Sodium trifluoromethanesulfinate (CF3SO2Na; Langlois reagent) is an inexpensive, bench-stable inorganic salt that serves as a versatile source of the trifluoromethyl (CF3•) radical under oxidative, photoredox, or electrochemical activation. First developed by Langlois at CNRS Lyon and brought to widespread synthetic utility by the Baran group's bench-friendly aqueous–oxidative protocol, it has become a workhorse reagent for radical CF3 installation in medicinal chemistry, agrochemical research, chemical biology, and process-scale fluorination — complementing electrophilic CF3 sources such as Togni and Umemoto reagents.
Direct C–H Trifluoromethylation of Aromatic and Heteroaromatic Substrates under Thermochemical Oxidative Conditions. Under oxidative conditions — most commonly with t-butyl hydroperoxide (TBHP) as the terminal oxidant in aqueous–organic biphasic media as popularised by the Baran group, or with persulfate-based systems — sodium trifluoromethanesulfinate releases the trifluoromethyl radical via single-electron oxidation of the sulfinate followed by loss of SO2. The released CF3• radical adds directly to electron-rich aromatic and heteroaromatic substrates with high innate selectivity for π-rich positions of pyridines, pyrroles, indoles, pyrazines, pyrimidines, purines, methylxanthines, and nucleobase-derived heterocyclic scaffolds. The protocol is operationally simple, scalable from milligram to multigram, and tolerates a wide range of pharmacophoric functional groups, supporting late-stage trifluoromethylation of medicinal-chemistry scaffolds without protecting-group manipulation. Regioselectivity is governed by the local electron density of the substrate and by the choice of oxidant, solvent, and temperature. Silver(I) oxide-catalysed protocols extend the manifold to give either aryl-CF3 or aryl-SCF3 (trifluoromethylthio ether) products from the same Langlois reagent depending on substrate selection, providing a single-reagent entry to both CF3 and SCF3 chemistry classes. The methodology supports rapid access to CF3-substituted heteroaromatic analogues of interest in medicinal and agrochemical discovery.
Visible-Light Photoredox and Single-Electron CF3 Radical Transfer. Under visible-light photoredox catalysis with iridium- or ruthenium-based polypyridyl photocatalysts, organic photocatalysts (mesityl acridinium, 4CzIPN, 3DPAFIPN, eosin Y), or persulfate-based oxidative cycles operating under air, sodium trifluoromethanesulfinate is oxidised to release the trifluoromethyl radical under near-ambient conditions. The released radical adds to alkenes, alkynes, enol ethers, vinyl ethers, isocyanides, oxime ethers, α,β-unsaturated carbonyl compounds, and related radical acceptors, supporting trifluoromethyl-functionalisation, atom-transfer radical chemistry, hydrotrifluoromethylation (anti-Markovnikov H–CF3 addition with thiol-mediated hydrogen-atom transfer using methyl thiosalicylate or thiophenol as H-atom donors, as developed by the Nicewicz group), and CF3-mediated cyclisation cascades for the construction of fluorinated heterocycles, fluoroalkylated quaternary centres, CF3-substituted oxindoles, trifluoromethylated isoxazolines, and trifluoromethyl-functionalised polymer architectures. The reagent is also used as a CF3 source in mechanistic studies of single-electron transfer chemistry and in the development of new photocatalytic systems, where its relatively slow oxidative release of CF3 radical complements faster CF3 surrogates such as CF3I, CF3SO2Cl, and Umemoto- and Togni-type reagents, providing access to selectivity regimes inaccessible with kinetically faster radical sources.
Tandem CF3 and SO2 Insertion for Sulfone-Functionalised Heterocycles. A reactivity profile unique among trifluoromethyl-source reagents is the capacity of sodium trifluoromethanesulfinate to serve as both a CF3 source and an SO2 source in the same transformation. Under appropriately tuned conditions, single-electron oxidation generates the CF3SO2• sulfonyl radical, which can be intercepted by alkenyl, alkynyl, or aryl radical acceptors before desulfonylation occurs, delivering products that incorporate both the CF3 group and the SO2 unit. This dual-function reactivity has enabled trifluoromethylation/SO2-insertion/cyclisation cascades that construct trifluoromethylated cyclic sulfones, sulfonyl-functionalised oxindoles, dihydrothiophene-1,1-dioxides, sulfonylated indolines, and related sulfur-rich heterocycles in a single operation from simple precursors. Such tandem cascades are not accessible from alternative CF3 sources (CF3I, Togni, Umemoto), which do not carry a transferable SO2 unit. The pathway exploits the intermediate stability of the CF3SO2• radical and the kinetic competition between radical addition and SO2 extrusion, with reaction temperature, solvent, and substrate electronics dictating which pathway dominates.
Bioconjugation, Late-Stage Peptide CF3 Installation, and PET Radiochemistry. Copper-catalysed and metal-free photoredox protocols using sodium trifluoromethanesulfinate have extended radical trifluoromethylation chemistry to peptide substrates under near-physiological aqueous conditions. Site-selective C(sp2)–H radical trifluoromethylation of tryptophan residues in peptides has been demonstrated with chirality preservation, broad functional-group tolerance, scalability, and chemoselectivity for Trp over other amino acid and heterocyclic residues, providing late-stage CF3 installation on indole-containing peptides without protecting-group manipulation or prior side-chain functionalisation. The resulting CF3-tryptophan motif increases local hydrophobic and fluorinated character and may provide a 19F NMR handle for downstream studies of peptide structure, binding, or tracking, depending on the substrate and experimental design. The methodology has been extended to the 18F-radiolabelled ammonium analogue [18F]CF3SO2NH4, used for direct C–H 18F-trifluoromethylation of native tryptophan or tyrosine residues in unmodified peptides up to recombinant human insulin and octreotide, enabling automated radiosynthesis of 18F-CF3 peptide tracers for in vivo positron emission tomography imaging — work for which the non-radioactive sodium Langlois reagent serves as the cold chemistry reference and practical method-development analogue.
Electrochemical and Continuous-Flow Trifluoromethylation for Sustainable Methodology Development. Electrochemical activation of sodium trifluoromethanesulfinate provides an oxidant-free route to CF3• radicals using anodic oxidation as the sole driving force, in line with sustainable-methodology trends that aim to replace stoichiometric chemical oxidants (TBHP, persulfate, hypervalent iodine reagents) with electrons. Electrochemical C(sp2)–H trifluoromethylation of arenes, heteroarenes, alkenyl oximes (giving trifluoromethylated isoxazolines and cyclic nitrones via radical annulation), enamides, and related radical-acceptor substrates has been demonstrated under undivided-cell conditions with carbon, graphite, or platinum electrodes, including in microflow-cell formats that mitigate electrode passivation. In parallel, copper-catalysed continuous-flow protocols using Langlois reagent and TBHP have been developed for laboratory-scale flow and early process-development trifluoromethylation chemistry, with reported productivities of 305 mg h−1 in the flow synthesis of 3-trifluoromethyl-7-diethylamino-4-methyl coumarin at 68% isolated yield. These developments position sodium trifluoromethanesulfinate as a viable CF3 source for scaled-up academic and early-development trifluoromethylation chemistry, where its low cost, bench-stability, high water solubility, and non-volatile solid form provide significant practical advantages over volatile, photolabile, or moisture-sensitive trifluoromethyl-source alternatives.
