Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Spontaneous trisulfide metathesis in polar aprotic solvents

Nature Chemistry (2026)Cite this article

Subjects

Abstract

Sulfur–sulfur bonds are ubiquitous across broad classes of natural products, peptides and proteins, drug molecules, and synthetic polymers and materials. The ability to make and break these bonds in a controlled manner is critical for their many scientific and technological applications. Here we report the discovery of an unusual S–S metathesis reaction of organic trisulfides. When exposed to certain polar aprotic solvents, trisulfides were found to undergo spontaneous metathesis, with the reaction equilibrium established in seconds in some cases. No exogenous reagents, heat, light or other stimuli were required to provoke this reaction. Furthermore, the trisulfide metathesis process can occur both inter- and intramolecularly. Understanding the scope and mechanism of this reaction enabled diverse applications of this chemistry in dynamic combinatorial library synthesis, the covalent modification of complex natural products, and S–S metathesis polymerization and depolymerization as a platform for chemically recyclable plastics.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A summary of S–S exchange reactions in disulfides and trisulfides, including the unusual trisulfide metathesis studied in this report.
Fig. 2: Influence of solvent on trisulfide metathesis and mechanistically relevant observations and control experiments.
Fig. 3: Substrate scope of spontaneous trisulfide metathesis in DMF and NMP.
Fig. 4: Mechanistic hypothesis of the trisulfide metathesis reaction featuring a polar thiosulfoxide intermediate and a concerted S–S metathesis event.
Fig. 5: Direct modification of calicheamicin γ1 by trisulfide metathesis.
Fig. 6: Dynamic combinatorial libraries by trisulfide metathesis.
Fig. 7: Chemically recyclable analogue of HDPE prepared by trisulfide metathesis polymerization.

Similar content being viewed by others

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2420468 (Bn2S3), 2479704 (Ph2S2) and 2486578 (18-membered ring). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. Source data are provided with this paper.

References

  1. Steudel, R. The chemistry of organic polysulfanes R−Sn−R (n > 2). Chem. Rev. 102, 3905–3946 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Jiang, C.-S., Müller, W. E. G., Schröder, H. C. & Guo, Y.-W. Disulfide- and multisulfide-containing metabolites from marine organisms. Chem. Rev. 112, 2179–2207 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Wedemeyer, W. J., Welker, E., Narayan, M. & Scheraga, H. A. Disulfide bonds and protein folding. Biochemistry 39, 4207–4216 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Góngora-Benítez, M., Tulla-Puche, J. & Albericio, F. Multifaceted roles of disulfide bonds. Peptides as therapeutics. Chem. Rev. 114, 901–926 (2014).

    Article  PubMed  Google Scholar 

  5. Zein, N., Sinha, A. M., McGahren, W. J. & Ellestad, G. A. Calicheamicin γ1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science 240, 1198–1201 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, R., Nie, T., Fang, Y., Huang, H. & Wu, J. Poly(disulfide)s: from synthesis to drug delivery. Biomacromolecules 23, 1–19 (2022).

    Article  PubMed  Google Scholar 

  7. Lee, T., Dirlam, P. T., Njardarson, J. T., Glass, R. S. & Pyun, J. Polymerizations with elemental sulfur: from petroleum refining to polymeric materials. J. Am. Chem. Soc. 144, 5–22 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Canadell, J., Goossens, H. & Klumperman, B. Self-healing materials based on disulfide links. Macromolecules 44, 2536–2541 (2011).

    Article  CAS  Google Scholar 

  9. Houk, J. & Whitesides, G. M. Structure-reactivity relations for thiol-disulfide interchange. J. Am. Chem. Soc. 109, 6825–6836 (1987).

    Article  CAS  Google Scholar 

  10. Sarma, R. J., Otto, S. & Nitschke, J. R. Disulfides, imines, and metal coordination within a single system: interplay between three dynamic equilibria. Chem. Eur. J. 13, 9542–9546 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Caraballo, R., Rahm, M., Vongvilai, P., Brinck, T. & Ramström, O. Phosphine-catalyzed disulfide metathesis. Chem. Commun. 6603-6605 (2008).

  12. Alcock, L. J., Perkins, M. V. & Chalker, J. M. Chemical methods for mapping cysteine oxidation. Chem. Soc. Rev. 47, 231–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Sattler, L. E., Otten, C. J. & Hilt, G. Alternating current electrolysis for the electrocatalytic synthesis of mixed disulfide via sulfur–sulfur bond metathesis towards dynamic disulfide libraries. Chem. Eur. J. 26, 3129–3136 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Otsuka, H., Nagano, S., Kobashi, Y., Maeda, T. & Takahara, A. A dynamic covalent polymer driven by disulfide metathesis under photoirradiation. Chem. Commun. 46, 1150–1152 (2010).

