Amine Oxidative N-Dealkylation via Cupric Hydroperoxide Cu-OOH Homolytic Cleavage Followed by Site-Specific Fenton Chemistry

Abstract

Copper(II)-hydroperoxide species are significant intermediates in processes such as fuel cells and (bio)chemical oxidations, all involving stepwise reduction of molecular oxygen. We previously reported a CuII-OOH species that performs oxidative N-dealkylation on a dibenzylamino group that is appended to the 6-position of a pyridyl donor of a tripodal tetradentate ligand. To obtain insights into the mechanism of this process, reaction kinetics and products were determined employing ligand substrates with various para- substituent dibenzyl pairs (-H,-H; -H,-Cl; -H,-OMe and -Cl,-OMe), or with partially or fully deuterated dibenzyl N-(CH2Ph)2 moieties. A series of ligand-copper(II) bis-perchlorate complexes were synthesized, characterized, and the X-ray structures of the -H, -OMe analog was were determined. The corresponding metastable CuII-OOH species were generated by addition of H2O2/base in acetone at –90 °C. These convert (t1/2 ~ 53 s) to oxidatively N-dealkylated products, producing para-substituted benzaldehydes. Based on the experimental observations and supporting DFT calculations, a reaction mechanism involving dibenzylamine H-atom abstraction or electron-transfer oxidation by the CuII-OOH entity could be ruled out. It is concluded that the chemistry proceeds by rate limiting Cu–O homolytic cleavage of the CuII–(OOH) species, followed by site-specific copper Fenton chemistry. As a process of broad interest in copper as well as iron oxidative (bio)chemistries, a detailed computational analysis was performed, indicating that a CuIOOH species undergoes O–O homolytic cleavage to yield a hydroxyl radical and CuIIOH rather than heterolytic cleavage to yield water and a CuII-O•−.

Mechanism of O2activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases

“…4A, Left) is initial protonation of the proximal O to the hydrogen peroxide complex Cu II M -OðHÞOH (reaction b; ΔG = +8.7 kcal/mol) followed by ET from Cu H (reaction c; ΔG = -9.5 kcal/mol). This would generate H 2 O 2 in the presence of Cu I , which is known experimentally to lead to Fenton chemistry via homolytic O-O cleavage and release of • OH (12). Indeed, O-O cleavage in Cu I M -OðHÞOH to produce • OH would be thermodynamically accessible in PHM with calculated ΔG = -2.2 kcal/mol ( Fig.…”

Copper–Oxygen Complexes Revisited: Structures, Spectroscopy, and Reactivity

“…N-dealkylation reactions of complexes ( 27 ) of L41g (R = H) and L41i – k (R = aryl) (refs 182, 186, and 189). …”

Oxygen Activation by Cu LPMOs in Recalcitrant Carbohydrate Polysaccharide Conversion to Monomer Sugars

“…Model complex chemistry was reported using 6-[bis(phenylmethyl)amino]- N , N -bis(2-pyridinylmethyl)-2-pyridinemethanamine derivatives as ligands to Cu(I). 273 Reaction of the Cu(I) complex with H 2 O 2 formed a Cu(I)–OOH complex that can be protonated at either the proximal nonprotonated or the distal protonated O of the hydroperoxy moiety (Figure 33A). DFT calculations showed that distal protonation of the Cu(I)–OOH to yield a Cu(II)–oxyl species is thermodynamically more favorable than protonation at the proximal oxygen.…”