{ "id": "eptzzfwveg", "slug": "sulfur-vi-fluoride-exchange", "title": "Sulfur(VI) fluoride exchange", "updated": "2026-10-15", "topic_path": [ { "id": "physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/topics/physical" }, { "id": "physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry" }, { "id": "physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods" }, { "id": "physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z", "label": "Titles Ho to Z", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z" } ], "geo": [ { "id": "geo.nongeo.t2001.physical.chemistry.methods.chemical-synthesis", "label": "Non-geographic · 2001 to 2020: Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001.physical.chemistry.methods.chemical-synthesis", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.t2001", "label": "Non-geographic · 2001 to 2020", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001" }, { "id": "geo.nongeo.t2001.physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001.physical" }, { "id": "geo.nongeo.t2001.physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001.physical.chemistry" }, { "id": "geo.nongeo.t2001.physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001.physical.chemistry.methods" }, { "id": "geo.nongeo.t2001.physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t2001.physical.chemistry.methods.chemical-synthesis" } ] } ], "excerpt": "Sulfur(VI) fluoride exchange (SuFEx) is a metal-free click chemistry reaction class, reported in 2014, in which sulfonyl fluorides and fluorosulfates form stable sulfonamides, sulfonates, and polysulfates.", "snippet": "Sulfur(VI) fluoride exchange (SuFEx) is a metal-free click chemistry reaction class, reported in 2014, in which sulfonyl fluorides and fluorosulfates form stable sulfonamides, sulfonates, and polysulfates.", "node": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z", "markdown": "# Sulfur(VI) fluoride exchange\n\nSulfur(VI) fluoride exchange (SuFEx) is a metal-free click chemistry reaction class in which sulfur(VI) fluorides, chiefly aryl sulfonyl fluorides and fluorosulfates, undergo nucleophilic substitution to form stable sulfonamides, sulfonates, sulfamates, and polysulfate linkages.[1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039) • [2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf) It is regarded as a second-generation click reaction, complementing the copper-catalyzed azide–alkyne cycloaddition (CuAAC) by forming S–O and S–N bonds instead of triazoles, and it can run under ambient conditions without glovebox or Schlenk techniques.[3](https://www.nature.com/articles/s43586-023-00241-y) • [2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf)\n\n| Key fact | Detail |\n|---|---|\n| Introducing paper | Dong, Krasnova, Finn, and Sharpless, *Angewandte Chemie International Edition*, 2014[4](https://doi.org/10.1002/anie.201309399) |\n| Core transformation | Nucleophilic substitution at S(VI)–F, forming S–O and S–N linkages (sulfonamides, sulfonates, sulfamates, polysulfates)[2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf) |\n| S–F bond strength | 81 ± 2 kcal mol⁻¹ (one review cites 90 kcal mol⁻¹), versus 46 ± 4 kcal mol⁻¹ for S–Cl[5](https://doi.org/10.1016/j.trechm.2025.01.003) • [1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039) |\n| Common catalysts | Bifluoride salts (down to 0.05 mol%), BTMG/HMDS (ASCC, down to 1 mol%), Ca(NTf₂)₂/DABCO, TBAF[6](https://doi.org/10.1038/nchem.2796) • [7](https://doi.org/10.26434/chemrxiv.13623179) • [8](https://doi.org/10.1021/acs.orglett.0c01397) • [9](https://doi.org/10.1039/c7py01636k) |\n| Connective hubs | Sulfonyl fluorides, fluorosulfates, sulfamoyl fluorides, iminosulfur oxydifluorides[2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf) |\n| Key limitation | Alkyl sulfonyl fluorides undergo α-deprotonation, dimerization, and oligomerization under strong base[5](https://doi.org/10.1016/j.trechm.2025.01.003) |\n\n## How it works\n\nThe reaction rests on a reactivity–stability balance in the S(VI)–F bond. The bond-dissociation energy of sulfonyl fluorides is 81 ± 2 kcal mol⁻¹, against 46 ± 4 kcal mol⁻¹ for the S–Cl analog, which explains why sulfonyl fluorides tolerate water, hydrolysis, and routine synthetic manipulations.