| Title: |
Anti-Friedel–Crafts alkylation via electron donor–acceptor photoinitiation |
| Authors: |
Vahey, David M; Mu, Manting; Bonke, Shannon A; Sommer, Timo; Vangal, Prithvi; Mallia, Carl; García-Melchor, Max; Reisner, Erwin |
| Publisher Information: |
Springer Nature; //doi.org/10.1038/s44160-026-00994-w |
| Publication Year: |
2026 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
3402 Inorganic Chemistry; 3405 Organic Chemistry; 34 Chemical Sciences; 3407 Theoretical and Computational Chemistry; Machine Learning and Artificial Intelligence |
| Description: |
The ubiquity of C–H bonds in organic molecules makes direct C–H functionalization 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 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 functionalization of pharmaceutical compounds. The mechanistic design exploits a redox-active phthalimide ester tag to form an electron donor–acceptor 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 framework necessary to forecast selectivity in previously ‘unseen’ substrates, thereby enabling selective alkylation of a wide range of complex molecules and late-stage pharmaceuticals. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/396476; https://doi.org/10.17863/CAM.125774 |
| DOI: |
10.17863/CAM.125774 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/396476; https://doi.org/10.17863/CAM.125774 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.52691FEA |
| Database: |
BASE |