Steric hindrance aromatic substitution

Certain ortho substituted derivatives of aromatic amines are difficult to acetylate under the above conditions owing to steric hindrance. The process is facilitated by the addition of a few drops of concentrated sulphuric acid (compare Section IV,47), which acts as a catalyst, and the use of a large excess of acetic anhydride. 

The usual directive influences are not operative in this and similar reactions for ortho - para substitution occurs (this may be modified by steric hindrance) irrespective of the nature of R in the aromatic liquid CsHjR, e.g. phenyldlazo hydroxide and nitrobenzene yield 4-nitrodiphenyl this supports the assumption that neutral free radicals are formed. 

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). 

Diarylamines couple with considerably more difficulty than alkylarylamines. In contrast to primary aromatic amines and alkylarylamines, dialkylarylamines are substituted by diazonium ions only in the 4-, not in the 2-position. This is due to the considerable sensitivity of azo coupling reactions to steric hindrance. 

It is interesting to note that the oxidation of sulphoxides by peracids is faster in alkaline than in acidic solution. This is in contrast to the oxidation of sulphides and amines with the same reagents " . The oxidation rate of ortho-substituted aryl alkyl sulphoxides with aromatic peracids is less than the corresponding meta- and para-substituted species due to steric hindrance of the incoming peracid anion nucleophiles . Steric bulk in the alkyl group also has some effect . Such hindrance is not nearly so important in the oxidation reaction carried out under acidic conditions . 

The results obtained with different amines cannot be explained merely on the effects of amine basicity. Thus, to obtain complete hydrogenation of Q to DHQ, the basicity has to be tailored by other factors such as the steric hindrance of the amine and its electronic interaction with the catalyst active sites this seems to be favored by the presence of an electron-rich aromatic ring. Of note, the positive effect of substituted aromatic amines, with a 49% DHQ yield being obtained for ethylanilines, is independent of the substituent position of the alkyl group. 

Nieuwstad, Klapwijk, and van Bekkum (105) have added to the knowledge of aromatic hydrogenation by their study of the influence of alkyl substituents in the 1 and 2 positions of naphthalene on the rate. Tetrahydro-naphthalenes were the products of hydrogenation over palladium at 80°C. The selectivity of the reaction was also followed and expressed as the ratio of the rate constants for the saturation of the unsubstituted and substituted rings, respectively. Steric effects play an important role, and, beside steric hindrance by the bulky substituents, steric acceleration also has been observed, the latter being caused by a release of the strain between the 1-alkyl group and hydrogen in position 8. 

Relatively few bisindole derivatives having unnatural aromatic substituents have been prepared. The most reactive aromatic center to electrophilic substitution is certainly at C-12, where steric hindrance is minimized and electron density favors stabilization of positive charge. Treatment of vinblastine (1) with less than 1.0 equiv of bromine in dichlo-romethane results in selective bromination at C-12 to give 12 -bromovin-blastine (5) (45,46). If excess bromine is employed, then bromination in the dihydroindole ring is also observed, and mixtures of (5) and 12, 17-dibromovinblastine (6) are obtained (46). 

On the other hand, hydrogenation with Raney nickel causes reduction mainly in the substituted aromatic ring [Eq. (11.16)]. Differences in product composition brought about by the different metals are explained in terms of steric hindrance of the substituted ring (Pt, Pd) versus the anchor effect of the methyl substituent (Ni).106... 

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