Off-diagonal thermodynamics and its connection with other factors as a route to predictable selectivity in C-H bond cleavage

Despite the boom in the development of syntheses based on the cleavage of aliphatic C-H bonds, there is a lack of quantitatively predictive and easily applicable theory to guide chemists in designing new efficient synthetic routes. Regardless of advances in theory, most are devoted to rationalizing experiments and/or exploring the mechanistic richness of coupled proton- and electron-transfer reactions, including C-H bond cleavage. In the project, we will develop a theory together with a methodology enabling high-fidelity predictions of H-atom abstraction selectivity based on recently discovered (experimentally and computationally achievable) offdiagonal thermodynamic factors – frustration and asynchronicity. Toward this goal, it is crucial to elucidate (i) the physical origin of their variable predominance in different reaction sets, (ii) their variable coupling with other (non-thermodynamic) factors affecting reactivity, and (iii) chemical strategies for efficient tuning of catalysts to perform functionalization of C −H bonds with unequivocal selectivity.