Electrophilic aromatic steric effects

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

The substituent effects in aromatic electrophilic substitution are dominated by resonance effects. In other systems, stereoelectronic effects or steric effects might be more important. Whatever the nature of the substituent effects, the Hammond postulate insists diat structural discussion of transition states in terms of reactants, intermediates, or products is valid only when their structures and energies are similar. 

Equipped with these reference trends for steric and electronic effects, one is prepared to survey more general classes of electrophilic aromatic substitution on benzocycloalkenes. Such reactions include nitration, halogenation, sulfonation, and alkylation. Each has its own mechanistic peculiarities, but their product distributions can be rationalized by consideration of the appropriate reference. 

Now that we have determined that the intermediate in electrophilic aromatic substitution is usually a a complex (see, however, p. 394), let us return to a consideration of Reaction 7.76. Two factors probably combine to cause the observed isotope effect and base catalysis. First, the strong electron-donating groups stabilize the intermediate 76 (Equation 7.77) and make departure of the proton more difficult than proton loss in many other electrophilic substitutions. [Remember, however, that k1 < k2 (see p. 386).] Second, steric interactions between the large diazonium group and the nearby substituents increase the rate... 

For any of the nucleophilic aromatic reactions covered in this chapter, regioselectivity, when more than one activated position is available, depends in most cases on the selectivity of attack by the nucleophile. However, when the conversion of the cr-adduct to product is the rate-limiting step, as in the VNS reaction, the final product distribution may differ from that expected, based on the relative electrophilic reactivity of the possible reaction sites.15 Important roles are played by deactivating steric effects and by stabilizing specific interactions such as those, for example, between an ion-paired nucleophile and a nitro activating group, which favor attack at the ortho position. 

Hydrogen exchange can occur under either acid- or base-catalyzed conditions. Both can be considered electrophilic aromatic substitutions, the latter involving attack of the electrophile upon an aromatic anion, zwitterion, or ylide. The former reaction is aided by electron supply, the latter by electron withdrawal (particularly by -/ effects) as the ratedetermining step is the initial proton loss. Steric hindrance, negligible in virtually all cases under acid-catalyzed conditions, appears to be of slightly greater importance under base-catalyzed conditions. 

The effect of the o-c-Pr group in electrophilic aromatic substitution is anomalous Thus in nitration high o, p-product ratios were obtained (2.0-4.7), whereas in halogenation the ratios are much lower. It was found in aromatic detritiation, a reaction suggested to be free of steric effects that the ratio of partial rate factors for /p//o for cyclopropyl was 9, and this was interpreted that the high fraction of o-nitration was a peculiarity of this particular reaction and not a general effect of the cyclopropyl group. ... 

We cannot, then, expect this approach to understanding chemical reactivity to explain everything. We should bear in mind its limitations, particularly when dealing with subjects like ortho/para ratios in aromatic electrophilic substitution, where steric effects are well known to be important. Likewise solvent effects (which usually make themselves felt in the entropy of activation term) are also well known to be part of the explanation of the principal of hard and soft acids and bases. Some mention of all these factors will be made again in the course of this book. Arguments based on the interaction of frontier orbitals are powerful, as we shall see, but they must not be taken so far that we forget these very important limitations. 

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