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. 2026 Sep 15. Online ahead of print. doi: 10.1039/d6sc06249k

A sulfinate–azide hybrid reagent for sequential radical fluoroalkylation and click reaction†

Pallavi Halkarni a,b,‡, Mykyta Ziabko a,b,‡, Veronika Vrábelová a, Marek Opelka a, Yu Qianfei c, Xihe Bi c, Sergeii Suikov a, Petr Pospíšil a,d, Tomáš David a, Soňa Boháčová a, Blanka Klepetářová a, Petr Beier a,✉
PMCID: PMC13576151  PMID: 42746477

Abstract

A new clickable radical fluoroalkylating reagent, sodium 2-azido-1,1,2,2-tetrafluoroethanesulfinate, was prepared in one step from tetrafluoroethylene, sodium azide and sulfur dioxide. Oxidant-induced radical fluoroalkylation of arenes, heteroarenes, alkenes, and thiols, using this reagent, afforded azidotetrafluoroalkylated adducts. Their subsequent click reactions with alkynes led to N-fluoroalkylated triazoles. The synthetic sequence demonstrated the use of the new reagent as a clickable azidotetrafluoroethyl radical synthon, enabling connection to a diverse array of moieties, including a monoclonal antibody, via a triazole linker.

2-Azido-1,1,2,2-tetrafluoroethanesulfinate is a new radical reagent to introduce the CF2CF2N3 moiety to a variety of (hetero)aromatics, thiols and alkenes. The adducts were clicked to alkynes, including a modified antibody.graphic file with name d6sc06249k-ga.webp

Introduction

Organic azides are valuable reagents in synthesis (serving as amine precursors or in the preparation of heterocycles), medicinal chemistry and materials science (producing explosives, propellants, nitrene precursors for crosslinking or functionalized polymers, etc.).1–7 With the advent of azide–alkyne cycloaddition, organic azides have been utilized in bioconjugation, biomolecule labelling, drug delivery, and molecular imaging.8–16 Their fluorinated derivatives developed recently have the advantage of increased stability, excellent click reactivity and versatility in synthesis.17,18 They have been used in bioconjugation19 and in the synthesis of new fluorine-containing structures such as N-fluoroalkylated azoles,20–24 other heterocycles25,26 and N-alkenyl compounds.27,28 However, only one of the known fluoroalkyl azides has so far been used for further functionalization of the fluoroalkyl group before or after the click reaction: N3CF2SO2Ph.29 The product of the click reaction of this azide underwent a modification of the phenylsulfonyl group to the silyl group, amenable to activation by a fluoride ion and substitution by an electrophile (Scheme 1A). This way, N3CF2SO2Ph effectively served as an equivalent of the azidodifluoromethyl anion. We envisaged a more general bifunctional reagent, which would serve as a clickable fluoroalkyl radical synthon. Specifically, nucleophilic addition of the azide anion to tetrafluoroethylene and capture of the generated fluoroalkyl anion by sulfur dioxide would form a new reagent 1. Sequential generation of the azidotetrafluoroethyl radical and its addition to substrates, followed by a click reaction (or vice versa) would generate functionalized triazoles. This chemistry would allow for the mild and selective joining of alkynes with other substrates via a triazole linker, using the universal reagent (Scheme 1B).

Scheme 1. Reported functionalized fluoroalkyl azides and their application in click reactions with alkynes (A); proposed new bifunctional, click-ready radical reagent 1 and its application (B).

Scheme 1

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Fluoroalkylated sulfinates, such as CF3SO2Na (Langlois reagent),30,31 ClCF2SO2Na,32 CH3CF2SO2Na33 and zinc(ii) difluoromethane- or trifluoromethane-sulfinates34–36 and related α,α-difluorinated sulfinates, have been used as precursors of fluoroalkyl radicals37 in addition to various thiols and aromatic or unsaturated substrates. Bifunctional38,39 azide-containing radical reagents are rare. An azide-containing fluorinated sulfonyl chloride, N3CH2CF2SO2Cl, was used by Dolbier and co-workers for the photocatalytic generation of the fluoroalkyl radical and its addition to alkenes in the presence of hydrogen atom donors.40 Neither fluoroalkylation of aromatics with this reagent nor the azide click reaction of adducts was demonstrated. In another report by Baran and co-workers, a bifunctional seven-carbon azido–sulfinate reagent, N3(CH2)6CF2SO2Na, was prepared in five steps and used for the radical fluoroalkylation of aryl-containing drugs and other substrates. The adducts were attached to a monoclonal antibody by strain-promoted azide–alkyne cycloaddition (SPAAC).41 In contrast, our reagent 1 was assembled in one step and contains a much shorter spacer between the azido group and the fluoroalkyl radical. The click reactivity of fluorinated azides was reported to be much faster than in alkyl azides, especially with electron-rich alkynes.19

