Functional Modeling of Tyrosinase. Mechanism of Phenolortho-Hydroxylation by Dinuclear Copper Complexes

Abstract

The copper-mediated oxygenation of methyl 4-hydroxybenzoate (1) in acetonitrile has been investigated by employing a series of dinuclear copper(I) complexes with polybenzimidazole ligands. The reaction mimics the activity of the copper enzyme tyrosinase, since the initial product of the reaction is the o-catechol, methyl 3,4-dihydroxybenzoate (2). The ligand systems investigated include α,α‘-bis{bis[2-(1-methyl-2-benzimidazolyl)ethyl]amino}-m-xylene (L-66) α,α‘-bis{bis[2-(1-methyl-2-benzimidazolyl)methyl]amino}-m-xylene (L-55), α,α‘-bis{[(1-methyl-2-benzimidazolyl)methyl][2-(1-methyl-2-benzimidazolyl)ethyl]amino}-m-xylene (L-56), and α,α‘-bis{[(2-pyridyl)methyl][2-(1-methyl-2-benzimidazolyl)ethyl]amino}-m-xylene (L-5p6). The most effective among the dicopper(I) complexes is that derived from L-66, while its mononuclear Cu(I) analogue, with the ligand N,N-bis[2-(1-methyl-2-benzimidazolyl)ethyl]amine is inactive in the monooxygenase reaction. The catechol 2 is the only product of phenol hydroxylation when the reaction is carried out at low temperature (−40 °C). As the temperature is increased, methyl 2-[4-(carbomethoxy)phenoxy]-3,4-dihydroxybenzoate (4), formally resulting from Michael addition of the starting phenol to 4-carbomethoxy-1,2-benzoquinone (3) and probably resulting from the reaction between free phenolate and some intermediate copper−catecholate species, becomes a major product of the reaction. In order to gain insight into the mechanism of the reaction, the dicopper(I)−phenolate adducts and dicopper(II)−catecholate adducts of the L-66, L-55, and L-6 complexes have been studied. In a few cases the adducts containing catecholate monoanion or catecholate dianion have been isolated and spectrally characterized. It has been shown that the final product of the monooxygenase reaction corresponds to the dicopper(II)−catecholate dianion complex. A mechanism for the biomimetic phenol ortho-hydroxylation has been proposed and its possible relevance for tyrosinase discussed.