    Article  CAS  Google Scholar 

  15. Belenguer, A. M., Friščić, T., Day, G. M. & Sanders, J. K. M. Solid-state dynamic combinatorial chemistry: reversibility and thermodynamic product selection in covalent mechanosynthesis. Chem. Sci. 2, 696–700 (2011).

    Article  CAS  Google Scholar 

  16. Belenguer, A. M., Lampronti, G. I., Wales, D. J. & Sanders, J. K. M. Direct observation of intermediates in a thermodynamically controlled solid-state dynamic covalent reaction. J. Am. Chem. Soc. 136, 16156–16166 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Sobczak, S. et al. Dynamic covalent chemistry under high-pressure: a new route to disulfide metathesis. Chem. Eur. J. 24, 8769–8773 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Fritze, U. F. & von Delius, M. Dynamic disulfide metathesis induced by ultrasound. Chem. Commun. 52, 6363–6366 (2016).

    Article  CAS  Google Scholar 

  19. Chalker, J. M., Bernardes, G. J. L., Lin, Y. A. & Davis, B. G. Chemical modification of proteins at cysteine: opportunities in chemistry and biology. Chem. Asian J. 4, 630–640 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Saito, G., Swanson, J. A. & Lee, K.-D. Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. Adv. Drug Deliv. Rev. 55, 199–215 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Corbett, P. T. et al. Dynamic combinatorial chemistry. Chem. Rev. 106, 3652–3711 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, Y. & Urban, M. W. Self-healing polymeric materials. Chem. Soc. Rev. 42, 7446–7467 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Rekondo, A. et al. Catalyst-free room-temperature self-healing elastomers based on aromatic disulfide metathesis. Mater. Horiz. 1, 237–240 (2014).

    Article  CAS  Google Scholar 

  24. Block, E. The organosulfur chemistry of the genus Allium—implications for the organic chemistry of sulfur. Angew. Chem., Int. Ed. Engl. 31, 1135–1178 (1992).

    Article  Google Scholar 

  25. Clennan, E. L. & Stensaas, K. L. Recent progress in the synthesis, properties and reactions of trisulfanes and their oxides. Org. Prep. Proced. Int. 30, 551–600 (1998).

    Article  CAS  Google Scholar 

  26. Nicolaou, K. C., Smith, A. L. & Yue, E. W. Chemistry and biology of natural and designed enediynes. Proc. Natl Acad. Sci. USA 90, 5881–5888 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bertozzi, E. R. Chemistry and technology of elastomeric polysulfide polymers. Rubber Chem. Technol. 41, 114–160 (1968).

    Article  CAS  Google Scholar 

  28. Morrison, N. J. & Porter, M. Temperature effects on the stability of intermediates and crosslinks in sulfur vulcanization. Rubber Chem. Technol. 57, 63–85 (1984).

    Article  CAS  Google Scholar 

  29. Wu, M. et al. Organotrisulfide: a high capacity cathode material for rechargeable lithium batteries. Angew. Chem. Int. Ed. 55, 10027–10031 (2016).

    Article  CAS  Google Scholar 

  30. Trivette, C. D. Jr & Coran, A. Y. Polysulfide exchange reactions. I. Kinetics and mechanism of the thermal exchange between diethyl trisulfide and di-n-propyl trisulfide. J. Org. Chem. 31, 100–104 (1966).

    Article  CAS  Google Scholar 

  31. Pickering, T. L., Saunders, K. J. & Tobolsky, A. V. Disproportionation of organic polysulfides. J. Am. Chem. Soc. 89, 2364–2367 (1967).

    Article  CAS  Google Scholar 

  32. Tonkin, S. J. et al. Chemically induced repair, adhesion, and recycling of polymers made by inverse vulcanization. Chem. Sci. 11, 5537–5546 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yan, P. et al. Stretchable and durable inverse vulcanized polymers with chemical and thermal recycling. Chem. Mater. 34, 1167–1178 (2022).

    Article  CAS  Google Scholar 

  34. Lundquist, N. A. et al. Reactive compression molding post-inverse vulcanization: a method to assemble, recycle, and repurpose sulfur polymers and composites. Chem. Eur. J. 26, 10035–10044 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Kende, I., Pickering, T. L. & Tobolsky, A. V. The dissociation energy of the tetrasulfide linkage. J. Am. Chem. Soc. 87, 5582–5586 (1965).

    Article  CAS  Google Scholar 

  36. Chauvin, J.-P. R., Griesser, M. & Pratt, D. A. The antioxidant activity of polysulfides: it’s radical! Chem. Sci. 10, 4999–5010 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jabbour, E., Paul, S. & Kantarjian, H. The clinical development of antibody–drug conjugates—lessons from leukaemia. Nat. Rev. Clin. Oncol. 18, 418–433 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Myers, A. G., Cohen, S. B. & Kwon, B. M. A study of the reaction of calicheamicin γ1 with glutathione in the presence of double-stranded DNA. J. Am. Chem. Soc. 116, 1255–1271 (1994).

