Transition State Asymmetry in C-H Bond Cleavage by Proton-Coupled Electron Transfer

The selective transformation of C-H bonds is a longstanding challenge in modern chemistry. A recent report details C-H oxidation via multiple-site concerted proton-electron transfer (MS-CPET), where the proton and electron in the C-H bond are transferred to separate sites. Reactivity at a specific C-H bond was achieved by appropriate positioning of an internal benzoate base. Here, we extend that report to reactions of a series of molecules with differently substituted fluorenyl-benzoates and varying outer-sphere oxidants. These results probe the fundamental rate versus driving force relationships in this MS-CPET reaction at carbon by separately modulating the driving force for the proton and electron transfer components. The rate constants depend strongly on the pK_a of the internal base, but depend much less on the nature of the outer-sphere oxidant. These observations suggest that the transition states for these reactions are imbalanced. Density functional theory (DFT) was used to generate an internal reaction coordinate, which qualitatively reproduced the experimental observation of a transition state imbalance. Thus, in this system, homolytic C-H bond cleavage involves concerted but asynchronous transfer of the H⁺ and e^-. The nature of this transfer has implications for synthetic methodology and biological systems.