Ambident Heterocyclic Reactivity: Alkylation of 4-Substituted and 2,4-Disubstituted Benzimidazoles

Abstract

The N¹/N³-alkylation patterns of 4-amino-, 4-methyl- and 4-nitro-benzimidazole anions, and their 2-methyl analogues, with a standard set of primary alkyl halides (in dimethylformamide, 30°) have been determined and compared. The observed regioselectivities are dominated by proximal effects-electrostatic field, non-bonded steric and in some cases specific association (hydrogen bonding)-the interplay of which is critically dependent on the (variable) geometries of the S_N2 transition states involved, in particular on the N---C distance of the developing N-alkyl bonds. The presence of a symmetrically placed 2-methyl group produces an enhanced N1/N3 site selectivity, very sensitive to the loose-tight nature of the transition state. Halide leaving group effects on butylation regioselectivities of 2-unsubstituted, 2-ethoxy-, 2-methyl- and 2-chloro-4-methylbenzimidazole anions, whilst small, are consistent with a Bell-Evans-Polanyi analysis of S_N2 transition state variations, with the earlier transition states of CH₃(CH₂)₃I leading to reduced regioselectivities.