Cross-Couplings via Electroreductive C–F, C–O, and C–S Bond Cleavage and Radical-Polar Crossover Mechanisms

Conspectus Electrochemical synthesis has emerged as a powerful platform for generating reactive intermediates under conditions that are difficult to achieve with conventional chemical reductants or oxidants. In particular, cathodic electron transfer to polarized C–X bonds can provide direct access to carbon-centered radicals, while a second electron transfer enables radical-polar crossover to carbanions that can be intercepted by suitable electrophiles. This umpolung sequence offers an attractive alternative to classical organometallic chemistry, allowing nucleophilic carbon intermediates to be generated without pyrophoric metals or strong bases. The apparent simplicity of this process, however, masks several selectivity challenges. Productive reactivity requires the substrate to be reduced and undergo mesolytic bond cleavage before the solvent, supporting electrolyte, electrophile, or product is consumed at the cathode. The resulting carbon-centered radical must thereafter accept a second electron faster than it undergoes hydrogen atom transfer, dimerization, or unproductive addition reactions. The resulting carbanion must subsequently be trapped within the same strongly reducing environment. Electrode materials, the anodic counter reaction, and concentration of the different species influence the kinetics and thermodynamics of electroreductive radical-polar crossover, requiring the matching of every component of the electrochemical setup rather than consideration of the substrate reduction potential alone. This Account describes our recent advances in addressing these challenges for electroreductive activation of C–F, C–O, and C–S bonds. In the context of C–F cleavage, trifluoromethyl arenes were converted into hydroxymethylated difluoromethyl arenes through selective monodefluorination followed by trapping with N,N-dimethylformamide. Mechanistic and electroanalytical studies revealed the privileged role of DMF and rationalized the high selectivity against over-reduction. In the context of C–O bond cleavage, deoxygenative strategies from alcohols and alcohol derivatives were explored. Under operationally simple galvanostatic conditions, benzylic and propargylic alcohols underwent hydrodeoxygenation and, in some cases, C–C bond formation with CO2 without prior derivatization. The reaction design was extended to deoxygenative C–Si bond formation in which hydrosilanes serve a dual function as activating agents and electrophilic reaction partners. Finally, aryl alkyl thioethers were developed as tunable alkyl radical precursors with the S-aryl group acting as an electroauxiliary that modulates the reduction potential and selectivity of bond cleavage. Depending on the reaction conditions and trapping partner, the resulting radical or carbanion intermediates provide access to C–H, C–D, C–C, and C–B bonds. For several of the protocols, borohydride oxidation was employed as an anodic counter reaction with a similar performance as the use of sacrificial metal anodes. Together, the highlighted studies show how electroreductive sequences with radical-polar crossover events can convert strong C–F, C–O, and C–S bonds into programmable synthetic handles. Future advances in mediators, electrocatalysts, and electrode design should further expand scope, improve chemoselectivity, and enable the construction of molecular complexity from abundant functional groups.