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:

Anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons using iron photocatalysis

Nature Synthesis volume 4, pages 314–326 (2025)Cite this article

Subjects

Abstract

The hydrochlorination of unsaturated hydrocarbons is a fundamental reaction in organic synthesis. Traditional acid-mediated approaches proceed with Markovnikov selectivity, but direct access to anti-Markovnikov hydrochlorination products is still a longstanding pursuit. Previous methods are restricted by the need for multiple synthetic steps, stoichiometric chlorine and hydride sources and/or highly oxidative photocatalysis, resulting in limited scope and, in some cases, low regioselectivity. So, the development of redox-neutral hydrochlorination with high anti-Markovnikov regioselectivity compatible with both alkenes and alkynes remains important. Here we report a photocatalytic anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons enabling access to diverse alkyl and alkenyl chlorides regio- and stereoselectively. Broad scope (125 examples), mild conditions and regio- and isotopo-divergent syntheses are demonstrated. Key to this method is the combination use of ligand-to-metal charge transfer photoreactivity of earth-abundant iron and hydrogen atom transfer reactivity of redox-active thiol. This cooperative system offers a powerful strategy for anti-Markovnikov hydrofunctionalization of unsaturated hydrocarbons.

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: Previous strategies for anti-Markovnikov hydrochlorination and the design of cooperative iron and thiol catalysis for hydrochlorination of unsaturated hydrocarbons.
Fig. 2: Scope of hydrochlorination of alkenes.
Fig. 3: Scope of deuterochlorination of alkenes.
Fig. 4: Scope of hydrochlorination and dichlorination of alkynes.
Fig. 5: Scope of anti-Markovnikov deuterochlorination of alkynes.
Fig. 6: Gram-scale synthesis and mechanistic studies.

Similar content being viewed by others

Data availability

The data supporting the findings of this research are available within the article and its Supplementary Information.

References

  1. Gribble, G. W. in Naturally Occurring Organohalogen Compounds—A Comprehensive Update 349–365 (Springer, 2010).

  2. Hernandes, Z. M., Cavalcanti, T. S. M., Moreira, M. D. R., de Azevedo Junior, F. W. & Leite, L. A. C. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr. Drug Targets 11, 303–314 (2010).

    PubMed  CAS  Google Scholar 

  3. Tang, M. L. & Bao, Z. Halogenated materials as organic semiconductors. Chem. Mater. 23, 446–455 (2011).

    CAS  Google Scholar 

  4. Nunnery, J. K. et al. Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J. Org. Chem. 77, 4198–4208 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  5. Togo, H. in Advanced Free Radical Reactions for Organic Synthesis (Elsevier, 2004).

  6. Carey, F. A. & Sundberg, R. J. in Advanced Organic Chemistry: Part A: Structure and Mechanisms 1–117 (Springer, 2007).

  7. Terao, J. & Kambe, N. Cross-coupling reaction of alkyl halides with grignard reagents catalyzed by Ni, Pd, or Cu Complexes with π-carbon ligand(s). Acc. Chem. Res. 41, 1545–1554 (2008).

    PubMed  CAS  Google Scholar 

  8. Rudolph, A. & Lautens, M. Secondary alkyl halides in transition-metal-catalyzed cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).

    CAS  Google Scholar 

  9. Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Johansson Seechurn, C. C. C., Kitching, M. O., Colacot, T. J. & Snieckus, V. Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 51, 5062–5085 (2012).

    Google Scholar 

  11. Markownikoff, W. I. Ueber die Abhängigkeit der verschiedenen Vertretbarkeit des Radicalwasserstoffs in den isomeren Buttersäuren. Justus Liebigs Ann. Chem. 153, 228–259 (1870).

    Google Scholar 

  12. Kharasch, M. S. & Mayo, F. R. The peroxide effect in the addition of reagents to unsaturated compounds. I. The addition of hydrogen bromide to allyl bromide. JACS 55, 2468–2496 (1933).

    CAS  Google Scholar 

  13. Blanksby, S. J. & Ellison, G. B. Bond dissociation energies of organic molecules. Acc. Chem. Res. 36, 255–263 (2003).

    PubMed  CAS  Google Scholar 

  14. Mayo, F. R. Free radical addition and transfer reactions of hydrogen chloride with unsaturated compounds. JACS 76, 5392–5396 (1954).

