing methylene groups on the directing effect of the nitro group57,58.

As Ingold’s version of the electronic theory developed, NH2, NR2 and NHAcyl groups were classified as I and CT in their electronic effects, signifying electron attraction through the Inductive Effect and electron release by the Tautomeric Effect59. Later the latter was subdivided into the Mesomeric Effect M (polarization) and Electromeric Effect E (polarizability)60. The NO group was also classified as I and CT in its electronic effect, while NO2 was classified as I and T.

Work of a rather different nature involving the directive effects of NHAcyl groups was pursued in the nineteen-twenties by Orton and colleagues, and after Orton’s death in 1930 was continued by Brynmor Jones in a long series of papers on ‘Halogenation of Phenolic Ethers and Anilides’61. The emphasis of the work was rather on the phenolic ethers, i.e. on the directive effects of alkoxy groups, and this aspect was discussed by the present author in an earlier contribution to the Chemistry of Functional Groups series5. This work concerned the measurement of the velocities of halogenation (usually chlorination) of many series of phenolic ethers and a few series of anilides in 99% acetic acid. In these studies the complication of isomer formation in electrophilic aromatic substitution was eliminated by using substrates in which either the para or the para and one ortho position was already occupied by a group such as CH3, Cl, NO2 etc. In this way the velocity of substitution was brought within range of convenient measurement and only one product was obtained, as in 10 or 11.

Of general interest for chemical kinetics in this extensive work was the demonstration of the additive effects of the various substituents involved and the finding that the effects of substituents on reaction velocity were exerted largely through the energy of activation rather than the non-exponential factor of the Arrhenius equation62. Much information was obtained on the activating influences of the various alkoxy groups5,62 and some on the activating influences of various acylamino groups. For example63, the series p- AcNHC6H4X, where X D Cl, Br or COOH, gave the following order of diminishing activating power:

EtCONH > MeCONH > PhCONH > p-MeC6H4SO2NH > PhSO2NH × Cl3CCONH.

(See also earlier related work by Orton and Bradfield64.)

Nitro and amino groups also played an important role in the elucidation of structural effects through dipole moment measurements in the nineteen-thirties65. There was great interest in comparing the dipole moments of corresponding aliphatic and aromatic compounds, e.g. MeNO2 and PhNO2. It was found that these frequently differed somewhat, in

a direction which appeared to confirm the occurrence in the aromatic compound of a movement of electrons corresponding to the mesomeric effect that had been postulated in the electronic theory of organic chemistry. This led to the concept of ‘mesomeric moment’ and various ways of estimating this from observed dipole moments were devised. The actual values depended on the method of estimation employed, but various methods applied to a series of substituents gave similar trends. Thus Sutton66 suggested a value of 0.68 for the mesomeric moment of PhNO2, the minus sign indicating mesomeric electron withdrawal by the nitro group in the aromatic system. Marsden and Sutton67 found 1.12D and 1.55D for the mesomeric moments of PhNH2 and PhNMe2 respectively. (Observed dipole moments are usually between 1D and 4D.) It was found, however, that the mesomeric moment associated with a given group may vary when other substituents are present in the molecule. Bennett and Glasstone68 measured the dipole moments of several para- substituted anilines (among various series of compounds) and compared the experimental values with those calculated from the corresponding monosubstituted compounds. In the case of p-nitroaniline, the observed dipole moment was 6.20D, compared with a calculated value of 4.66D, corresponding to enhanced mesomeric effects through participation of the canonical structure 12 in the resonance hybrid. However, much of the way in which dipole moment measurements were interpreted in the nineteen-thirties is now regarded as over-simplified69, but there was great interest at the time in the relationship of the signs of the mesomeric moments to the ortho/para or meta orientating influence of the groups, i.e. whether electrons were moving from the substituent into the ring or vice versa65.

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II. THE HAMMETT EQUATION70

A. Introduction

The Hammett equation is the best-known example of a linear free-energy relationship (LFER), that is an equation which implies a linear relationship between free energies (Gibbs energies) of reaction or activation for two related processes71. It describes the influence of polar meta- or para-substituents on reactivity for side-chain reactions of benzene derivatives.

The Hammett equation (1937)72 77 takes the form of equation 1 or 2:

The symbol k or K is the rate or equilibrium constant, respectively, for a side-chain reaction of a meta- or para-substituted benzene derivative, and k0 or K0 denotes the statistical quantity (intercept term) approximating to k or K for the ‘parent’ or ‘unsubstituted’ compound. The substituent constant measures the polar (electronic) effect of replacing H by a given substituent (in the meta- or para-position) and is, in principle, independent of the nature of the reaction. The reaction constant depends on the nature of the reaction (including conditions such as solvent and temperature) and measures the susceptibility of the reaction to polar effects. Hammett chose the ionization of benzoic

aThese values, drawn from various sources, are presented solely for illustration. The table should not itself be used uncritically as a source of values for correlations. See rather References 74, 78 and 79. The values for NMe2 and NO2 will be discussed later in this chapter.

acids in water at 25 °C as a standard process. For this, is defined as 1.000, and the value of for a given substituent is then log Ka/K0a , where Ka is the ionization constant of the substituted benzoic acid and K0a that of benzoic acid itself. Selected values of for well-known substituents are given in Table 1. They are readily interpreted qualitatively in simple electronic terms, i.e. through the inductive (I) effect and the resonance or conjugative (R) effect.

Jaffe´ (1953)80 showed that while many rate or equilibrium data conform well to the Hammett equation (as indicated by correlation coefficient), many such data are outside the scope of the equation in its original form and mode of application. Deviations are commonly shown by para-substituents with considerable CR or R effect81. Hammett himself found that p-NO2 (CR) showed deviations in the correlation of reactions of anilines or phenols. The deviations were systematic in that a value of ca 1.27 seemed to apply, compared with 0.78 based on the ionization of p-nitrobenzoic acid. Other examples were soon discovered and it became conventional to treat them similarly in terms of a ‘duality of substituent constants’.

When values based on the ionization of benzoic acids are used, deviations may occur with CR para-substituents for reactions involving R electron-rich reaction centres, and with R para-substituents for reactions involving CR electron-poor reaction centres. The explanation of these deviations is in terms of ‘cross-conjugation’, i.e. conjugation involving substituent and reaction centre.

In the ionization of the p-nitroanilinium ion, the free base is stabilized by delocalization of electrons involving the canonical structure 13. An analogous structure is not possible for the p-nitroanilinium ion. In the ionization of p-nitrophenol, analogous delocalization is possible in both phenol and phenate species, but is more marked in the ion. Thus, in both the aniline and the phenol system p-NO2 is effectively more electron-attracting than in the ionization of benzoic acid, where the reaction centre is incapable of a R effect, and indeed shows a small CR effect (14).

An example of a reaction series in which large deviations are shown by R para- substituents is provided by the rate constants for the solvolysis of substituted t-cumyl chlorides. ArCMe2Cl82. This reaction follows an SN1 mechanism, with intermediate formation of the cation ArCMe2C . A R para-substituent such as OMe may stabilize the