Marcus cross relation in the space of H-atom abstraction reactions boosted through off-diagonal thermodynamics

Proton-coupled electron transfer (PCET) and hydrogen-atom transfer (HAT) reactions play critical roles in biological processes and modern organic synthesis. The kinetics of these processes can align with the principles described in the renowned Marcus cross relation (MCR), a framework initially formulated to describe electron transfer mechanisms. The MCR provides an outstanding link between the kinetics of PCET/HAT reaction involving two distinct reactants and two related auxiliary self-exchange reactions – each between a molecule of one of the reactants and its coupled radical. In this study, we investigate the applicability and limitations of the canonical MCR across over 300 PCET and HAT reactions, providing a comprehensive theoretical analysis. Our findings reveal the need for an enhanced framework that incorporates 'off-diagonal' thermodynamic factors—asynchronicity and frustration. Of these factors, asynchronicity, which quantifies the imbalance between the proton vs. electron transfer components of the reaction, is identified as the dominant contributor to the improved predictive accuracy of the MCR. Notably, the incorporation of off-diagonal thermodynamics yields a more pronounced enhancement for HAT reactions than for PCET reactions. This advancement offers a refined theoretical basis for understanding H-atom abstraction mechanisms and underscores the importance of off-diagonal effects in PCET/HAT chemistry.