Intramolecular nucleophilic and general acid catalysis in the hydrolysis of an amide. Some comments on the mechanism of catalysis by serine proteases

Abstract

The lactonisation of N-(2-aminoethyl)-6-endo-hydroxybicyclo[2.2.1]heptane-2-endo-carboxamide shows a sigmoid pH–rate profile which is interpreted, kinetically, in terms of the hydroxide-ion-catalysed hydrolysis of the amide with the terminal amino-group unprotonated and protonated. Reaction of the latter species occurs with a rate enhancement of ca. 10⁹ compared with an amide lacking the hydroxy-and protonated amino-groups. This is attributed to intramolecular nucleophilic and general acid-catalysis. The relative effectiveness of these two processes are compared and it is concluded that intramolecular general acid-catalysis makes a relatively minor contribution to the rate enhancement even though the breakdown of the tetrahedral intermediate is thought to be a concerted process. Some comments are made about the mechanisms proposed for the chymotrypsin-catalysed hydrolysis of amides and concerted breakdown of the tetrahedral intermediate is suggested as a possible mechanism.