Mimicking enzymes: Cooperation between organic functional groups and metal ions in the cleavage of phosphate diesters

A series of ligands derived from the bis-2-pyridinylmethylamine structure, which bear either additional hydroxyl or aromatic amino groups, were prepared and their Zn-II complexes were studied as catalysts for the cleavage of bis-p-nitrophenyl phosphate (BNP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) diesters. A comparative kinetic study indicated that the insertion of organic groups, capable of acting as nucleophiles or as hydrogen-bond donors, substantially increases the hydrolytic activity of the metal complex. Dissection of the effects of the individual groups revealed that the increase in reactivity can reach up to three orders of magnitude. The improved efficiency of the systems studied, combined with the benefits resulting from the low pK(a) value of the active nucleophile, result in an acceleration of the BNP cleavage at pH 7 of six orders of magnitude. The pH-dependent reactivity profiles follow a bell-shaped curve and the maximum reactivity is observed at pH 9. The mechanism of the reactions and the structure of the complexes were investigated in detail by means of kinetic analysis, NMR spectroscopy experiments, and theoretical calculations. The reactivity of the complexes that cleave HPNP closely resembles the reactivity observed for BNP, but the accelerations achieved are lower as a result of different reaction mechanisms.