trifluoromethylating

Trifluoromethylating, or the introduction of a trifluoromethyl group, refers to forming a C–CF3 bond on a substrate. The CF3 group imparts high lipophilicity, metabolic stability, and influences acidity and pKa, making trifluoromethylated motifs valuable in pharmaceuticals, agrochemicals, and materials. The field encompasses electrophilic, nucleophilic, and radical trifluoromethylation, applicable to arenes, alkenes, carbonyl compounds, and heterocycles.

Electrophilic trifluoromethylation uses reagents that deliver CF3 as an electrophile to nucleophilic or electron-rich sites. Prominent reagents include Togni reagents and Umemoto reagents, enabling trifluoromethylation of arenes, heterocycles, and enolates under metal- or Lewis acid-catalyzed conditions. Nucleophilic trifluoromethylation employs CF3− sources, such as Ruppert–Prakash reagent (TMS-CF3) activated with fluoride, or Langlois reagent (CF3SO2Na) in the presence of metal catalysts, to install CF3 on carbonyl compounds, alkenes, and alkynes. Radical trifluoromethylation relies on CF3 radicals generated from Langlois reagent, CF3I, or Togni reagents under photoredox or radical-initiating conditions to add CF3 across C=C bonds and to C–H bonds in various substrates.

The choice of method affects regiochemistry, stereochemistry, and functional-group tolerance. Modern strategies emphasize late-stage functionalization of complex molecules, mild conditions, and operational simplicity. Limitations include reagent cost, environmental considerations, and sometimes limited substrate scope.

Trifluoromethylation remains a dynamic area of organic synthesis, integrating photoredox catalysis, transition-metal catalysis, and radical chemistry to access CF3-containing motifs for drug discovery and materials science.