Catalytic Role of\nMethanol in Anodic Coupling Reactions\nInvolving Alcohol Trapping of Cation Radicals

In anodic electrosynthesis, cation radicals are often\nkey intermediates\nthat can be highly susceptible to nucleophilic attack and/or deprotonation,\nwith the selectivity of competing pathways dictating product yield.\nIn this work, we computationally investigate the role of methanol\nin alcohol trapping of enol ether cation radicals for which substantial\nmodulation of the reaction yield by the solvent environment was previously\nobserved. Reaction free energies computed for intramolecular coupling\nunequivocally demonstrate that the key intramolecular alcohol attack\non the oxidized enol ether group is catalyzed by methanol, proceeding\nthrough overall second-order kinetics. Methanol complexation with\nthe formed oxonium ion group gives rise to a “Zundel-like”,\nshared proton conformation, providing a critical driving force for\nthe intramolecular alcohol attack. Free energies computed for methanol\nsolvent attack of enol ether cation radicals demonstrate an analogous\nmechanism and overall third-order kinetics, due to similar complexation\nfrom a secondary methanol molecule to form the “Zundel-like”,\nshared proton conformation. As catalyzed by methanol, both intramolecular\nalcohol attack and methanol attack on the oxidized enol ether group\nare barrierless or low-barrier reactions, with kinetic competition\ndictated by the conformational free energy profile of the cation radical\nsubstrate and the difference in reaction rate orders.