Kinetics and mechanism of the cyclization of substituted N-phenyl-2-methyl-2(2-aminophenyl)propanamides and analogues

Abstract

The cyclization of six N-aryl-2-(2-aminophenyl)alkylamides has been studied at various pH values. Compounds 1a, 2a and 3a had a similar leaving group (4-methoxyaniline) and varying degrees of steric bulk adjacent to the amide, while compounds 1a–1d had varying substituents on the leaving amine. The cyclization of all the compounds was found to be subject to general catalysis by acidic buffer components, with the buffer-independent pH profiles obeying the equation k₀=k_H3O⁺[H₃O⁺]+k_H2O. Brønsted analysis of the rate coefficients for buffer catalysis gave α values of ca. 0.4 for all compounds. The relative observed pseudo-first-order rate coefficients at pH 6.6 for compounds 3a, 2a and 1a were 1, 9 and 800, respectively, indicating the importance of ‘stereopopulation control’(Milstein and Cohen, J. Am. Chem. Soc., 1972, 94, 9158) on the rate of cyclization. However, cyclization rates were found to be independent of the electronic properties of the leaving amine. The mechanism of cyclization was considered to be rate-determining, concerted attack by the neutral amine, followed by proton transfer from a general acid to the amide oxygen.