Formal Hydride Abstraction: A Unified Photoredox Platform for Nucleophilic C(sp3)-H Functionalization

Carbocations are among the most versatile reactive intermediates in organic synthesis. Serving as the electrophilic linchpin for fundamental transformations such as SN1 substitutions, Friedel-Crafts alkylations, Ritter reactions, polyene cyclization cascades, and many other transformations, they provide a powerful means to construct C-C and C-heteroatom bonds. Classically, however, access to these high-energy intermediates has been restricted to the ionization of reactive precursors ─ alkyl halides or sulfonates ─ often requiring harsh thermal, acidic and/or solvolytic conditions that limit functional group tolerance and favor competitive elimination. The ability to generate carbocations directly from ubiquitous, inert C(sp3)-H bonds has long been considered a holy grail of chemical synthesis. Otherwise known as hydride abstraction, it is hampered by a steep thermodynamic barrier; the heterolytic cleavage of a C-H bond is significantly more endergonic than its homolytic counterpart. This Account describes our laboratory's development of a catalytic platform that overcomes this thermodynamic challenge to enable a general formal hydride abstraction. We reasoned that the high-energy process of removing a hydride (H-) in a single step could be decoupled into two lower-energy, kinetically accessible steps mediated by visible-light photoredox catalysis: Hydrogen Atom Transfer (HAT) followed by oxidative Radical-Polar Crossover (RPC), or [HAT+RPC]. By utilizing a photocatalyst to orchestrate both the generation of a carbon-centered radical and its subsequent oxidation to a carbocation, we have unlocked a manifold for SN1-type reactivity on simple hydrocarbons under mild conditions. We trace the evolution of this concept from its genesis in nucleophilic C-H fluorination, where we utilized tert-butyl peroxybenzoate (TBPB) to engage the fluoride anion ─ a classically difficult coupling partner in homolytic transformations. Building on this success, we expanded the platform to oxygen nucleophiles, establishing a photochemical alternative to the Williamson ether synthesis that avoids the elimination side-reactions typical of strong bases. We further detail the critical reagent evolution necessitated by nitrogen nucleophiles, where the introduction of N-alkoxypyridinium salts solved the problem of competitive byproduct nucleophilicity, enabling the synthesis of N-benzyl azoles. Finally, we discuss our deep mechanistic interrogation of C-H sulfonamidation, where the identification and suppression of a parasitic proton-coupled electron transfer (PCET) pathway proved essential for catalytic efficiency. Collectively, these studies demonstrate that with the correct polarity-inversion machinery, C-H bonds can be viewed not merely as radical precursors, but as latent carbocations ready to engage in the full spectrum of polar reactivity.