Nucleophilic substitution reactions of α-chloroacetanilides with benzylamines in dimethyl sulfoxide

Abstract

Kinetic studies of the reactions of α-chloroacetanilides (YC₆H₄NRC(O)CH₂Cl; R = H (5) and CH₃ (6)) with benzylamines (NH₂CH₂C₆H₄X) were carried out in dimethyl sulfoxide at 55.0 °C. The Brønsted β_X values were in the range from 0.6 to 0.9 and cross-interaction constants ρ_XY were positive: ρ_XY = +0.21 and +0.18 for 5 and 6, respectively. The rates were faster with 6 than with 5 and inverse secondary kinetic isotope effects involving deuterated benzylamine (ND₂CH₂C₆H₄X) nucleophiles, k_H/k_D < 1.0, were obtained. Based on these and other results, a stepwise mechanism with rate-limiting expulsion of the chloride leaving group from a zwitterionic tetrahedral intermediate, T^±, is proposed. In this mechanism, a prior carbonyl addition to T^± is followed by a bridged type transition state to expel the chloride. An enolate-like transition state in which the developing negative charge on C_α delocalizes toward the carbonyl group (n_C→π*_CO interaction) is not feasible for the present series of reactions due to a stronger charge transfer involving the lone pair on the anilino nitrogen (n_AN→π*_CO interaction).