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. 2026 Feb 10;6(2):965–972. doi: 10.1021/jacsau.5c01407

Photoredox Catalytic Hydropentafluorosulfanylation of Alkynes by Sulfur Hexafluoride

Max Flügge †, Sven Klehenz †, Silas Leidenheimer †, David Rombach ‡,*, Hans-Achim Wagenknecht †,*
PMCID: PMC12933376  PMID: 41755855

Abstract

The interest in organic compounds bearing the pentafluorosulfanyl (SF5) group has increased significantly. The photocatalytic utilization of the cheap and nontoxic sulfur hexafluoride (SF6) as an SF5-donating motif is an extremely valuable and still underdeveloped pathway in comparison to the well-established methodology employing the highly toxic SF5Cl gas. However, due to the high stability and associated low redox potential of SF6, paired with the ambiphilicity of the SF5 radical, the development of catalytic systems to gain SF5-bearing organic molecules from SF6 is particularly challenging. We hereby present the first photocatalytic hydropentafluorosulfanylation of aryl acetylenes by SF6 using Ir­(ppy)3 as a visible-light photoredox catalyst and Hantzsch ester as a sacrificial reductant as well as a hydrogen atom transfer (HAT) reagent. The method delivers the corresponding pentafluorosulfanylated alkenes in good to excellent yields.

Keywords: photochemistry, photocatalysis, fluorine, electron transfer

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Introduction

Recently, the pentafluorosulfanyl (−SF5) group experienced a tremendous increase in research interest. − The introduction of fluorinated motifs in organic molecules has gained significant momentum during the last decades through their gradual expansion in the fields of agrochemistry, , optoelectronics, − and pharmaceutical chemistry. However, the development of fluorinated non-PFAS motifs (per- and polyfluorinated alkyl substances) is a pressing need in contemporary organofluorine chemistry. − Besides the well-established trifluoromethyl (−CF3) and trifluoromethoxy (−OCF3) groups in medicinal chemistry, − the −SF5 group has been shown to modify the properties of active pharmaceutical ingredients (API), agrochemicals, but also optoelectronic materials and catalysts. − In comparison to the widely explored −CF3 group, the −SF5 group has been suggested as a bioisosteric replacement of −tBu, −NO2, halogens, or −CF3. Additionally, it significantly exceeds electronegativity (3.65 vs 3.3) and lipophilicity of −CF3 as reflected by its Hansch π parameters (π = 1.23 vs 0.88). − Furthermore, aromatic SF5 compounds possess a high hydrolytic stability. The latter properties render it a useful substituent for being used in pharmaceuticals and agrochemical industries. ,,− In contrast, synthetic access in particular to SF5-functionalized aliphatic and vinyl compounds is still a central challenge and limits the knowledge about these fundamental motifs. Conventionally, the synthesis of aliphatic SF5-organic compounds requires the use of SF5Cl, which is a highly toxic gas. , Recently, several groundbreaking strategies have been developed to overcome this restriction. These comprise the in situ or ex situ preparation of SF5Cl, the development of SF5-transfer reagents based on β-fragmentation or N-SF5 bonds (Figure A), as well as the development of prefunctionalized platform reagents rendering the on-site use of SF5Cl obsolete. ,− Sulfur hexafluoride (SF6) is a nontoxic, but highly potent greenhouse gas, for a long time indispensable in high-voltage switch gear insulation and only most recently replaced by alternative materials. , Its inertness is caused by its unique electronic structure. First, all bonding and nonbonding orbitals are fully occupied. Second, two additional weak contributions contribute to the overall bonding situation: (i) Weak interaction of the eg set of the nonbonding orbitals located at the fluoride substituents with the eg subset of sulfur 3d-orbitals. (ii) Back-bonding from highly charged fluorine substituents of t2 symmetry to the FSF σp bonds. This unique bonding situation and tight fluorine shielding around the comparably small sulfur atom result in significantly reduced reactivity and render the application of SF6 as a synthetically useful reagent, an unsolved problem for decades. Nagorny et al. were able to fluorinate glycosides via the photocatalytic activation of SF6. Other examples include deoxyfluorinations using SF6 reported by Jamison and co-workers and Xie et al. The application of SF6 as an nucleophilic fluorination reagent was shown by Wang and co-workers. However, these cases focus only on the degradation of SF6 to generate new C–F bonds, whereas the selective linkage of the SF5 group to organic compounds would be much more valuable.

