Thermodynamic Principles Behind Mechanisms and Reactivities: Hydrogen Atom Abstraction and Related Radical Reactions

ConspectusHydrogen atom abstraction (HAA) is one of the most pervasive radical reactions in biology and chemistry. It is central to enzymatic catalysis, respiration, and photosynthesis, and underpins modern synthetic strategies like selective C-H functionalization. Despite its ubiquity, predicting HAA reactivity and selectivity remains notoriously difficult: comparably strong X-H bonds (with X = C, O, N, ...) within the same molecule often display starkly contrasting reactivities that well-known linear free-energy relationships (LFERs) often fail to capture.In this Account, we describe how <i>off-diagonal</i> thermodynamics complements Hammond's view of transition states as early or late as a consequence of their <i>diagonal</i> thermodynamic driving force (Δ<i>G</i>₀). It does so by gauging the effect of proton-transfer (PT) and electron-transfer (ET) states in the <i>character</i> of a concerted HAA reaction, that is, whether the charge distribution in transition state resembles more PT or ET instead of neutral HAA. Two key descriptors are presented, asynchronicity (η) and frustration (σ), which account for the effect of PT/ET states on HAA kinetics and, together with Δ<i>G</i>₀, they formulate a three-component thermodynamic framework. Herein, we summarize and provide a unifying view of how this framework can be utilized to provide insight and quantification of reaction outcomes, e.g., through prediction of relative barriers and selectivity, tunneling contributions, polarity effects, and even judgement of the bias in post-HAA selectivity. Extending the concept of off-diagonal thermodynamics uncovers how H atom abstraction connects to broader radical-transfer chemistries, ultimately leading to the discovery of a newly described mechanism: hydride-coupled electron transfer (HCET). By integrating thermodynamic cycles, Marcus theory, and computational analyses, we propose that off-diagonal thermodynamics provide not only a unifying language in HAA and related radical chemistry, connecting quantum chemistry and experimental measurements, but also a practical predictive tool for chemists. Looking ahead, we outline how this framework can guide experimental design, bridge the gap between adiabatic and nonadiabatic regimes, and expand beyond HAA to an extended theory of radical reactivity.