[5](https://doi.org/10.1016/j.trechm.2025.01.003) • [1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039) Fluoride is normally a sluggish leaving group, so the sulfur center is inert toward most nucleophiles, including water. Specific activators, first identified as protons and silylium reagents (R₃Si⁺), convert complexed fluoride into a good leaving group, enabling clean redox-neutral substitution at sulfur(VI).[5](https://doi.org/10.1016/j.trechm.2025.01.003) The high charge of the central sulfur atom attracts nucleophiles to engage.[3](https://www.nature.com/articles/s43586-023-00241-y)\n\nThe exact mechanism is not fully settled: it remains unknown whether superbase catalysts form precatalysts, whether the reaction occurs at the sulfur or silicon center, and whether it proceeds through dissociation or an associative pathway with a concerted intermediary.[3](https://www.nature.com/articles/s43586-023-00241-y) Experimental and theoretical studies show that phenolates react with chiral sulfonimidoyl fluorides in an \\( S_{\\mathrm{N}}2 \\) fashion with inversion of configuration at sulfur, and rapid ¹⁸F/¹⁹F exchange suggests ligand redistribution on putative hypervalent silicon or sulfur intermediates.[3](https://www.nature.com/articles/s43586-023-00241-y) Temperature-dependent kinetics on RN=SOF₂-type substrates give small activation enthalpies of 4–15 kcal mol⁻¹ with nearly constant −TΔS‡₂₅ values of 10–14 kcal mol⁻¹, so the reaction is entropy-dominated or mixed enthalpy/entropy controlled.[10](https://research.wur.nl/en/publications/multimodal-svi-exchange-click-reactions-derived-from-sfsub2sub-mo/)\n\n## How it is done\n\n**Building-block preparation.** Arene sulfonyl fluorides are classically made by fluorinating sulfonyl chlorides with aqueous KF; a 1977 \"naked fluoride\" method used KF with 18-crown-6 in dry acetonitrile; and an improved potassium bifluoride (KHF₂) protocol converts alkyl and aryl sulfonyl chlorides to sulfonyl fluorides in high yield under mild conditions without hydrolysis.[11](https://castjournals.cast.org.cn/joweb/ccl/EN/1214570601046524162) Aryl fluorosulfates (Ar–O–SO₂–F) and iminosulfur oxydifluorides (R–N=SOF₂) are readily synthesized using the gases sulfuryl fluoride (SO₂F₂) and thionyl tetrafluoride (SOF₄), respectively.[12](https://doi.org/10.1021/jacs.7b12788)\n\n**Catalytic protocols.** Bifluoride salts (Q⁺[FHF]⁻) catalyze SuFEx between aryl silyl ethers and aryl fluorosulfates or alkyl sulfonyl fluorides, are significantly more active than organosuperbases, and enable loadings down to 0.05 mol%.[6](https://doi.org/10.1038/nchem.2796) The accelerated SuFEx click chemistry (ASCC) protocol pairs Barton's base BTMG (2-tert-butyl-1,1,3,3-tetramethylguanidine) with hexamethyldisilazane (HMDS), often completing S–O linkages within minutes at as little as 1 mol% catalyst; aromatic sulfonyl fluorides couple with primary alcohols at room temperature in about 30 minutes at 20 mol% catalyst.[7](https://doi.org/10.26434/chemrxiv.13623179) • [13](https://discovery.ucl.ac.uk/id/eprint/10189614/1/d3sc05729a.pdf) For amines, a unified Ca(NTf₂)₂/DABCO strategy activates sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides at room temperature: phenylsulfonyl fluoride gives a sulfonamide in 94% yield in under 30 minutes at room temperature, where the Ca(NTf₂)₂-only protocol required 60 °C and 24 h; Ca(NTf₂)₂ activates the substrate while DABCO enhances amine nucleophilicity, and NMR and LCMS studies support an activated N-sulfonyl-DABCO salt intermediate.