1.

1

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(A) Overview of pentafluorosulfanylation reactions from previous work. ,− (B) Examples of direct SF6 activation. ,, (C) This work, the direct SF6 activation for hydropentafluorosulfanylation of terminal alkynes.

While its activation by transition metals or as a fluorination or deoxyfluorination reagent has been previously reported by Ernst, Braun, and many more, − selective activation modes maintaining the SF5 scaffold, adding a significant amount of sustainability, have only recently been unlocked. In 2015, the first selective photocatalytic activation of SF6 was a proof-of-principle study describing the addition of SF6 to styrenes. While the initial method was limited to the concomitant formation of a C–F bond, we could expand the versatility of this approach to concomitant C–O and C–C bond formation, yielding SF5-substituted oxo-heterocycles (Figure B). , Moreover, we developed the concept of redox-convertible groups to expand the pentafluorosulfanylation substrate scope. The major limitation of this approach is the consecutive two-photon photoredox cycle being operative, striving potentials of −2.1 to 2.1 V (vs SCE), therefore dictating a tight redox corridor to substrates. The quest for simplifying the initially reported method to mitigate this problem led us to reinvestigate potential catalysts without critical radical–radical recombination. The previously required necessity of re-excitation of the primary oxidation product was rendered impossible by shifting to a d7-IrII species. Capping the oxidative manifold of the process at E ox(Ir­(III)/Ir­(II)) = +0.77 V allowed to turn to alkynes as competent substrates for the addition of SF5 radicals in the absence of a possibility for single electron oxidation. The change of substrates allowed us to enter a new photocatalytic approach without a conPET: Herein, we report a new protocol for pentafluorosulfanylation of alkynes based on the application of Ir­(ppy)3 as a photoredox catalyst and the Hantzsch ester as a sacrificial reductant and a hydrogen atom transfer (HAT) reagent proceeding via a single excitation cycle. During the preparation of this manuscript, a related approach was reported by Wang et al. using DIPEA as the reducing agent to access SF5–BCP cores.

Results and Discussion

Activation of SF6 Using Ir­(ppy)3

The reduction potential of SF6 has been determined to be −1.90 V (vs SCE), or −2.17 V (vs Fc/Fc+), respectively. , Our previous studies show that a reduction potential of −2.1 V vs SCE is crucial for the cleavage of SF6 into the open-shell SF5 radical, instead of the closed-shell SF5 anion. This can be achieved by using the highly reductive N-phenyl phenothiazine as an organophotoredox catalyst. Tris­(2-phenylpyridine)­iridium (Ir­(ppy)3) is commonly used as a photoredox catalyst engaging in oxidative or reductive quenching cycles. , However, the reduction has a potential of E 1/2(IrIV/IrIII) = −1.73 V vs SCE, which is not sufficient for the desired activation of SF6 under the formation of SF5 radicals. Therefore, any attempts to use direct photoinduced electron transfer (ET) from (Ir­(ppy)3) to SF6 failed to deliver pentafluorosulfanylated reaction products. Reductive quenching of the catalyst forming an IrII is thermodynamically not feasible due to the reduction potential of E 1/2(IrIII*/IrII) = 0.31 V vs SCE.

