Hammett equation nucleophilic substitution

The third volume of this series covers three specific groups of compounds the carbolines (reviewed by R. A. Abramovitch and I. D. Spenser), the thiatriazoles (K. A. Jensen and C. Pedersen), and the pentazoles (I. Ugi). The remaining four chapters deal with topics of general chemical interest from the heterocyclic viewpoint the quaternization of heterocyclics (G. F. Duffin), carbene reactions (C. W. Rees and C. E. Smithen), applications of the Hammett equation (H. H. Jaffe and H. Lloyd Jones), and some aspects of the nucleophilic substitution of heterocyclic azines (G. Rluminati). 

The fundamental understanding of the diazonio group in arenediazonium salts, and of its reactivity, electronic structure, and influence on the reactivity of other substituents attached to the arenediazonium system depends mainly on the application of quantitative structure-reactivity relationships to kinetic and equilibrium measurements. These were made with a series of 3- and 4-substituted benzenediazonium salts on the basis of the Hammett equation (Scheme 7-1). We need to discuss the mechanism of addition of a nucleophile to the P-nitrogen atom of an arenediazonium ion, and to answer the question, raised several times in Chapters 5 and 6, why the ratio of (Z)- to ( -additions is so different — from almost 100 1 to 1 100 — depending on the type of nucleophile involved and on the reaction conditions. However, before we do that in Section 7.4, it is necessary to give a short general review of the Hammett equation and to discuss the substituent constants of the diazonio group. 

The special substituent constants for + R para-substituents are denoted by a, and those for — R para-substituents are denoted by a+ 54. They are based respectively on the reaction series discussed above. Selected values are given in Table 1. Characteristic a or a+ values are sometimes distinguished for meta-substituents also, but only for a minority of substituents which show very marked + R or — R effects do these differ significantly from ordinary a values. The range of applicability of the Hammett equation is greatly extended by means of a and cr+, notably to nucleophilic (by a ) and to electrophilic (by cr+) aromatic substitution. 

Some radicals (e.g., tert-butyl, benzyl, and cyclopropyl), are nucleophilic (they tend to abstract electron-poor hydrogen atoms). The phenyl radical appears to have a very small degree of nucleophilic character. " For longer chains, the field effect continues, and the P position is also deactivated to attack by halogen, though much less so than the a position. We have already mentioned (p. 896) that abstraction of an a hydrogen atom from ring-substituted toluenes can be correlated by the Hammett equation. 

In order to gain an insight into the mechanism on the basis of the slope of a Type A correlation requires a more complicated procedure. Consider the Hammett equation. The usual statement that electrophilic reactions exhibit negative slopes and nucleophilic ones positive slopes may not be true, especially when the values of the slopes are low. The correct interpretation has to take the reference process into account, for example, the dissociation equilibrium of substituted benzoic acids at 25°C in water for which the slope was taken, by definition, as unity (p = 1). The precise characterization of the process under study is therefore that it is more or less nucleophilic than the reference process. However, one also must consider the possible influence of temperature on the value of the slope when the catalytic reaction has been studied under elevated temperatures there is disagreement in the literature over the extent of this influence (cf. 20,39). The sign and value of the slope also depend on the solvent. The situation is similar or a little more complex with the Taft equation, in which the separation of the molecule into the substituent, link, and reaction center may be arbitrary and may strongly influence the values of the slopes obtained. This problem has been discussed by Criado (33) with respect to catalytic reactions. 

Polar effects in radical reactions seem also not quite well understood. There are some attempts to divide radicals into electrophilic and nucleophilic classes (Pryor, 1966 Pryor et al., 1969 Johnston et al., 1966) resembling the pattern of ionic reactants, generally on the basis of the Hammett equation. This classification, however, seems to be alien to the nature of most carbon radicals. In addition reactions (2) the Hammett />-value is usually positive (radical addition to substituted nitrobenzenes Bartlett and Kwart, 1950, 1952 Sinitsyna and... 

Selenophene compounds are also more reactive in nucleophilic substitutions. Thus, 3-nitro- and 5-nitro-2-bromoselenophenes90 react with piperidine faster than do the corresponding thiophenes.91 The effect of electron-accepting substituents on the nucleophilic substitution of bromine located at the 2-position of 3,5-disubstituted selenophenes has been studied, as also has the applicability of the Hammett equation to this piperidino-debromination.92... 

The hydrolysis rates of 1,3-dioxolanes are decreased by substitution of four methyl groups at the positions 4 and 5. 2,4,4,5,5-Pentamethyl-l,3-dioxolane reacts 6.5 times more slowly than 2-methy 1-1,3-dioxolane [161]. The AS value is decreased by 9 eu. A Hammett p value of—2.0 has been found for the substituent effect on the hydrolysis of 2-phenyl-4,4,5,5-tetramethyl-l,3-dioxolane in dilute aqueous hydrochloric acid [167]. The data obey the simple Hammett equation, and it is not necessary to apply o+ values. For the reaction of the unsubstituted 2-phenyl-4,4,5,5-tetramethyl compound, the solvent isotope effect is kH/kD = 0.42, and AS is —14.2 eu. General catalysis by formic acid has been observed in the hydrolysis of the p-methoxy compound. However, the rate is not significantly increased by addition of strong nucleophiles. 

An example of a quantitative SMR study correlating electronic properties and catalytic parameters is provided by the glutathione conjugation of para-substituted l-chloro-2-nitro-benzene derivatives (183). The values of log/j2 (second order rate constant of the nonenzy-matic reaction) and log (enzymatic reaction catalyzed by various glutathione transferase preparations) were correlated with the Hammett resonance cr value of the substrates, a measure of their electrophilicity. Regression equations with positive slopes and values in the range 0.88-0.98 were obtained. These results quantitate the influence of substrate electrophilicity on nucleophilic substitutions mediated by glutathione, be they enzymatic or nonenzymatic. 

Rate constants for three distinct competing processes were separately determined solvolysis k, unimolecular k, and bimolecular k2. The Hammett equation with cross-terms was applied to the effects of substituents X in the nucleophile and Z in the leaving group on the analysed rate constants, but in most cases the pxz term was negligible. The Hammett equation with cross-terms has also been applied to the reactions of Z-substituted benzyl X-benzenesulfonates with Y-substituted thiobenzamides in acetone at 45 The findings pz < 0 and pyz > Pxz indicate that this reaction proceeds by a dissociative 5ivr2 mechanism. 

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