Results and discussion

The synthesis of fluoroalkyl azide 1 began with the generation of tetrafluoroethylene by thermal depolymerization of poly(tetrafluoroethylene) shavings under vacuum.24 The resulting tetrafluoroethylene was condensed in a trap immersed in liquid nitrogen and transferred into a steel autoclave containing a solution of dry SO2 in DMF and sodium azide. Mild heating for three days, followed by solvent evaporation, afforded reagent 1 on an 8.80 g scale as a white solid of high purity and yield (Scheme 2). 19F and 13C NMR and 19F–15N gradient-enhanced HMBC NMR spectroscopy, together with HRMS and IR spectroscopy, were used to fully characterize the product. Compound 1 displays good stability, and in DMSO solution it is thermally stable at 100 °C for at least 2 hours. DSC analysis confirmed the stability of 1 until about 110 °C. Oxygen from air slowly oxidizes 1 to the respective sodium sulfonate. The oxidation potential of 1, measured by cyclic voltammetry in DMF, was Epa = 1.03 V vs. SCE, which is close to the value reported for CF3SO2Na.42 Therefore, it might be feasible to generate the fluoroalkyl radical for fluoroalkylation by using a suitable oxidant and elimination of SO2.

Scheme 2. Synthesis of sulfinate 1.

Scheme 2

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Optimization of the fluoroalkylation of aromatics with reagent 1 was performed on caffeine as a model heteroaromatic substrate (Table 1). While iodine or PhI(OAc)2 did not serve as an efficient oxidant, potassium persulfate or t-butyl hydroperoxide was effective. Excess K2S2O8 and heating of the reaction mixture to 80 °C were essential to achieve high NMR yields of 2a. The optimal conditions used were 5 equiv. of the oxidant and 3 equiv. of reagent 1 (entry 6). Using aqueous MeCN as the solvent was less efficient than DMSO (entries 7 and 8). With t-BuOOH, the reaction worked at room temperature in aqueous MeCN or a two-phase system of DCM/water, albeit less efficiently than with K2S2O8 (entries 9 and 10).

Table 1. Optimization of the azidotetrafluoroalkylation of caffeine using reagent 1.

graphic file with name d6sc06249k-u1.jpg
Entry Oxidant (equiv.) Solvent Temp. (°C) 2a yielda (%)
1 I2 (4) DMSO 25 0
2 PhI(OAc)2 (4) DMSO 25 0
3 K2S2O8 (3) DMSO 90 70
4b K2S2O8 (3) DMSO 90 90
5 K2S2O8 (5) DMSO 90 65
6 K2S2O8 (5) DMSO 80 99 (97)c
7 K2S2O8 (4) aq. MeCN (1 : 1) 25 30
8 K2S2O8 (4) aq. MeCN (1 : 1) 50 83
9 t-BuOOH (5) aq. MeCN (1 : 1) 25 55
10 t-BuOOH (5) DCM/H2O (1 : 1) 25 65
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a

19F NMR yield.

b

Using 1 (4 equiv.).

c

Isolated yield.

Optimized conditions (Method A) using potassium persulfate or an alternative method (Method B) using t-butylhydroperoxide was used to explore the reaction scope with a range of aromatic, heteroaromatic, thiol and alkene substrates to deliver azidotetrafluoroethylated adducts 2 (Scheme 3). 1,4-Dimethoxybenzene, 1,3,5-trimethoxybenzene and 1,2,3,4-tetramethylbenzene were fluoroalkylated in good to high yields. No 2c was observed when a mixture of 1,3,5-trimethoxybenzene and TEMPO (3 equiv.) were used, suggesting the involvement of free radicals during the reaction. Coumarin and its diethylamino derivative fluoroalkylated in position three in high yields. 1-Methyl-2(1H)-quinoxalinone was modified efficiently, and the crystal structure of the product (2g) indicated an unusual, synclinal conformation of the azidotetrafluoro moiety. We investigated this counter-intuitive phenomenon in more detail. DFT calculations using the CHELPG scheme at the ωB97XD/def2TZVPP level of theory provided an electron density map and a map of partial charges for 2g (Fig. 1A). This revealed two attractive electrostatic interactions between the nitrogen in the quinoxalinone core and the middle nitrogen atom of the azido group, as well as the carbon atom of the CF2N3 group.

Scheme 3. Synthesis of adducts 2 by azidotetrafluoroethylation of arenes, thiols and alkenes, using reagent 1.