    Article  CAS  Google Scholar 

  39. Ramström, O. & Lehn, J.-M. Drug discovery by dynamic combinatorial libraries. Nat. Rev. Drug Discov. 1, 26–36 (2002).

    Article  PubMed  Google Scholar 

  40. Black, S. P., Sanders, J. K. M. & Stefankiewicz, A. R. Disulfide exchange: exposing supramolecular reactivity through dynamic covalent chemistry. Chem. Soc. Rev. 43, 1861–1872 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Vidal, F. et al. Designing a circular carbon and plastics economy for a sustainable future. Nature 626, 45–57 (2024).

    Article  CAS  PubMed  Google Scholar 

  42. Clark, R. A. & Shaver, M. P. Depolymerization within a circular plastics system. Chem. Rev. 124, 2617–2650 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pyun, J. & Norwood, R. A. Infrared plastic optics and photonic devices using chalcogenide hybrid inorganic/organic polymers via inverse vulcanization of elemental sulfur. Prog. Polym. Sci. 156, 101865 (2024).

    Article  CAS  Google Scholar 

  44. Baran, T., Duda, A. & Penczek, S. Anionic polymerization of norbornene trisulfide (exo-3,4,5-trithia-tricyclo[5.2.1.02.6]decane). J. Polym. Sci. 22, 1085–1095 (1984).

    CAS  Google Scholar 

  45. Baran, T., Duda, A. & Penczek, S. Anionic polymerization of exo-3,4,5-trithiatetracyclo[5.5.1.0.2,608,12]tridec-10-ene (dicyclopentadiene trisulfide). Macromol. Chem. Phys. 185, 2337–2346 (1984).

    Article  CAS  Google Scholar 

  46. Pople, J. M. M. et al. Electrochemical synthesis of poly(trisulfides). J. Am. Chem. Soc. 145, 11798–11810 (2023).

    Article  CAS  PubMed  Google Scholar 

  47. Mann, M. et al. Integrated methods for gold leaching and recovery from ore and electronic waste. Nat. Sustain. 8, 947–956 (2025).

    Article  Google Scholar 

  48. Nicholls, T. P. et al. Making and un-making poly(trisulfides) with light: precise regulation of radical concentrations via pulsed LED irradiation. J. Am. Chem. Soc. 147, 46243–46258 (2025).

    Article  CAS  PubMed  Google Scholar 

  49. Chung, W. J. et al. The use of elemental sulfur as an alternative feedstock for polymeric materials. Nat. Chem. 5, 518–524 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Häußler, M., Eck, M., Rothauer, D. & Mecking, S. Closed-loop recycling of polyethylene-like materials. Nature 590, 423–427 (2021).

    Article  PubMed  Google Scholar 

  51. Eck, M. & Mecking, S. Closed-loop recyclable and nonpersistent polyethylene-like polyesters. Acc. Chem. Res. 57, 971–980 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, X. et al. Catalytic closed-loop recycling of polyethylene-like materials produced by acceptorless dehydrogenative polymerization of bio-derived diols. Nat. Chem. 17, 500–506 (2025).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Australian Research Council for funding (DP200100090 to J.M.C., DP230100587 to J.M.C., Z.J. and T.H., DP240100555 to M.L.C., FT220100054 to J.M.C., FT240100330 to W.M.B. and CE230100021 to M.L.C.), generous allocations at the National Facility of the Australian National Computational Infrastructure (M.L.C.) and support from the Flinders University High Impact Collaborative Research Development Fund (M.L.C., J.M.C. and Z.J.). We acknowledge the equipment and technical expertise provided by Flinders Microscopy and Microanalysis (FMMA), Adelaide Microscopy and Microscopy Australia. This research was undertaken in part using the MX1 and MX2 beamlines at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We thank J. Xu, K. Hakobyan, A. Birvé, J. Pople and S. Fraser-Miller for technical assistance. J. Beves is acknowledged for useful suggestions regarding dynamic covalent chemistry. The funders of this research had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Harshal D. Patel, Alfrets D. Tikoalu, James N. Smith, Zhipeng Pei.