However, thermal back ET of Ir­(II) to Ir­(III) seems to be thermodynamically accessible (E 1/2Red = −2.20 V vs SCE), which should be sufficient for the generation of SF5 radicals. To access the IrII species efficiently, the addition of a sacrificial reductant is required. While only few reports investigate the chemistry of IrII, Hantzsch ester 1 has been reported to be able to act as a reducing agent. Following the previously outlined mechanistic assumptions (Figure ), IrIII is reductively quenched by Hantzsch ester 1 forming IrII. Based on this mechanistic proposal, 4-methoxy-phenylacetylene 2a was chosen as a substrate bearing an electron-rich alkyne moiety, allowing the electron-deficient SF5 radical to attack the triple bond at low stationary SF5 radical concentrations. The substrate was converted into the SF5H adduct 3a by SF6 (2.8 bar) in the presence of Ir­(ppy)3 (5 mol %) and the Hantzsch ester 1 as the photocatalyst upon irradiation at 450 nm (LED). No product formation and no SF6 activation were observed in the absence of the Hantzsch ester 1, without Ir­(ppy)3 and without inert conditions (Table , entries 2–4). Addition of 1.2 equiv of 1 to the reaction mixture yielded 12% of the SF5H adduct 3a (Table , entry 5). Increasing the amount of 1 to 5 equiv to ensure fast quenching of the photoredox catalyst and HAT caused an increase of the yield of 3a from 12% to 20% (Table , entry 6). At this point, due to the limited solubility of 1 in MeCN, the solvent was changed to MeOH, which not only improves the solubility of 1 but also slightly improves the solubility of SF6, which increases the yield from 12% to 25% (Table , entry 7). Both elevating and lowering the temperature to 35 and 10 °C decrease the yield to 31% and 26%, in comparison to the standard conditions, respectively (Table , entries 8 and 9). During the initial reduction of the Ir photocatalyst, Hantzsch ester 1 undergoes a single ET step, while another Hantzsch ester undergoes a HAT reaction with the open-shell SF5 adduct species 4a. In order to generate the observed pyridine species 5, a proton (H+) is released as a byproduct. Therefore, the addition of a base might be required as a proton scavenger. In fact, adding 1 equiv of 2,6-lutidine increased the yield from 25% to 78% (Table , entry 1). Lowering (0.5 equiv) or increasing (2.0 equiv) the amount of 2,6-lutidine reduces the yield of 3a to 20% and 28%, respectively (Table , entries 10 and 11). It is not entirely clear in which step of the mechanism the deprotonation of the Hantzsch ester 1 or its radical intermediate 6 or 7 takes place, as the deprotonation of both 6 and 7 is considered a possible reaction pathway. However, the drastic yield increase due to the addition of 2,6-lutidine would suggest that the abstraction of the amino proton is crucial. Ultimately, increasing the irradiation time from 20 to 65 h led to the formation of 3a in quantitative yield (>99%, Table , entry 12). A time-dependent study utilizing the phenylacetylene (2b) showed a linear increase from 10 to 65 h, revealing the necessity of the increased irradiation time (see Supporting Information (SI) Figure S26).

2.

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(A) General reaction scheme of the SF6 activation with optimized parameters for model substrate 2a and the synthesis of 3a. (B) Proposed photoredox catalytic mechanism for the pentafluorosulfanylation of 2a using irradiation at 450 nm (LED).

1. Optimization of SF5H Addition of Substrate 2a to Product 3a .

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entry deviation from standard conditions solvent yield of 3a/%
1 - MeOH 78
2 no inert conditions MeCN -
3 No Ir(ppy)3, no 1 MeCN -
4 No 1 MeCN -
5 1.2 equiv of 1 MeCN 12
6 5 equiv of 1 MeCN 20
7 No 2,6-lutidine MeOH 25
8 T = 10 °C MeOH 26
9 T = 35 °C MeOH 31
10 0.5 equiv of 2,6-lutidine MeOH 20
11 2.0 equiv of 2,6-lutidine MeOH 28
12 65 h MeOH >99
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a

Standard conditions are given in the reaction scheme. All yields are given as the sum of the E- and Z-isomer mixture (10:1).

With respect to the electrophilic character of the SF5 radical, investigation of the substrate scope revealed the method to be highly versatile for the conversion of electron-rich substrates (Figure ). This observation might also be caused by competing photoreduction of the electron-deficient alkynes by IrII or thermal reduction by IrII. For example, the electron-deficient 4-ethynylbenzonitrile (2f) showcases no hydropentasulfanylation under the standard conditions. This is possibly due to the higher reduction potential of −1.26 V vs SCE in comparison to 2a (−2.94 V vs SCE) and 2b (−2.75 v vs SCE). Translating the standard conditions onto the less electron-rich phenylacetylene 2b showcases a yield of 45% for product 3b in the 19F NMR spectrum. However, increasing the reaction time to 65 h again leads to a quantitative yield.

3.

3

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Scope for hydropentafluorosulfanylated products. Yields determined via 19F NMR spectroscopy. Isolated yield is given in brackets. Ratio of Z-Isomer and E-Isomer in lower brackets (Z:E). aYield after 65 h reaction time. bFrom β-Pinene 10.