    CAS  Google Scholar 

  15. Brown, H. C. & De Lue, N. R. Organoboranes for synthesis. 12. The reaction of organoboranes with nitrogen trichloride. A convenient procedure for the conversion of alkenes into alkyl chloridesvia hydroborationi. Tetrahedron 44, 2785–2792 (1988).

    CAS  Google Scholar 

  16. Zheng, J. et al. Synthesis of diverse well-defined functional polymers based on hydrozirconation and subsequent anti-markovnikov halogenation of 1,2-polybutadiene. Macromolecules 45, 1190–1197 (2012).

    CAS  Google Scholar 

  17. Appel, R. Tertiary phosphane/tetrachloromethane, a versatile reagent for chlorination, dehydration, and P–N linkage. Angew. Chem. Int. Ed. Engl. 14, 801–811 (1975).

    Google Scholar 

  18. Wilger, D. J., Grandjean, J.-M. M., Lammert, T. R. & Nicewicz, D. A. The direct anti-Markovnikov addition of mineral acids to styrenes. Nat. Chem. 6, 720–726 (2014).

    PubMed  CAS  Google Scholar 

  19. Margrey, K. A. & Nicewicz, D. A. A general approach to catalytic alkene anti-markovnikov hydrofunctionalization reactions via acridinium photoredox catalysis. Acc. Chem. Res. 49, 1997–2006 (2016).

    PubMed  CAS  Google Scholar 

  20. Li, X., Jin, J., Chen, P. & Liu, G. Catalytic remote hydrohalogenation of internal alkenes. Nat. Chem. 14, 425–432 (2022).

    PubMed  CAS  Google Scholar 

  21. Kim, J., Sun, X., van der Worp, B. A. & Ritter, T. Anti-Markovnikov hydrochlorination and hydronitrooxylation of α-olefins via visible-light photocatalysis. Nat. Catal. 6, 196–203 (2023).

    CAS  Google Scholar 

  22. Petrone, D. A., Ye, J. & Lautens, M. Modern transition-metal-catalyzed carbon–halogen bond formation. Chem. Rev. 116, 8003–8104 (2016).

    PubMed  CAS  Google Scholar 

  23. Gaspar, B. & Carreira, E. M. Catalytic hydrochlorination of unactivated olefins with para-toluenesulfonyl chloride. Angew. Chem. Int. Ed. 47, 5758–5760 (2008).

    CAS  Google Scholar 

  24. Dérien, S., Klein, H. & Bruneau, C. Selective ruthenium-catalyzed hydrochlorination of alkynes: one-step synthesis of vinylchlorides. Angew. Chem. Int. Ed. 54, 12112–12115 (2015).

    Google Scholar 

  25. Ebule, R., Liang, S., Hammond, G. B. & Xu, B. Chloride-tolerant gold(I)-catalyzed regioselective hydrochlorination of alkynes. ACS Catal. 7, 6798–6801 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Derosa, J. et al. Palladium(II)-catalyzed directed anti-hydrochlorination of unactivated alkynes with HCl. JACS 139, 5183–5193 (2017).

    CAS  Google Scholar 

  27. Yu, P., Bismuto, A. & Morandi, B. Iridium-catalyzed hydrochlorination and hydrobromination of alkynes by shuttle catalysis. Angew. Chem. Int. Ed. 59, 2904–2910 (2020).

    CAS  Google Scholar 

  28. Koh, M. J., Nguyen, T. T., Zhang, H., Schrock, R. R. & Hoveyda, A. H. Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis. Nature 531, 459–465 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Abderrazak, Y., Bhattacharyya, A. & Reiser, O. Visible-light-induced homolysis of earth-abundant metal-substrate complexes: a complementary activation strategy in photoredox catalysis. Angew. Chem. Int. Ed. 60, 21100–21115 (2021).

    CAS  Google Scholar 

  30. Juliá, F. Ligand-to-metal charge transfer (LMCT) photochemistry at 3d-metal complexes: an emerging tool for sustainable organic synthesis. ChemCatChem 14, e202200916 (2022).

    Google Scholar 

  31. Kochi, J. K. Photolyses of metal compounds: cupric chloride in organic media. JACS 84, 2121–2127 (1962).

    CAS  Google Scholar 

  32. Shul’pin, G. B., Druzhinina, A. N. & Shul’pina, L. S. Photo-oxidation of cyclohexane by air in acetonitrile, catalysed by π-complexes of iron. Pet. Chem. 33, 321–325 (1993).

