biostudies-literatureLi BYBundesministerium für Bildung und ForschungChina Scholarship CouncilHerculesstichtingMinisterium für Kultur und Wissenschaft des Landes Nordrhein-WestfalenKU LeuvenFonds Wetenschappelijk OnderzoekVrije Universiteit Brussel2270-2279https://www.ebi.ac.uk/biostudies/studies/S-EPMC8864708biostudies-literatureUnknown13(8)Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the <i>ex situ</i> generation of trifluoromethanesulfonyl fluoride (CF₃SO₂F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the S^VI-F connector with a S[double bond, length as m-dash]O → S[double bond, length as m-dash]NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H₂O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols <i>vs.</i> amine groups, a phenomenon best explained-using <i>ab initio</i> metadynamics simulations-by a hydrogen bonded termolecular transition state for the CF₃SO₂F triflylation of amines.Chemical scienceSuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.PMC8864708G0D6221N20100225–71SA1121NDOA/2020/01312ZL820N1185221N12F4416NVoets LLi BYVerhelst SHLVan Lommel RAlonso MDe Borggraeve WMHoppenbrouwers FDemaerel JfalseSuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the <i>ex situ</i> generation of trifluoromethanesulfonyl fluoride (CF₃SO₂F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the S^VI-F connector with a S[double bond, length as m-dash]O → S[double bond, length as m-dash]NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H₂O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols <i>vs.</i> amine groups, a phenomenon best explained-using <i>ab initio</i> metadynamics simulations-by a hydrogen bonded termolecular transition state for the CF₃SO₂F triflylation of amines.2022-01-01T00:00:00Z2022 Feb2025-04-19T13:20:16.485Z2025-04-19T13:20:16.485ZS-EPMC88647083531048410.1039/d1sc06267k