Mechanistic Investigation

To shine light on the operating reaction mechanism, we carried out mechanistic studies. Initially, Stern–Volmer fluorescence quenching studies indicated quenching of Ir­(ppy)3 by 1 with a Stern–Volmer constant of K SV = 8.21 L/mol (Figure A), confirming an initial photoinduced ET generating the IrII-complex. To further prove a potential ET from IrII to SF6, we ran a comprehensive study using 19F NMR spectroscopy and photocyclovoltammetry (Figure B). While 1 was found to be stable in MeOH over a period of 45 min at room temperature in the dark, irradiation at 450 nm caused unproductive reduction of the solvent MeOH under the formation of pyridine 5 by putative direct excitation of 1. The IrIII/IrII half-wave was monitored by cyclovoltammetry under irradiation at 450 nm. In the presence of 1, the half-wave IrIII/IrII was depleted in solution. This result aligns with the Stern–Volmer experiments and 19F NMR studies, indicating reduction of IrIII by 1. Addition of SF6 to the prereduced catalyst restores the IrIII/IrII half-wave indicating reduction of SF6 by IrII in this case. This agrees again with the 19F NMR experiments, indicating the formation of fluorinated reaction products under the same conditions (Figure C). No activation of SF6 was observed in the absence of the Ir catalyst, excluding unproductive side product formation due to the rise of a reactive species caused by the background oxidation of 1 (see SI Figure S15). Furthermore, 2D labeling studies were carried out subjecting a set of deuterated Hantzsch ester species (1-(D 1 -D 3 )) to the reaction conditions in the presence of 2a. Analysis by GC/MS revealed that only species 1-D 2 and 1-D 3 were able generate the deuterated 3a-D species efficiently. Therefore, it is viable to assume that the CH2 bridge between the ester moieties of 1 partakes in the HAT (Figure D). In contrast, no deuterium transfer was observed using N-D derivative 1-D 1 . Control experiments in the presence of MeOD-d 4 did not show any incorporation of deuterium into the substrate, excluding the solvent from engaging in the HAT process.

4.

4

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Mechanistic investigations. (A) Stern–Volmer quenching experiment of Ir­(ppy)3 with Hantzsch ester 1. (B) Cyclic voltammograms of Ir­(ppy)3, Ir­(ppy)3 with 1 in darkness and under irradiation at 450 nm, respectively. (C) Time-resolved 19F NMR spectroscopy with Ir­(ppy)3, 1 and SF6 in CD3OD, showcasing only degradation of SF6 under irradiation at 450 nm. The 19F NMR spectra show an unidentified side product of the SF6 degradation. (D) Deuterium studies, using different deuterated Hantzsch esters (1-D 1 , 1-D 2 , 1-D 3 ).

To compare the observed reaction outcome with the previous report using SF5Cl by Paquin and to shine light on the operating reaction mechanism, we turned to a theoretical description of the catalytic cycle on the level of RI/CPCM/DLPNO–CCSD­(T)/ccp-VTZ//RI/CPCM/DFT/M062X/dhf-TZVP/D3(0). The obtained Gibbs free energy change of the addition step on 2a was found to be in very good agreement with previous results on the level of QICSD obtained by Paquin (ΔG R = −3.2 kcal/mol vs −3.5 kcal/mol, ΔG ‡ = 6.3 kcal/mol in both cases). However, in MeOH, we observe a very flat minimum corresponding to a slightly endergonic π-complex 12a or 12b, respectively, whose formation is slightly endergonic (ΔG = 6.0 or 5.4 kcal/mol). A more detailed analysis of the geometry of these π-complexes revealed a distance of the S-center of the SF5 radical to the π-system of 3.00 Å (2a) and 3.06 Å (2b), fairly close to the transition state for an addition to the acetylene forming the vinyl radical 13b (2.96 Å) and 13a (2.79 Å), respectively, indicating an early starting material like transition state for the addition step and explains the determined very low barriers for addition of 0.9 or 1.5 kcal/mol, for the respective species (Figure ).

5.

5

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(A) Energy profile of the proposed reaction mechanism on the level of DLPNO–CCSD­(T)/ccp-VTZ/CPCM in MeOH. All energies are given in kcal/mol. (B) Isomerization of primary product 3a-Z by Ir­(ppy)3 under triplet sensitization conditions.

