Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst

Abstract

A homogeneous Cu-based catalyst system consisting of [Cu(MeCN)4]PF6, N,N′-di-tert-butylethylenediamine (DBED), and p-(N,N-dimethylamino)pyridine (DMAP) mediates efficient aerobic oxidation of alcohols. Mechanistic study of this reaction shows that the catalyst undergoes an in situ oxidative self-processing step, resulting in conversion of DBED into a nitroxyl that serves as an efficient cocatalyst for aerobic alcohol oxidation. Insights into this behavior are gained from kinetic studies, which reveal an induction period at the beginning of the reaction that correlates with the oxidative self-processing step, EPR spectroscopic analysis of the catalytic reaction mixture, which shows the buildup of the organic nitroxyl species during steady state turnover, and independent synthesis of oxygenated DBED derivatives, which are shown to serve as effective cocatalysts and eliminate the induction period in the reaction. The overall mechanism bears considerable resemblance to enzymatic reactivity. Most notable is the “oxygenase”-type self-processing step that mirrors generation of catalytic cofactors in enzymes via post-translational modification of amino acid side chains. This higher-order function within a synthetic catalyst system presents new opportunities for the discovery and development of biomimetic catalysts.

Biomimetic Cu/Nitroxyl Catalyst Systems for Selective Alcohol Oxidation

“…Interestingly, the Cu/DBED catalyst system is selective for the oxidation of activated secondary over primary alcohols, which is in contrast with the Cu/TEMPO• catalyst system [2,96]. Initially they believed that their catalyst system acts as a type II Cu-based tyrosinase mimic, instead of GOase [96], but the groups of Stahl and Arndsten and co-workers used mechanistic studies to confirm the presence of a nitroxyl radical during the oxidation reaction [96,97]. They proposed that Cu/DBED-catalysed reactions involve both oxygenase-and oxidase-type reactivity.…”

A merged copper(I/II) cluster isolated from Glaser coupling

“…Copper–oxygen species are well-known in the active center of many enzymes 1–5 and organic synthetic transformations 6,7 to perform diversified oxidation reactions toward phenol 8 , alcohol 9 , amine 10 , and even hydrocarbons 11 . In efforts to obtain fundamental chemical insights into their structures and reactivity, a number of important copper–oxygen complexes have been identified 12–18 .…”

Copper-Promoted Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems to Organometallic Transformations

“…A mechanistic study suggested that the secondary amine DBED was oxidized to the corresponding N-oxide product to generate reaction intermediates similar to the ones formed in the Cu/TEMPO/bpy system, including the key Cu II /N-oxide/alkoxy adduct (species D in Figure 9). 107 These findings might trigger the development of oxidation protocols based on the in situ generation of these oxidants (i.e., N-oxides). Given the ubiquity of amines in catalysis, the implication of N-oxides in oxidative functionalizations might not be unusual.…”