Scheme 1
The mechanism of nucleophilic attack by hydroxylamine has been discussed extensively over the years. Jencks identified O-acylhydroxylamine derivatives as the major initial products in reactions of hydroxylamine with a number of acylating agents, and was the first to attribute the high reactivity to the zwitterionic form of hydroxylamine.3 However, alkylation of hydroxylamine occurs on nitrogen rather than on oxygen, and the high acylation reactivity of oxygen could involve intramolecular general acid-base catalysis: which would not be feasible in the concerted linear displacements involved in alkylation.1
We have recently shown, using computation and crystallography, that the zwitterionic tautomer 1z is the preferred form of hydroxylamine in the crystal of its half-hydrochloride (NH2OH)2.HCl. Although 1z (Scheme 1) is not an •-effect nucleophile as usually defined, it is well suited to substitution reactions involving addition-intermediates, because proton transfer from the H3N+ group to a developing negatively charged center, e.g., the oxygen of a C=O or P=O group in the substrate, becomes thermodynamically favorable as reaction proceeds (Scheme 1).4
Proton transfer catalysis is important in many substitution reactions, contributing significant rate enhancements. A classical example is the hydrolysis of the aspirin (acetyl salicylic acid) monoanion, for which water attack is facilitated by intramolecular general base catalysis by the carboxylate group (Scheme 2).5
Scheme 2
We report a study of the reactions of hydroxylamine with substituted aspirins, designed to identify the reactive nucleophile(s) involved – and possible further interesting mechanistic variations. We present new evidence consistent with the dominant nucleophilic contribution of
