Authors
James Mortimer, Patricia Z Musacchio
Published in
Accounts of chemical research. Jul 27, 2026. Epub Jul 27, 2026.
Abstract
ConspectusCarbocations 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.
PMID:
42504833
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.
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