The intermediate vinyl radicals are only slightly more stable than the starting materials, while the barrier for back reaction to the π-complex is only 9.8 and 10.8 kcal/mol, respectively, indicating a dynamic equilibrium with the starting material and the radical adduct species 4b. Interestingly, all attempts to optimize a transition state leading to the diastereomeric E-configured SF5 radical failed; as soon as constraints on the preoptimized structure were lifted, structure optimization converged to the Z-configured radicals 4a and 4b, indicating that there is no corresponding minimum for E-configured radical 4b- E . In the photocatalytic experiments, a ratio between E- and Z-product 3b- Z :3b- E of 94:6 is obtained. Previous calculations by Paquin et al. have determined a difference between the barrier for the HAT of 2.7 kcal/mol as the last step of the reaction mechanism explaining the preferred formation of the Z-product. However, we found an indication that the observed E/Z ratio might be a superposition between the primary reaction pathway controlled by the HAT and subsequent photoisomerization forming 3b- E . Subjecting pure 3b- Z to irradiation at 450 nm in CD3OD in the absence of the Ir complex yields the E- and Z- isomers in a photostationary state of 96:4 (3a- Z :3a- E ) (see SI Figure S25). Interestingly, in the presence of Ir­(ppy)3 (5.8 mol %, 2.0 mM), the photoisomerization at 450 nm gave an E-enriched ratio of 83:17 (3a- Z :3a- E ). Therefore, a potential pathway yielding an enrichment of the product 3a- E is proposed by the secondary photoisomerization induced by sensitization of the primary reaction product 3b- Z by Ir­(ppy)3. Accumulation of spin density on the β-SF5-carbon was confirmed by the observation of ring opening of the bicyclic system of β-pinene 10 forming product 9 in a yield of 10% (see Figure , lower right). Therefore, trapping of the vinyl radical 13a or 13b, respectively, is most likely induced by HAT from the 4-position of 1 in accordance with a calculated driving force of ΔG = −20.6 kcal/mol.

Conclusion

Vinylic SF5 compounds are conventionally synthesized via the addition of highly toxic SF5Cl gas to alkynes. We report a novel method for the synthesis of vinyl-SF5 species, representatively shown for 3a, utilizing cheap and nontoxic SF6 as an SF5-donating motif. For the first time, the hydropentafluorosulfanylation of alkynes was realized via the photocatalytic activation of SF6 using in situ-generated, highly reducing IrII as a photocatalyst. The generated open-shell SF5 species resulting from the reduction undergoes an addition onto 4-methoxyacetylene (2a). We assume that the initially formed open-shell adduct 4b is trapped by a HAT process to form 1,2-substituted SF5H styrene adduct 3a. Hantzsch ester 1 is employed both as a sacrificial reductant to access IrII and as the HAT donor. Detailed mechanistic studies by Stern–Volmer quenching, photocyclovoltammetry, and 1H and 19F NMR spectroscopy support the proposed reaction mechanism. This method, for the first time, allows the hydropentafluorosulfanylation of alkynes with several advantages: (i) It relieves from the detrimental effects of a conPET-like cycle, (ii) it allows to shift the photoredox catalysis to the visible light range, and (iii) it overcomes the inefficient radical addition to a triple bond by the use of the HAT mechanism. At the same time, the strongly reducing nature of IrII limits the substrate scope to electron-rich substrates.

Supplementary Material

au5c01407_si_001.pdf (15.7MB, pdf)

Acknowledgments

We thank Mathis Mitha, Sophia Abou El Mirate, and Jacqueline Lehner for experimental support, proof reading, and scientific discussion. The authors acknowledge the support by the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant no INST 40/575-1 FUGG (JUSTUS 2 cluster).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01407.

  • All experiments and the results; Emission spectra of the used LED LED450-03 (450 nm, 80 mW); The used irradiation setup with a magnetic stirrer, vial block with a cooling element, 450 nm LED array; Deuterium experiment (PDF)

§.

M.F. and S.K. contributed equally to this work.

This work was financially supported by the Deutsche Forschungsgemeinschaft (DFG, grant Wa 1386/23–1) and the Swiss National Science Foundation (SNSF, grant PZ00P2_209115). KIT and the University of Zurich are gratefully acknowledged.

The authors declare no competing financial interest.

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