Reactions of carbonyl compounds in basic solutions. Part 15. The alkaline hydrolysis of N-methyl, N-phenyl and bicyclo lactams, penicillins and N-alkyl-N-methylacetamides

Abstract

The rate coefficients for the alkaline hydrolysis of a series of N-methyl, N-phenyl and bicyclo lactams, penicillins and N-alkyl-N-methylacetamides in water or in aqueous dimethyl sulphoxide have been measured at several temperatures. The reactions were first order in both substrates and base. The reactivities are related to the structures of the substrates, especially N-substitution, ring size and fused ring effects. The reactivities, as well as the activation parameters, kinetic solvent and solvent isotope effects, are used to suggest the detailed mechanisms. All the β-lactams appear to react with rate-determining addition of hydroxide anion; while the N-alkyl γ- and δ-lactams and N-alkyl-N-methylacetamides have rate-determining ring fission of the tetrahedral adduct, assisted by water-catalysis. The reactivity of penicillin in alkaline hydrolysis has been analysed by the studies of model compounds. These show that the increased reactivity of the penicillin β-lactam ring arises from the direct action of the fused ring structure and the acylamino side-chain.