[8](https://doi.org/10.1021/acs.orglett.0c01397) • [14](https://www.theballlab.com/uploads/2/2/7/7/22777750/acs.orglett.0c01397.pdf) [Tetrabutylammonium fluoride](https://www.edgepedia.org/tetrabutylammonium-fluoride) (TBAF) is an excellent catalyst for polymer–polymer coupling, giving almost quantitative conversions within minutes.[9](https://doi.org/10.1039/c7py01636k)\n\n## Origin\n\nSuFEx was reported in the 2014 paper \"Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry\" by Jiajia Dong and colleagues in *Angewandte Chemie International Edition*.[4](https://doi.org/10.1002/anie.201309399) The paper credits a 1979 full paper on ethenesulfonyl fluoride (CH₂=CH–SO₂F), calling it \"the most perfect Michael acceptor ever found\", and notes that earlier sulfur fluoride work \"faded from view rather abruptly in the mid-20th century\".[4](https://doi.org/10.1002/anie.201309399) [Click chemistry](https://www.edgepedia.org/click-chemistry), conceived by Sharpless in the mid-1990s, became widely used after the 2002 discovery of CuAAC, and SuFEx is described as the second major click reaction.[15](https://www.scripps.edu/news-and-events/press-room/2014/20140813sharpless.html)\n\n## Variants\n\nThe common SuFExable hubs, sulfonyl fluorides, fluorosulfates, sulfamoyl fluorides, and iminosulfur oxydifluorides, exhibit distinct physical and chemical properties.[2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf) SOF₄-derived connective hubs support biocompatible SuFEx: under mild buffered conditions, amines react with iminosulfur oxydifluorides (Ar–N=SOF₂) to give sulfuramidimidoyl fluoride products (8 examples, up to 97%), and phenols give sulfurofluoridoimidates (13 examples, up to 99%), enabling bioconjugation to DNA and proteins.[16](https://doi.org/10.1002/anie.201902489) Related sulfur(VI)–phenolate exchange chemistry is known as SuPhenEx, and SuFEx on chiral RN=SOF(p-substituted-phenol) substrates proceeds enantiospecifically, as shown by chiral HPLC and [X-ray crystallography](https://www.edgepedia.org/x-ray-crystallography).[3](https://www.nature.com/articles/s43586-023-00241-y) • [10](https://research.wur.nl/en/publications/multimodal-svi-exchange-click-reactions-derived-from-sfsub2sub-mo/) A C–SuFEx variant links sulfonimidoyl fluorides with organotrifluoroborates, forming C–S bonds.[17](https://doi.org/10.1038/s41467-024-44998-6)\n\n## Applications\n\nIn drug discovery, SuFEx enables late-stage functionalization: the fluorosulfate derivative of [Combretastatin A4](https://www.edgepedia.org/combretastatin-a4) shows a 70-fold increase in potency in a drug-resistant colon cancer cell line relative to the parent drug.[12](https://doi.org/10.1021/jacs.7b12788) The Ca(NTf₂)₂/DABCO protocol translated to parallel medicinal chemistry format, generating more than 100 unique nitrogen-based S(VI) compounds with high success rate and purity.[14](https://www.theballlab.com/uploads/2/2/7/7/22777750/acs.orglett.0c01397.pdf) In polymers, bifluoride-catalyzed SuFEx delivers polysulfates and polysulfonates with high molecular weight, narrow polydispersity, and excellent functional group tolerance, without sensitivity to scale-up,[6](https://doi.org/10.1038/nchem.2796) and RAFT chain transfer agents bearing orthogonal SuFEx groups give well-defined polymers with no observable side reactions.[9](https://doi.org/10.1039/c7py01636k) Because SuFEx proceeds under transition-metal-free conditions with naturally occurring linkage partners such as phenols and anilines, it supports high-throughput screening, inverse drug discovery, antibody modification, and ¹⁸F-radiolabeling.[1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039) • [18](https://pmc.ncbi.nlm.nih.gov/articles/PMC6565498/)\n\n**Protein probing.