Designing Electrocatalytic Mediators and Understanding Site-selectivity for C(sp3)-H Activation Using First-Principles Calculations

Selective C-H bond activation is one of the most critical molecular transformations in synthesizing chemicals, pharmaceuticals, and natural product intermediates with broad applications. Recent efforts have focused on developing electrocatalytic mediators that rapidly and selectively activate specific C-H bonds. These mediated activations offer multiple benefits over direct electrochemical oxidation as they can occur at lower overpotentials, leading to higher faradaic efficiency and selectivity with reduced solvent oxidation. Our previous work described the development of N-alkyl ammonium ylides as a new class of electro-oxidative mediators. Despite its importance, the underlying principles of designing efficient mediators and understanding their site-selectivity are yet to be fully elucidated. The work discussed herein scrutinized mediator design using density functional theory calculations to highlight the critical features of mediators that govern C(sp3)-H activation. The design of newer mediators is guided by scaling relationships between the thermodynamic descriptors associated with the elementary steps involved in C(sp3)-H activation. We subsequently examine the results from detailed transition state calculations to elucidate the site-selectivity for C(sp3)-H activation for various substrates with quinuclidine and ylide mediators. The results show the critical interplay of thermodynamic, steric, and electronic features of the substrate and mediator that govern the corresponding site-selectivity. Finally, we present unifying trends across multiple substrates and mediators to understand the site-selectivity for mediated electrocatalytic C(sp3)-H activations and push our efforts toward predicting regio-selectivity in the future.