Effect of N-methylation of 2-carbamoylphenyl mesitoate upon the ability of the amide group to promote cleavage of the ester linkage and upon the susceptibility to hydrolysis of the imide intermediate

Abstract

Under alkaline conditions, an amide group located as in 2-carbamoylphenyl mesitoate provides a highly effective means of overcoming the steric resistance to addition at the ester carbonyl group via intramolecular nucleophilic participation of the amide group acting through the amido-nitrogen. The corresponding intermediate imide is, however, much less reactive than the ester itself and its breakdown often represents the rate-determining step in the overall solvolysis. Introduction of N-methyl into the amide group results in a slightly reduced rate of rearrangement of ester to imide but considerably increased rate of imide solvolysis and hence a much greater overall rate for the ester solvolysis. The great difference in reactivity of the two imides is shown to support a mechanism for hydrolysis of the imides involving a general acid-catalysed attack of hydroxide ion in preference to the kinetically equivalent general base-catalysed attack of water. This result serves to underline the potential importance of undissociated hydroxy-groups (e.g., of serine and tyrosine) in the neighbourhood of the active sites of enzymes such as the esterases and peptidases.