The ubiquity of C–H bonds in organic molecules makes direct C–H functionalisation an atom- and step-efficient strategy in synthetic chemistry. However, direct C–H alkylation, particularly of electron-poor aromatic substrates, remains a major challenge because current methods suffer from limited selectivity, functional group tolerance and/or require harsh acidic, pyrophoric or toxic reagents. Here, we introduce a highly selective, scalable, and transition metal-free synthetic strategy for C–H alkylation of electron-poor aromatics under mild conditions, which also exhibits high functional group tolerance applicable to the late-stage functionalisation of pharmaceutical compounds. The mechanistic design exploits a redox active phthalimide ester tag to form an electron donor-acceptor (EDA) complex that fragments upon photoexcitation to yield a nucleophilic alkyl radical, which selectively alkylates the most electrophilic position of electron-deficient aromatics, thereby exhibiting ‘anti-Friedel-Crafts’ selectivity. Mechanistic studies, microkinetic modelling simulations and computational analyses indicate that the reaction then propagates via radical anion autocatalysis. The ‘anti-Friedel-Crafts’ selectivity is consistent with theoretical predictions from Fukui indices and machine learning models that provide the predictive framework necessary to predict selectivity in previously ‘unseen’ substrates, thereby enabling selective alkylation of a wide range of complex molecules and late-stage pharmaceuticals.
Reisner et al. (2026) studied this question.