Metal-catalyzed hydroxylaminolysis of unactivated amide and peptide bonds

Abstract

Kinetics of the hydroxylaminolysis of acetamide, glycinamide, glycylglycine and triglycine have been studied in the range of temperatures 37–60 °C as a function of pH and hydroxylamine concentration. Rate constants for specific acid, general-acid and general-base catalyzed pathways have been determined for all substrates (for glycine derivatives rate constants for different protonation forms were obtained). Testing different metal ions as possible reaction catalysts revealed a significant catalytic effect of Zn(II) on the hydroxylaminolysis of glycine substrates, but not acetamide. On the basis of the kinetic results, a mechanism of Zn(II) catalysis is proposed, which involves the coordination of the metal ion to the α-amino group of the substrate and the base-assisted nucleophilic attack of hydroxylamine on the bound substrate. The product analysis by proton NMR shows that the primary reaction product in the catalytic reaction is glycine hydroxamic acid, which undergoes further Zn(II)-catalyzed hydrolysis to glycine. Thus the final result of the Zn(II)-catalyzed treatment of peptides by hydroxylamine is hydrolytic cleavage.