** When attached to a selective ligand, a sulfonyl fluoride head can be spatially activated inside a target protein pocket through close-contact H-bonding with protein residues, and undergo irreversible SuFEx with nucleophilic side chains such as lysine, serine, or tyrosine.[5](https://doi.org/10.1016/j.trechm.2025.01.003) Reactivity depends on a corridor that stabilizes fluoride exit, stabilizing side chains (Lys, Arg, His, Asp, Glu), and a proximal, properly oriented nucleophile.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC6565498/) In interacting proteins, SuFEx follows a two-step mechanism of noncovalent binding followed by covalent bond formation, with nonlinear rate dependence on protein concentration; in a nanobody–[SARS-CoV-2](https://www.edgepedia.org/sars-cov-2) spike system, viral mutations did not abolish covalent binding but decreased the SuFEx rate as affinity fell, and off-target cross-linking in human serum was not detected.[19](https://doi.org/10.1039/d3sc01921g)\n\n## Limitations and alternatives\n\nSuFEx reactions often suffer from sluggish reactivity owing to the inertness of the sulfonyl fluoride substrates.[5](https://doi.org/10.1016/j.trechm.2025.01.003) Alkyl sulfonyl fluorides are particularly challenging: decreased electrophilicity at sulfur and acidic α protons impede the use of strong bases, which lead to dimerization and oligomerization via α-deprotonation.[5](https://doi.org/10.1016/j.trechm.2025.01.003) Classical conditions conducive to catalyst degradation, notably hydrolysis of DBU, sometimes require loadings up to 30 mol%, complicating purification and downstream biological assays.[13](https://discovery.ucl.ac.uk/id/eprint/10189614/1/d3sc05729a.pdf) Under ASCC, secondary alcohols needed microwave heating to 60 °C for 30 minutes, and alkyl sulfonyl fluoride–alkyl alcohol couplings failed.[7](https://doi.org/10.26434/chemrxiv.13623179) Remaining gaps include thionyl tetrafluoride-free routes to sulfuramidimidoyl fluorides, enantiopure SuFEx hubs, aliphatic alcohols as nucleophiles (limited by \\( S_{\\mathrm{N}}2 \\) substitution of the product with fluoride), and carbon-based nucleophiles for some hubs.[1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039)\n\nCompared with sulfonyl chlorides, sulfonyl fluorides show higher thermal stability, better redox resistance, and greater acid tolerance; sulfonyl chlorides and sulfuryl chloride are often defeated by reductive collapse of the S(VI)–Cl bond to S(IV) species and Cl⁻, whereas sulfur(VI) fluorides leave only the substitution pathway open.[2](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf) • [4](https://doi.org/10.1002/anie.201309399) Unlike CuAAC, SuFEx can proceed without transition-metal catalysis.[1](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039) Published sources do not provide a direct quantitative rate or yield comparison between SuFEx and CuAAC, nor comparisons with isocyanates, NHS esters, or thiol–maleimide conjugation.\n\n## References\n\n1. [A Practical Guide to SuFEx Chemistry: An Overview of S(VI)-SuFEx Linkers and Their Reactivity (Synthesis, Thieme)](https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2410-2039)\n2. [The First Decade of SuFEx Chemistry: Advancements in SuFEx](https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/204525/1/T202500348.pdf)\n3. [Sulfur fluoride exchange | Nature Reviews Methods Primers](https://www.nature.com/articles/s43586-023-00241-y)\n4. [Jiajia Dong and colleagues (2014). Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angewandte Chemie International Edition.](https://doi.org/10.1002/anie.201309399)\n5. [Unconventional reactivity of sulfonyl fluorides (Trends in Chemistry, 2025)](https://doi.org/10.1016/j.trechm.2025.01.003)\n6. [Bing Gao and colleagues (2017). Bifluoride-catalysed sulfur(VI) fluoride exchange reaction for the synthesis of polysulfates and polysulfonates. Nature Chemistry.](https://doi.org/10.1038/nchem.2796)\n7. [Christopher J. Smedley, Timothy Gialelis, John Moses (2021). Accelerated SuFEx Click Chemistry for Modular Synthesis. ChemRxiv.](https://doi.org/10.26434/chemrxiv.13623179)\n8. [Subham Mahapatra and colleagues (2020). SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides. Organic Letters.](https://doi.org/10.1021/acs.orglett.0c01397)\n9. [Johannes C. Brendel and colleagues (2017). SuFEx – a selectively triggered chemistry for fast, efficient and equimolar polymer–polymer coupling reactions. Polymer Chemistry.](https://doi.org/10.1039/c7py01636k)\n10. [Multimodal S(VI) Exchange Click Reactions Derived from SF2 Moieties: Comparative Kinetics and Stereochemistry of SuFEx and SuPhenEx Reactions](https://research.wur.nl/en/publications/multimodal-svi-exchange-click-reactions-derived-from-sfsub2sub-mo/)\n11. [Recent progress in the synthesis of sulfonyl fluorides for SuFEx click chemistry (Chin. J. Org. Chem.)](https://castjournals.cast.org.cn/joweb/ccl/EN/1214570601046524162)\n12. [Zilei Liu and colleagues (2018). SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization. Journal of the American Chemical Society.](https://doi.org/10.1021/jacs.7b12788)\n13. [Modular synthesis of functional libraries by accelerated SuFEx click chemistry (RSC, UCL repository copy)](https://discovery.ucl.ac.uk/id/eprint/10189614/1/d3sc05729a.pdf)\n14. [SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides (Org. Lett., personal-site copy)](https://www.theballlab.com/uploads/2/2/7/7/22777750/acs.orglett.0c01397.pdf)\n15. [Scripps Research Institute Chemists Uncover Powerful New Click Chemistry Reactivity](https://www.scripps.edu/news-and-events/press-room/2014/20140813sharpless.html)\n16. [Feng Liu and colleagues (2019). Biocompatible SuFEx Click Chemistry: Thionyl Tetrafluoride (SOF4)‐Derived Connective Hubs for Bioconjugation to DNA and Proteins. Angewandte Chemie International Edition.](https://doi.org/10.1002/anie.201902489)\n17. [Suqin Zhao and colleagues (2024). C-SuFEx linkage of sulfonimidoyl fluorides and organotrifluoroborates. Nature Communications.](https://doi.org/10.1038/s41467-024-44998-6)\n18. [Novel approaches to access arylfluorosulfates and sulfamoyl fluorides based on sulfur (VI) fluoride exchange (SuFEx)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6565498/)\n19. [Bingchen Yu and colleagues (2023). The proximity-enabled sulfur fluoride exchange reaction in the protein context. Chemical Science.](https://doi.org/10.1039/d3sc01921g)\n\n---\n*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Chemical principles and methods › Chemical synthesis › Named synthetic methods › Titles Ho to Z*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/sulfur-vi-fluoride-exchange", "markdown_url": "https://www.edgepedia.org/sulfur-vi-fluoride-exchange.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Sulfur(VI) fluoride exchange\", Edgepedia (EdgeChat), https://www.edgepedia.org/sulfur-vi-fluoride-exchange. Edgepedia Community License 1.0.", "credit_md": "\"[Sulfur(VI) fluoride exchange](https://www.edgepedia.org/sulfur-vi-fluoride-exchange)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/sulfur-vi-fluoride-exchange](https://www.edgepedia.org/sulfur-vi-fluoride-exchange). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Sulfur(VI) fluoride exchange\", Edgepedia (EdgeChat), https://www.edgepedia.org/sulfur-vi-fluoride-exchange. Edgepedia Community License 1.0.", "speakable": "Sulfur fluoride exchange is a metal-free click chemistry reaction class, reported in 2014, in which sulfonyl fluorides and fluorosulfates form stable sulfonamides, sulfonates, and polysulfates." }