Mechanism of Alcohol Oxidation Mediated by Copper(II) and Nitroxyl Radicals

Abstract

2,2′-Bipyridine-ligated copper complexes, in combination with TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), are highly effective catalysts for aerobic alcohol oxidation. Considerable uncertainty and debate exist over the mechanism of alcohol oxidation mediated by CuII and TEMPO. Here, we report experimental and density functional theory (DFT) computational studies that distinguish among numerous previously proposed mechanistic pathways. Oxidation of various classes of radical-probe substrates shows that long-lived radicals are not formed in the reaction. DFT computational studies support this conclusion. A bimolecular pathway involving hydrogen-atom-transfer from a CuII–alkoxide to a nitroxyl radical is higher in energy than hydrogen transfer from a CuII–alkoxide to a coordinated nitroxyl species. The data presented here reconcile a collection of diverse and seemingly contradictory experimental and computational data reported previously in the literature. The resulting Oppenauer-like reaction pathway further explains experimental trends in the relative reactivity of different classes of alcohols (benzylic versus aliphatic and primary versus secondary), as well as the different reactivity observed between TEMPO and bicyclic nitroxyls, such as ABNO (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl).

Design concept for α-hydrogen-substituted nitroxides

“…These conditions have been shown to involve the nitroxides alternating between these two oxidation states, and between a copper bound and a free state 54 . Oxidation of benzyl alcohol using nitroxides 25b, 32 and 35 is complete within 1-2 h at room temperature.…”

Gas–Liquid Segmented Flow Microfluidics for Screening Copper/TEMPO‐Catalyzed Aerobic Oxidation of Primary Alcohols

“…[5] Sheldon et al found the accelerating effect of 2,2'-bipyridine (bpy) ligands on the Cu(II) catalytic system, [6] Koskinen et al optimized the type and amount of base with Cu(II), [7] and Stahl et al performed scope and limitation studies as well as kinetic and mechanistic investigations demonstrating the importance of Cu(I) salts and N-methyl-A C H T U N G T R E N N U N G imidazole (NMI) as base. [8][9][10][11] The applicability of the system has been expanded to prepare nitriles from aldehydes or alcohols using aqueous ammonia [12] or to oxidize amine [13] and amino alcohols [14] into imines and amino carbonyl compounds, respectively.…”

“…It was reported by Stahl et al that the reaction rate is limited by aerobic oxidation of Cu(I). [11] One way this issue can be addressed is to operate at a higher oxygen pressure and this was recently reported by Stahl et al in a continuous flow reactor. [15] However, even if near quantitative formation of benzaldehyde from benzyl alcohol was obtained with a residence time of 5 min with 35 bar of diluted oxygen source (9% O 2 in N 2 ) at 100 8C, these experimental conditions (diluted O 2 and elevated temperature) might not be optimum for the following reasons.…”

“…[20] Thus if aerobic oxidation is the turnover-limiting step, [11] the increase in temperature will have a limited effect on the rate of the oxidation. It should also be noticed that a small Ea has also been calculated for the Cu(II)/nitroxylmediated oxidation of the alcohol to aldehyde via the H abstraction (steps C of the catalytic cycle in Scheme 1).…”

“…Simplified catalytic cycle for the Cu-catalysed aerobic oxidation of primary alcohols (adapted from refs. [10,11] ). (about 2 and 5% absolute and relative conversion, respectively), both possibilities lead to the same dependency between conversion and residence time.…”