    Google Scholar 

  33. Giedyk, M., Goliszewska, K. & Gryko, D. Vitamin B12 catalysed reactions. Chem. Soc. Rev. 44, 3391–3404 (2015).

    PubMed  CAS  Google Scholar 

  34. Shields, B. J. & Doyle, A. G. Direct C(sp3)–H cross coupling enabled by catalytic generation of chlorine radicals. JACS 138, 12719–12722 (2016).

    CAS  Google Scholar 

  35. Hossain, A., Bhattacharyya, A. & Reiser, O. Copper’s rapid ascent in visible-light photoredox catalysis. Science 364, eaav9713 (2019).

    PubMed  Google Scholar 

  36. de Groot, L. H. M., Ilic, A., Schwarz, J. & Wärnmark, K. Iron photoredox catalysis—past, present, and future. JACS 145, 9369–9388 (2023).

    Google Scholar 

  37. Heitz, D. R., Tellis, J. C. & Molander, G. A. Photochemical nickel-catalyzed C–H arylation: synthetic scope and mechanistic investigations. JACS 138, 12715–12718 (2016).

    CAS  Google Scholar 

  38. Lian, P., Long, W., Li, J., Zheng, Y. & Wan, X. Visible-light-induced vicinal dichlorination of alkenes through LMCT excitation of CuCl2. Angew. Chem. Int. Ed. 59, 23603–23608 (2020).

    CAS  Google Scholar 

  39. Chábera, P. et al. A low-spin Fe(III) complex with 100-ps ligand-to-metal charge transfer photoluminescence. Nature 543, 695–699 (2017).

    PubMed  Google Scholar 

  40. Li, Z., Wang, X., Xia, S. & Jin, J. Ligand-accelerated iron photocatalysis enabling decarboxylative alkylation of heteroarenes. Org. Lett. 21, 4259–4265 (2019).

    PubMed  CAS  Google Scholar 

  41. Gygi, D. et al. Capturing the complete reaction profile of a C–H bond activation. JACS 143, 6060–6064 (2021).

    CAS  Google Scholar 

  42. Jin, Y. et al. Photo-induced direct alkynylation of methane and other light alkanes by iron catalysis. Green Chem. 23, 9406–9411 (2021).

    CAS  Google Scholar 

  43. Kang, Y. C., Treacy, S. M. & Rovis, T. Iron-catalyzed photoinduced LMCT: a 1 °C–H abstraction enables skeletal rearrangements and C(sp3)–H alkylation. ACS Catal. 11, 7442–7449 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Wang, M., Wen, J., Huang, Y. & Hu, P. Selective degradation of styrene-related plastics catalyzed by iron under visible light. ChemSusChem 14, 5049–5056 (2021).

    PubMed  CAS  Google Scholar 

  45. Zhang, G., Zhang, Z. & Zeng, R. Photoinduced FeCl3-catalyzed alkyl aromatics oxidation toward degradation of polystyrene at room temperature. Chin. J. Chem. 39, 3225–3230 (2021).

    CAS  Google Scholar 

  46. Dai, Z.-Y., Zhang, S.-Q., Hong, X., Wang, P.-S. & Gong, L.-Z. A practical FeCl3/HCl photocatalyst for versatile aliphatic C–H functionalization. Chem. Catal. 2, 1211–1222 (2022).

    CAS  Google Scholar 

  47. Tu, J.-L., Hu, A.-M., Guo, L. & Xia, W. Iron-catalyzed C(sp3)–H borylation, thiolation, and sulfinylation enabled by photoinduced ligand-to-metal charge transfer. JACS 145, 7600–7611 (2023).

    CAS  Google Scholar 

  48. Gonzalez, M. I. et al. Taming the chlorine radical: enforcing steric control over chlorine-radical-mediated C–H activation. JACS 144, 1464–1472 (2022).

    CAS  Google Scholar 

  49. Niu, B., Sachidanandan, K., Blackburn, B. G., Cooke, M. V. & Laulhé, S. Photoredox polyfluoroarylation of alkyl halides via halogen atom transfer. Org. Lett. 24, 916–920 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  50. Oh, S. & Stache, E. E. Chemical upcycling of commercial polystyrene via catalyst-controlled photooxidation. JACS 144, 5745–5749 (2022).

    CAS  Google Scholar 

  51. Zhang, Q. et al. Iron-catalyzed photoredox functionalization of methane and heavier gaseous alkanes: scope, kinetics, and computational studies. Org. Lett. 24, 1901–1906 (2022).

    PubMed  CAS  Google Scholar 

  52. Bian, K.-J., Kao, S.-C., Nemoto, D., Chen, X.-W. & West, J. G. Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Nat. Commun. 13, 7881 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Bian, K.-J. et al. Photocatalytic, modular difunctionalization of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Chem. Sci. 15, 124–133 (2023).

    PubMed  PubMed Central  Google Scholar 

  54. Kao, S.-C. et al. Photochemical iron-catalyzed decarboxylative azidation via the merger of ligand-to-metal charge transfer and radical ligand transfer catalysis. Chem. Catal. 3, 100603 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  55. Lu, Y.-C. & West, J. G. Chemoselective decarboxylative protonation enabled by cooperative earth-abundant element catalysis. Angew. Chem. Int. Ed. 62, e202213055 (2023).

    CAS  Google Scholar 

  56. Bian, K.-J. et al. Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids. Nat. Chem. 15, 1683–1692 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Isse, A. A., Lin, C. Y., Coote, M. L. & Gennaro, A. Estimation of standard reduction potentials of halogen atoms and alkyl halides. J. Phys. Chem. B 115, 678–684 (2011).

    PubMed  CAS  Google Scholar 

  58. Börgel, J. & Ritter, T. Late-stage functionalization. Chem 6, 1877–1887 (2020).

    Google Scholar 

  59. Soulard, V., Villa, G., Vollmar, D. P. & Renaud, P. Radical deuteration with D2O: catalysis and mechanistic insights. JACS 140, 155–158 (2018).

    CAS  Google Scholar 

  60. Shi, Q. et al. Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions. Nat. Commun. 13, 4453 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  61. Zhu, Z., Qian, S. & Nicewicz, D. A. Divergent functionalization of alkynes enabled by organic photoredox catalysis. Synlett 34, 1023–1028 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  62. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge financial support from CPRIT (RR190025), NIH (R35GM142738), the Welch Foundation (C-2085), RCSA (CS-CSA-2023-007), and ACS-PRF (62397-DNI1). J.G.W. is a CPRIT Scholar in Cancer Research. Y. H. Rezenom (TAMU/LBMS), I. M Riddington (UT Austin Mass Spectrometry Facility) and C. L. Pennington (Rice University Mass Spectrometry Facility) are acknowledged for assistance with mass spectrometry analysis.

Author information

Authors and Affiliations

  1. Department of Chemistry, Rice University, Houston, TX, USA

    Kang-Jie Bian, David Nemoto Jr, Ying Chen, Yen-Chu Lu, Shih-Chieh Kao, Xiao-Wei Chen, Angel A. Martí & Julian G. West

  2. Department of Materials Science and Nanoengineering, Rice University, Houston, TX, USA

    Ying Chen & Angel A. Martí

  3. Department of Bioengineering, Rice University, Houston, TX, USA

    Ying Chen & Angel A. Martí

Authors
  1. Kang-Jie Bian
    View author publications

    Search author on:PubMed Google Scholar

  2. David Nemoto Jr
    View author publications

    Search author on:PubMed Google Scholar

  3. Ying Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Yen-Chu Lu
    View author publications

    Search author on:PubMed Google Scholar

  5. Shih-Chieh Kao
    View author publications

    Search author on:PubMed Google Scholar

  6. Xiao-Wei Chen
    View author publications

    Search author on:PubMed Google Scholar

  7. Angel A. Martí
    View author publications

    Search author on:PubMed Google Scholar

  8. Julian G. West
    View author publications

    Search author on:PubMed Google Scholar

Contributions

K.-J.B. and J.G.W. designed the project. K.-J.B., D.N.Jr., Y.C., Y.-C.L., S.-C.K. and X.-W.C. performed the experiments. K.-J.B., D.N.Jr. and J.G.W. wrote the paper. J.G.W. directed the project. All authors interpreted the results in the paper.

Corresponding author

Correspondence to Julian G. West.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Additional information

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

Supplementary information

Supplementary Information

Supplementary methods, discussion, figures and references.

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

Bian, KJ., Nemoto, D., Chen, Y. et al. Anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons using iron photocatalysis. Nat. Synth 4, 314–326 (2025). https://doi.org/10.1038/s44160-024-00698-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s44160-024-00698-z

This article is cited by

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