Mechanistic studies of aliphatic ligand hydroxylation of a copper complex by dioxygen: A model reaction for copper monooxygenases

Mechanistic studies on the aliphatic ligand hydroxylation in a copper complex of tridentate ligand la {N,N-bis[2-(2-pyridyl)ethyl]-2- phenylethylamine} by O₂ have been performed in order to shed light on the structure and reactivity of the active oxygen species of our functional model for copper monooxygenases (Itoh, S.; et al. J. Am. Chem. Soc. 1995, 117, 4714). When the copper complex [Cu(II)(1a)(ClO₄)₂] was treated with an equimolar amount of benzoin and triethylamine in CH₂Cl₂ under O₂ atmosphere, efficient hydroxylation occurred selectively at the benzylic position of the ligand to provide oxygenated product 2a {N,N-bis[2- (2pyridyl)ethyl]-2-phenyl-2-hydroxyethylamine} quantitatively. An isotope labeling experiment using ¹⁸O₂ confirms that the oxygen atom of the OH group in 2a originates from molecular oxygen. Spectroscopic analyses using UV-vis, resonance Raman, and ESR on the reaction of [Cu(I)(la)]⁺ and O₂ at low temperature show that a μ-η²:η²-peroxodicopper(II) complex is an initially formed intermediate. Kinetic analysis on the peroxo complex formation indicates that the reaction of the Cu(I) complex and the monomeric superoxocopper(II) species is rate-determining for the formation of the μ- η²:η²-peroxodicopper(II) intermediate. When ligand 1a is replaced by 1,1,2,2-tetradeuterated phenethylamine derivative 1a-d₄, a relatively small kinetic deuterium isotope effect (k(H)/k(D) = 1.8 at -40 °C) is observed for the ligand hydroxylation step. The rate of the hydroxylation step is rather insensitive to the p-substituent of the ligand [(PyCH₂CH₂)₂NCH₂CH₂Ar, 1a Ar = C₆H₅; 1b Ar = p-CH₃C₆H₄, 1c Ar = p-ClC₆H₄, and 1d Ar = p- NO₂C₆H₄)], but it varies depending on the solvent (THF > acetone > CH₃OH > CH₂Cl₂). The p-substituent, the solvent, and the kinetic deuterium isotope effects suggest that O-O bond homolysis of the μ-η²:η²- peroxodicopper(II) intermediate is involved as a rate-determining step in the aliphatic ligand hydroxylation process. Based on the results of the kinetics and the crossover experiments, we propose a mechanism involving intramolecular C-H bond activation in a bis-μ-oxodicopper(III) type intermediate for the ligand hydroxylation reaction.