Scheme 3

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Fig. 1. Calculated partial charges in 2g (middle) and distribution of electron density (right) (A); conformers of 2g in Newman projection with computed Ar–CF2–CF2–N3 dihedral angles (α) and their relative energies (Erel) (B).

Fig. 1

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Conformational analysis identified an absolute minimum for the synclinal (gauche) conformer, a transition state with the anticlinal conformation and a second minimum with the antiperiplanar conformation (Fig. 1B). The relative potential energies of the three states were refined at the DLPNO-CCSD(T)/def2QZVPPD level of theory. The calculated upper limit of the absolute rate constant of the conformer transition at 25 °C was k = 1.1 × 1010 s−1, and the equilibrium constant was K = 0.017 (anti/syn). Another factor contributing to the preference of the synclinal conformer (apart from the electrostatic N–N interaction mentioned above) might be the three F–F gauche interactions in this conformer, as opposed to only two of such interactions in the antiperiplanar conformer.

N-Phenylpyrrole was fluoroalkylated in a good yield in position two of the pyrrole ring. Other heterocycles tested, such as uracil, dimethyluracil, azauracil, the drug allopurinol, or protected tryptophan, were fluoroalkylated efficiently. Dibenzo-18-crown-6 was mono(fluoroalkylated) in a good yield to 2n. With an excess of both reagent 1 and the oxidant, bis(fluoroalkylated) product 2o was formed.

Aromatic or heteroaromatic thiols, such as thiophenol, 4-mercaptobenzoic acid, 4-methoxythiophenol, 4-hydroxythiophenol, or mercaptobenzothiazole, were fluoroalkylated on their sulfur atoms. Cysteine derivatives also provided sulfides 2u and 2v in good to high yields. Finally, two alkenes were tested. 1,1-Diphenylethylene provided a product of hydrogen substitution for the azidotetrafluoroethyl group 2w. This reaction most probably proceeds by radical addition to the C Created by potrace 1.16, written by Peter Selinger 2001-2019 C bond, followed by oxidation and deprotonation. N-Methyl-N-phenylmethacrylamide following radical addition cyclized to lactam 2x. Alkenes prone to radical polymerization (styrene, ethyl methacrylate, etc.) were not suitable substrates for fluoroalkylation with 1.

The presence of the azide group in reagent 1 or adducts 2 was exploited by regioselective copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) or SPAAC (Scheme 4). Being water-soluble, reagent 1 was subjected to CuAAC with phenylacetylene under classical reaction conditions involving Cu(ii) salts and a reductant, providing the product of the click reaction, sulfinate 3a, in a good yield. Other substrates 2 were subjected to the click reaction using a THF-soluble Cu(i) catalyst in organic media. Aromatic or aliphatic alkynes were used, and products 3b–3e were obtained in excellent yields. Coumarin- and BODIPY-containing alkynes were efficiently clicked with 2m and 2g, respectively, to afford triazoles in high yields. Interestingly, the click reaction of 2n with propargyl-substituted adenine afforded 3h as the major isomer and 3i as the minor one. This selectivity was unexpected and can be explained by possible simultaneous coordination of the copper(i) catalyst to the crown ether moiety and nitrogen ligand of N-propargyladenine forcing the cyclization to proceed preferably to isomer 3f. However, this effect was not investigated further.

Scheme 4. Click reaction of adducts 2 to triazoles 3. aCuSO4·5H2O (10 mol%), sodium ascorbate (15 mol%), THF/H2O (1 : 1), and 40 °C. bReaction temperature: 55 °C. cUsing 10 mol% of the Cu(i) catalyst. dReaction temperature: 35 °C. eReaction temperature: 40 °C. fWithout any Cu(i) catalyst and 3 h reaction time.

Scheme 4

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Mono(trimethylsilyl)-protected bis(alkyne) clicked to afford 3h in a high yield, and silyl deprotection afforded alkyne 3i. Finally, a cyclooctyne structure underwent a SPAAC reaction with 2u to provide the tricyclic triazole product 3l without any Cu(i) catalyst.

Sulfinate 3a also served as a fluoroalkyl radical precursor to 3e in a reaction with dimethyluracil (Scheme 5), demonstrating that compounds 3 are accessible in two complementary ways, as proposed in Scheme 1B.

Scheme 5. Complementary synthesis of 3e by fluoroalkylation of N,N-dimethyluracil with 3a.

Scheme 5

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Next, we evaluated the performance of a coumarin-containing probe for protein labelling using the therapeutic monoclonal antibody trastuzumab.43 Trastuzumab (Herceptin) is the first HER2-targeted therapy approved for the treatment of breast cancer.44 Its molecular target, the human epidermal growth factor receptor 2 (HER2), is a receptor tyrosine kinase overexpressed in approximately 25% of breast cancers, making it an important target for a wide range of therapeutic strategies.

