Intramolecular nucleophilic attack on carboxylate by ureide anion. General acid–base catalysis of the alkaline cyclisation of 2,2,3,5-tetramethylhydantoic acid

Abstract

The cyclisation of the title compound to the corresponding hydantoin is a model for the carboxylation of biotin by hydrogen carbonate. The reaction is rapid over the whole pH range, and is catalysed by both general acids and general bases. Above pH 9.2 the reaction is first order in hydroxide, which is shown to act as a general bases. The preferred mechanism is specific base–general acid catalysis, involving nucleophilic attack by the ureide anion on the ionised carboxy group, assisted by proton transfer from the general acid. This defines also the mechanism of the reverse reaction, and clarifies for the first time the role of the second hydroxide ion in the [HO^–]² term for the hydrolysis of amides with good leaving groups.