Authors and Affiliations

  1. College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia

    Harshal D. Patel, Alfrets D. Tikoalu, James N. Smith, Zhipeng Pei, Samuel J. Tonkin, Ryan Shapter, Steven Tsoukatos, Witold M. Bloch, Martin R. Johnston, Michael V. Perkins, Michelle L. Coote, Zhongfan Jia & Justin M. Chalker

  2. Department of Chemistry, University of Liverpool, Liverpool, UK

    Peiyao Yan & Tom Hasell

  3. Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia

    Jeffrey R. Harmer

  4. Flinders Microscopy and Microanalysis, College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia

    Christopher T. Gibson

  5. Adelaide Microscopy, The University of Adelaide, Adelaide, South Australia, Australia

    Christopher T. Gibson

Authors
  1. Harshal D. Patel
    View author publications

    Search author on:PubMed Google Scholar

  2. Alfrets D. Tikoalu
    View author publications

    Search author on:PubMed Google Scholar

  3. James N. Smith
    View author publications

    Search author on:PubMed Google Scholar

  4. Zhipeng Pei
    View author publications

    Search author on:PubMed Google Scholar

  5. Samuel J. Tonkin
    View author publications

    Search author on:PubMed Google Scholar

  6. Ryan Shapter
    View author publications

    Search author on:PubMed Google Scholar

  7. Peiyao Yan
    View author publications

    Search author on:PubMed Google Scholar

  8. Steven Tsoukatos
    View author publications

    Search author on:PubMed Google Scholar

  9. Witold M. Bloch
    View author publications

    Search author on:PubMed Google Scholar

  10. Martin R. Johnston
    View author publications

    Search author on:PubMed Google Scholar

  11. Jeffrey R. Harmer
    View author publications

    Search author on:PubMed Google Scholar

  12. Christopher T. Gibson
    View author publications

    Search author on:PubMed Google Scholar

  13. Michael V. Perkins
    View author publications

    Search author on:PubMed Google Scholar

  14. Tom Hasell
    View author publications

    Search author on:PubMed Google Scholar

  15. Michelle L. Coote
    View author publications

    Search author on:PubMed Google Scholar

  16. Zhongfan Jia
    View author publications

    Search author on:PubMed Google Scholar

  17. Justin M. Chalker
    View author publications

    Search author on:PubMed Google Scholar

Contributions

H.D.P. led the metathesis mechanism and substrate scope studies, the calicheamicin modifications, ring-closing and ring-opening metathesis experiments, and S–S metathesis polymerization experiments. A.D.T. contributed to the metathesis mechanism and substrate scope studies, as well as the dynamic combinatorial library synthesis. J.N.S. contributed to the ring-closing and ring-opening metathesis experiments, monomer synthesis and S–S metathesis polymerization experiments. Z.P. contributed to the mechanistic analysis and computational studies. R.S. contributed to the solvent effect studies. S.J.T. and P.Y. discovered the original S–S metathesis phenomenon. S.J.T. carried out mechanical testing of the poly(trisulfide). W.M.B. and M.R.J. contributed to the structural characterization and mechanistic analysis. S.T. and W.M.B. contributed to the X-ray crystallographic analysis, including crystal isolation, data acquisition and refinement. J.R.H. led the EPR studies, supervising H.D.P. and A.D.T. in these experiments. C.T.G. contributed to spectroscopic studies and characterization. M.V.P. and T.H. contributed mechanistic hypotheses, analysis and supervision. M.L.C. led the computational and kinetic studies and mechanistic analysis, and contributed to the polymerization studies and supervision. Z.J. and J.M.C. directed the project and supervised students. The project was conceived by J.M.C., who wrote the paper in close collaboration with Z.J. and M.L.C. All authors contributed to the analysis, critical review and revision of the paper.

Corresponding authors

Correspondence to Michelle L. Coote, Zhongfan Jia or Justin M. Chalker.

Ethics declarations

Competing interests

Provisional patent applications have been filed that cover applications of the trisulfide metathesis disclosed in this study, including the dynamic combinatorial libraries, modification of natural products and chemically recyclable polymers (Australia patent application nos. AU2024900381 and AU2025900199). H.D.P., A.D.T., J.N.S., S.J.T., Z.J. and J.M.C. are inventors on these patents. The other authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Courtney Jenkins, Mike Larsen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information (download PDF )

Supplementary Methods, Discussion, X-ray data and Computational data.

Source data

Source Data Fig. 2 (download ZIP )

GC–MS data and NMR spectra.

Source Data Fig. 3 (download ZIP )

GC–MS data and NMR spectra.

Source Data Fig. 5 (download ZIP )

GC–MS data, LC–MS data and NMR spectra.

Source Data Fig. 6 (download ZIP )

GC–MS data.

Source Data Fig. 7 (download ZIP )

NMR, IR and Raman spectra, and GPC, DSC, TGA, tensile strength and coefficient of friction data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, H.D., Tikoalu, A.D., Smith, J.N. et al. Spontaneous trisulfide metathesis in polar aprotic solvents. Nat. Chem. (2026). https://doi.org/10.1038/s41557-026-02091-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41557-026-02091-z

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing