— Innovation of Radical Trifluoromethylation Enabled by Photocatalytic Activation of Flioroform —
Key Points
- Sustainable utilization of inexpensive and low-toxicity fluoroform as a trifluoromethyl radical source
- A new strategy for direct CF₃ radical generation from fluoroform by ketone-mediated photoactivation
- Broadly applicable photocatalytic radical trifluoromethylation of diverse substrates
Summary
A research group led by Dr. Shun Zhou and Specially Appointed Associate Professor Hiroki Hayashi at the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, who are now a Postdoctoral Researcher and an Associate Professor at the Research Center of Materials Sciences, Nagoya University, respectively, and Ms. Yan Song, a doctoral student in the Graduate School of Chemical Sciences and Engineering at Hokkaido University, has developed a new strategy that enables the generation of trifluoromethyl (CF₃) radicals from fluoroform, an inexpensive, low-toxicity, and sustainable CF₃ source in synthetic chemistry, for radical trifluoromethylation.
The trifluoromethyl (CF₃) group is widely utilized in medicinal chemistry, with numerous pharmaceuticals containing this valuable motif. Among methodologies for introducing the CF₃ group into organic compounds, radical trifluoromethylation is highly advantageous because it enables the direct introduction of the trifluoromethyl group into unsaturated functionalities without the need for pre-activation of substrates. Despite the widespread utility of radical trifluoromethylation, access to CF₃ radicals has remained largely dependent on preactivated reagents that are often expensive, hazardous, and generate substantial waste. Fluoroform, an abundant industrial byproduct that is inexpensive, low in toxicity, and offers high atom economy, represents an attractive and sustainable source of CF₃ groups. However, the direct generation of CF₃ radicals from fluoroform has remained a major challenge because of the difficulty in activating its strong C–H bond.
Researchers have uncovered a new mode of fluoroform activation that enables its use in radical trifluoromethylation. Guided by computational analysis using the Artificial Force Induced Reaction (AFIR) method, the researchers discovered that ketones under photoirradiation in the presence of a Brønsted base can activate fluoroform to generate CF₃ radicals through a photoexcited alkoxide intermediate. This new activation pathway operates without exogenous redox reagents and enables broad radical trifluoromethylation of alkenes, alkynes, and aromatic compounds under mild conditions, including catalytic reactions and late-stage modification of complex molecules.
This innovative strategy transforms fluoroform from an underutilized industrial byproduct into a valuable synthetic resource, establishing a new platform for sustainable access to CF₃-containing molecules. By enabling the direct use of fluoroform as a radical trifluoromethyl source, this technology is expected to drive the development of next-generation synthetic methodologies, accelerate the discovery of fluorinated pharmaceuticals and functional materials, and contribute to more sustainable chemical manufacturing.
The results of this study were published in J. Am. Chem. Soc. on August 4th, 2026.
