Morris, Jeffrey J. and Page, Michael I. (1980) Intramolecular nucleophilic and general acid catalysis in the hydrolysis of an amide. Some comments on the mechanism of catalysis by serine proteases. Journal of the Chemical Society, Perkin Transactions 2 (7). pp. 1131-1136. ISSN 1472-779X

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

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