Kinetic and mechanistic investigation of the selective acidolysis of the C ‐terminal amide bond of N ‐acyl‐ N ,α,α‐trialkyl glycine amides

Accurate rate constants were calculated from HPLC kinetic measurements of the selective acidolysis of the C ‐terminal amide bond of eight N ‐acyl‐ N ‐(4‐methoxybenzyl)‐α,α‐trialkyl glycine amides in TFA at 25.00 °C. The results were in all cases consistent with a first order behaviour with respect to the substrate and, apparently, also to the acid, and a clear relationship between reactivity and structure could be observed. The data collected also allowed experimental evidence to be obtained for the first time in support of the previously postulated formation of an intermediate oxazolonium salt. In the case of the more crowded species this intermediate compound undergoes slow hydrolytic ring opening, which takes place in competition with cleavage of the N ‐alkyl group to give another oxazolonium derivative that hydrolysed still more slowly. The stability of the intermediate cyclic compounds may result either from conjugation of the phenyl group with the oxazolonium ring in the case of N ‐benzoyl derivatives, or from conformational assistance imparted by the bulky amino acid side chains of the α,α‐dialkyl glycine species, or both. The loss of the N ‐alkyl group also seems to be assisted by the bulkiness of the amino acid side chains, which thus tends to decrease the selectivity of cleavage. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.