A radical new way to alkylate aromatic rings

Chemists in Erwin Reisner’s group at the University of Cambridge have discovered a light-activated way to attach saturated carbon groups to the most electron-poor sites on aromatic rings without a transition metal catalyst (Nat. Synth. 2026, DOI: 10.1038/s44160-026-00994-w).The researchers dubbed it the “anti-Friedel-Crafts” reaction, because its selectivity is opposite to that of the nearly 150-year-old aromatic substitution reaction, which favors electron-rich sites on electron-rich rings.“This is far milder, and it does something completely different to established methods,” says David Vahey, the PhD student who led the experimental work. And it all came about thanks to an unexpected product from a control reaction.Vahey had been working on aldehyde-ketone coupling with a semiconductor photocatalyst, an offshoot of the group’s broader focus on solar-powered chemistry. When he ran a control reaction without any photocatalyst, he found that the starting materials still reacted—and formed an aromatic alkylation product rather than the expected coupling product. Intrigued, the researchers decided to investigate the mechanism further.The team determined that the reaction was mediated by a light-generated radical ion pair composed of a bulky amine base and a redox-active phthalimide ester bearing the alkyl group that would ultimately transfer to the product.The Cambridge team joined forces with computational chemist Max García-Melchor of CIC energiGUNE and Trinity College Dublin to model the mechanism and develop a machine learning algorithm. The algorithm predicts which position on the ring the alkyl group will end up on based on an index of electron density. The team also partnered with AstraZeneca to run the