To assess the performance of the coumarin-containing probe 2f in protein labelling, trastuzumab was first modified by site-selective disulfide rebridging,45 using the bis-bromopyridazinedione linker 4 to introduce a BCN clickable handle. The resulting trastuzumab conjugate 5 was then reacted with a 10-fold molar excess of the azide-functionalized coumarin probe 2fvia SPAAC. Excess reagents were removed by desalting after each modification step, and conjugate 6 was used for subsequent characterization by mass spectrometry, clearly demonstrating that the antibody trastuzumab was modified by our reagent 2f with three and four chains, as shown in Scheme 6.

Scheme 6. Modification of the monoclonal antibody trastuzumab by the reduction of disulfide bridges, using TCEP, rebridging with 4, and a SPAAC click reaction with 2f, introducing a modified coumarin fluorophore. Below, respective intact MS (ESI) spectra of native trastuzumab (left) and its conjugates 5 (middle) and 6 (right).

Scheme 6

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Conclusions

A new bifunctional fluoroalkylating reagent, sodium 2-azido-1,1,2,2-tetrafluoroethanesulfinate, was synthesized on a multigram scale from sodium azide, sulfur dioxide and tetrafluoroethylene. Under oxidative conditions, the sulfinate group served as a precursor to the electrophilic ˙CF2CF2N3 radical, enabling efficient installation of the azidotetrafluoroethyl motif onto arenes, heteroarenes, thiols and alkenes through radical functionalization. The resulting azido-functionalized products, together with the parent sulfinate reagent, readily underwent both CuAAC and SPAAC reactions with alkynes to furnish diverse 1,2,3-triazoles, highlighting the unique bifunctional character of the reagent. The synthetic utility of this platform was further demonstrated by the efficient SPAAC-mediated modification of a monoclonal antibody in vitro. This reagent therefore provides a practical and scalable route to azidotetrafluoroethyl-containing molecules while integrating radical fluoroalkylation with bioorthogonal click chemistry in a single molecular platform.

Author contributions

PH: investigation, methodology, validation, writing – original draft; MZ: investigation, methodology, validation, writing – original draft; VV: investigation, methodology, validation, writing – original draft; MO: calculation, validation; YQ: investigation, methodology; XB: writing – review & editing; SS: investigation; PP: investigation, methodology; TD: investigation, methodology, formal analysis; SB: investigation; BK: investigation, formal analysis, visualization; PB: conceptualization, formal analysis, funding acquisition, project administration, supervision, writing – original draft, writing – review & editing.

Conflicts of interest

The authors PH, MZ, VV and PB declare a conflict of interest arising from the fact that they are listed as inventors in Czech Patent Application PV 2026-379 (priority date: July 21, 2026).

Supplementary Material

SC-OLF-D6SC06249K-s001
SC-OLF-D6SC06249K-s002

Acknowledgments

This research was financially supported by the Czech Academy of Science (Research Plan RVO: 61388963). We thank Dr František Filandr from IOCB Prague for intact MS analyses.

†

This paper honours Professor David O’Hagan, who has mentored and inspired many students, including one of the authors.

Data availability

The data supporting this article are included as part of the supplementary information (SI). Primary data (NMR, HRMS, MS, DSC and X-ray) are openly available in Zenodo at https://doi.org/10.5281/zenodo.21702274. Supplementary information: experimental procedures, compound characterization, copies of NMR and MS spectra, crystallography data, and computational details. See DOI: https://doi.org/10.1039/d6sc06249k.

CCDC 2565009 contains the supplementary crystallographic data for this paper.46

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Citations

  1. CCDC 2565009: Experimental Crystal Structure Determination, 2026, 10.5517/ccdc.csd.cc2s3378 [DOI]

Supplementary Materials

SC-OLF-D6SC06249K-s001
SC-OLF-D6SC06249K-s001.pdf (6.2MB, pdf)
SC-OLF-D6SC06249K-s002
SC-OLF-D6SC06249K-s002.cif (17.2KB, cif)

Data Availability Statement

The data supporting this article are included as part of the supplementary information (SI). Primary data (NMR, HRMS, MS, DSC and X-ray) are openly available in Zenodo at https://doi.org/10.5281/zenodo.21702274. Supplementary information: experimental procedures, compound characterization, copies of NMR and MS spectra, crystallography data, and computational details. See DOI: https://doi.org/10.1039/d6sc06249k.

CCDC 2565009 contains the supplementary crystallographic data for this paper.46

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