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 1a { N, N -bis[2-(2-pyridyl)ethyl]-2-phenylethylamine} by O 2 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 )(ClO 4 ) 2 ] was treated with an equimolar amount of benzoin and triethylamine in CH 2 Cl 2 under O 2 atmosphere, efficient hydroxylation occurred selectively at the benzylic position of the ligand to provide oxygenated product 2a { N, N -bis[2-(2-pyridyl)ethyl]-2-phenyl-2-hydroxyethylamine} quantitatively. An isotope labeling experiment using 18 O 2 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 ( 1a )] + and O 2 at low temperature show that a μ-η 2:η 2 -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-η 2:η 2 -peroxodicopper(II) intermediate. When ligand 1a is replaced by 1,1,2,2-tetradeuterated phenethylamine derivative 1a- d 4, 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 [(PyCH 2 CH 2 ) 2 NCH 2 CH 2 Ar, 1a Ar = C 6 H 5; 1b Ar = p -CH 3 C 6 H 4, 1c Ar = p -ClC 6 H 4, and 1d Ar = p -NO 2 C 6 H 4 )], but it varies depending on the solvent (THF > acetone > CH 3 OH > CH 2 Cl 2 ). The p -substituent, the solvent, and the kinetic deuterium isotope effects suggest that O−O bond homolysis of the μ-η 2:η 2 -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.