NUCLEAR VERSUS SIDE-CHAIN BROMINATION OF METHYL-SUBSTITUTED ANISOLES BY N-BROMOSUCCINIMIDE

The reactions of methyl-substituted anisoles with N-bromosuccinimide in CCl4 are reported. In the absence of a catalyst and under irradiation, some of these substrates undergo nuclear bromination in competition with the well-known side-chain bromination. With 2-methylanisole and with 2,6-dimethylanisole, nuclear bromination is not observed, whereas with 3,5-dimethylanisole, nuclear bromination at the 4-position is the dominating reaction. Investigation of the reactivity of several other methyl-substituted anisoles revealed the following general trend: methyl-substituted anisoles are attacked at the position para to the methoxy group rather than at the side chain when (at least) two methyl groups are present at positions 3 and 5. When positions 2 and 6 are both occupied, nuclear bromination is retarded; in 2,6-dimethylanisole and in 2,3,6-trimethylanisole, only side-chain bromination is observed. In contrast, in 2,3,5,6-tetramethylanisole, the 4-position is sufficiently reactive to be brominated, because the decrease in reactivity by the presence of two methyl groups at positions 2 and 6 is overruled by the two additional methyl groups at positions 3 and 5; as a result, both nuclear and side-chain bromination occur. The observed chemospecificity can be rationalized by a difference in mechanism: the side-chain bromination is a radical reaction, while the nuclear bromination is an electrophilic aromatic substitution reaction, which is so far contrary to expectation, as irradiation had been expected to favor radical processes.