The selective oxidation of a C(sp³)-H bond is essential towards synthesizing drug metabolites and motifs for many biologically active compounds. Accessing drug metabolites is critical for designing more effective drugs and determining a specific drug's safety. Direct electrosynthesis techniques employ an anode surface to carry out the oxidation. Common substrate functionalities such as carboxylates and aromatic rings and the solvent, requiring much lower oxidation potentials, will likely be activated before the C(sp³)-H bonds of the substrate. Indirect electrosynthesis routes generate catalytic oxidizing agents known as mediators in-situ to oxidize the C(sp³)-H bonds. The mediator promotes hydrogen atom transfer and suppresses electron transfer from the substrate. Herein, we propose a catalytic cycle for forming the active mediator and its role in the activation of the substrate. The mediator (M) is first oxidized to generate the oxidized mediator (M^●⁺). The oxidized mediator (M^●⁺) then abstracts a hydrogen atom from the substrate to form the protonated M-H⁺ species that can then be deprotonated to regenerate the original mediator (M). The substrate radical generated is further oxidized with atmospheric O₂. An efficient mediator requires a low oxidation potential (E_ox), a more exergonic H-binding free energy (△G_H-bind), and a low deprotonation free energy (DPFE). However, these thermodynamic descriptors were found to be coupled and cannot be optimized independently, which drives the search to achieve an overall optimum by exploring potential mediators. First-principles density functional theory (DFT) calculations were carried out to screen potential mediators using these descriptors. The computational screening resulted in the discovery of N-ammonium ylides for chemoselective C(sp³)–H oxidation, which experimentally shows either superior or orthogonal site-selectivity and reactivity to know oxidation systems. Transition state calculations further elucidate the specific mediator-substrate interactions and examine factors that govern the experimentally obtained selectivity to different oxidation products.

Shelley Minteer

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