Homolytic Activation of Alcohol O–H Bonds Enabled by Proton-Coupled Electron Transfer

Abstract

The homolytic cleavage of alcohol O–H bonds to generate alkoxy radicals has been a long-standing challenge that lacked a satisfactory solution in the form of a mild, catalytic system that acts directly on unfunctionalized alcohols. We proposed the use of a proton-coupled electron transfer (PCET) event to achieve this transformation. Through the joint action of a photo-oxidant and a Brønsted base, the homolysis of these strong O–H bonds was accomplished with excellent efficiency and broad compatibility with various functional groups. Two complementary strategies were chosen to enable the formation of alkoxy radicals and the overall isomerization of cycloalkanol to open-chain carbonyl products. The first relied on the oxidation of tertiary arylalkanol substrates to facilitate a rapid, efficient, pseudo-unimolecular multisite PCET, while having a scope limitation due to its mechanism. The second went through the intermediacy of a hydrogen-bonded complex between the substrate and the base in order to promote bimolecular multisite PCET on a broad substrate scope including aliphatic alcohols. The redox-neutral isomerization transformations of certain cycloalkanols to open-chain products were found to be endergonic, an unusual feature for systems without stoichiometric reagents that we explained through a kinetic partitioning in the mechanism. Whereas we first designed these reactions to be terminated with hydrogen atom transfer, we additionally demonstrated that halogen donors, Michael acceptors, and hydrogen-evolution cocatalyst could also be utilized to generate synthetically useful products with distal functionalization. Lastly, we applied our system to a new class of substrates, vicinal 1,2-diols, to illustrate the potential of a redox-neutral cleavage of the diol C–C bond to obtain products orthogonal to typical oxidative protocols.