Mechanism of aromatic hydroxylation in a copper monooxygenase model system. 1,2-methyl migrations and the NIH shift in copper chemistry

Article abstract of DOI:10.1021/ja00033a024

The NIH shift mechanism appears to be operative in a copper monooxygenase model system involving dicopper ion complex mediated O₂ hydroxylation of an arene substrate. Previous studies have shown that when a dicopper(I) complex containing two tridentate PY2 units (PY2 = bis[2-(2-pyridyl)ethyl]amine) which are linked by a m-xylyl group, i.e., [Cu₂(XYL-H)]²⁺ (1), is reacted with dioxygen, a Cu₂O₂ intermediate forms and hydroxylation in the intervening 2-xylyl position occurs. Here, corresponding reactions of 2-methyl substituted analogues [Cu₂(Me₂XYL-CH₃)]²⁺ (4) and [Cu₂(XYL-CH₃)]²⁺ (5) are described in detail. Oxygenation of these causes xylyl hydroxylation reactions producing new phenol products, with concomitant 1,2-migration of the methyl group, loss of one PY2 ligand arm, and formaldehyde formation. Manometric O₂ uptake experiments and an ¹⁸O₂ labeling study confirm that the stoichiometry of these reactions are consistent with that observed for monooxygenases. A reaction carried out using a dinucleating ligand which has been deuterated in benzylic positions confirms that the CH₂O product is derived from this carbon atom, a result also consistent with migration of the 2-methyl group. A small yield of methylbis[2-(2-pyridyl)ethyl]amine (MePY2) is consistently obtained, and experiments suggest this may be derived from the reduction of an intermediate iminium salt [CH₂=N[CH₂CH₂PY]₂]⁺ (PY = 2-pyridyl). The hydroxylation induced 1,2-methyl migrations observed here are reminiscent of the NIH shift reactions previously observed only in iron hydroxylases and suggest that the copper ion mediated reactions proceed by the electrophilic attack of a Cu₂O₂ intermediate upon the proximate aromatic substrate. A detailed mechanism is proposed and discussed in terms of the known O₂ reactivity and structure of these dinuclear copper complexes. The biological relevance and significance of this monooxygenase model system is also discussed.