HYDROLYTIC CLEAVAGE OF PEPTIDES BY PALLADIUM(II) COMPLEXES IS ENHANCED AS COORDINATION OF PEPTIDE NITROGEN TO PALLADIUM(II) IS SUPPRESSED

We report on the kinetics and mechanism of regioselective hydrolysis of amide bonds in various dipeptides and tripeptides after these substrates react with [Pd(H2O)3(OH)]+ and cis-[Pd(en)(H2O)2]2+. Peptides devoid of coordinating side chains form mononuclear palladium(II) complexes and hydrolyze slowly, over weeks. Peptides containing thio ether side chains (of methionine and S-methylcysteine) as anchors form binuclear palladium(II) complexes and hydrolyze rapidly, with half-lives that are measured in minutes. The ethylenediamine ligand stabilizes the initial complex but is released prior to hydrolysis, so that the two mononuclear complexes form similar binuclear promoter complexes with anchoring peptides. Hydrolysis requires acidic solutions, but this reaction is not catalyzed by acid; the palladium(II) promoter is required. Binding of the sulfur-anchored palladium(II) atom to the deprotonated nitrogen atom in the amide bond inhibits hydrolysis. Methylation of the amide nitrogen atom suppresses binding of palladium(II) to it and enhances the hydrolysis rate constant as much as 300-fold.