Continuous-Flow Aerobic Oxidation of Primary Alcohols with a Copper(I)/TEMPO Catalyst

Abstract

A scalable, continuous-flow process has been developed to implement a homogeneous Cu I /TEMPO catalyst system for aerobic oxidation of primary alcohols to aldehydes. This catalyst system is compatible with a wide range of alcohols bearing diverse functional groups. A dilute oxygen source (9% O 2 in N 2 ) is used to avoid flammable oxygen/organic mixtures. Residence times in the heated reaction zone can be as low as 5 min with activated (e.g., benzylic) alcohols. The method has been demonstrated with nine different alcohols, including one up to 100 g scale. This flow-based catalytic method exhibits significant advantages for aerobic oxidation of alcohols, including substantially shorter residence times and broader substrate scope relative to a Pd-catalyzed method that we reported recently.

PTFE-Membrane Flow Reactor for Aerobic Oxidation Reactions and Its Application to Alcohol Oxidation

“…5 The reactor was originally demonstrated with homogeneous Pd-catalysts for aerobic alcohol oxidation, and it was later applied to homogeneous Cu/TEMPO-catalyzed aerobic alcohol oxidations. 6 Subsequently, a number of other flow-based methods and (micro)-reactors that enable safe use of O 2 in liquid-phase aerobic oxidation reactions have been reported by other groups. 7,8 Membrane reactors present an intriguing alternative to slugflow, bubble-flow and related continuous processes in which the gas and liquid flow together through the reactor.…”

Aerobic Oxidations in Continuous Flow

“…This limitation can be elegantly circumvented by the well-established homogeneous copper-catalyzed aerobic oxidation protocol developed by Stahl using a catalytic mixture of Cu(OTf) 2 , 2,2 0 -bipyridine, TEMPO, and NMI [49]. Similar reactor concepts as for the Pd-catalyzed protocol were used in order to test the feasibility of the copperbased system for continuous purposes [109,110]. Importantly, a stainless steel syringe pump and storage unit for the catalyst mixture caused severe problems since a significant drop in catalytic activity was observed [109].…”

“…Similar reactor concepts as for the Pd-catalyzed protocol were used in order to test the feasibility of the copperbased system for continuous purposes [109,110]. Importantly, a stainless steel syringe pump and storage unit for the catalyst mixture caused severe problems since a significant drop in catalytic activity was observed [109]. This was attributed to a reaction of the catalyst material with stainless steel.…”

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

“…[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.…”

“…One possibility is to operate outside the flammability limits of the solvent/reactants [15] or to use the safety advantages of flow chemistry already demonstrated for highly reactive chemical processes. [16,17] While the composition and temperature of the gas phase in microreactors are generally far above the flammability limits, the small dimensions of the channels prevent explosion as demonstrated for the H 2 /O 2 reaction.…”