Reaction of N-Acyloxy-N-alkoxyamides with Biological Thiol Groups

Mutagenic N-acyloxy-N-alkoxyamides 1 react with thiols by an SN2 process at nitrogen with displacement of carboxylate. They react with glutathione 4 in [D6]DMSO/D2O and methyl and ethyl esters of cysteine hydrochloride, 11 and 12, in [D4]methanol but the intermediate N-alkoxy-N-(alkylthio)amides undergo a rapid substitution reaction at sulfur by a second thiol molecule to give hydroxamic esters and disulfides. Arrhenius activation energies and entropies of activation obtained for a series of different N-benzyloxy-N-(4-substitutedbenzoyloxy)benzamides 13–17 were similar to those found for the SN2 reaction of the same series with N-methylaniline. Entropies of activation were strongly negative in keeping with polar separation and attendant solvation in the transition state, and in keeping with this, bimolecular reaction rate constants at 298 K correlated with Hammett σ constants with a positive ρ-value of 1.1. The structure of model N-methoxy-N-(methylthio)acetamide has been computed at the B3LYP/6–31G(d) level and exhibits properties atypical of other anomeric amides with more electronegative atoms at nitrogen. Relative to N,N-bisoxyl substitution, the combination of a sulfur and an oxygen atom at the amide nitrogen results in a relatively small reduction in amide resonance.