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Electrochemically driven cross-electrophile coupling of alkyl halides


Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons—those bonded to four other atoms—in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)–carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling—commonly known as cross-electrophile coupling—provides a promising route towards this objective3,4,5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)–carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon–carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.

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Fig. 1: Cross-coupling and XEC for C(sp3)–C(sp3) bond formation.
Fig. 2: Electroreductive coupling of α-halo Bpin with alkyl halides.
Fig. 3: Substrate scope and synthetic application.
Fig. 4: Anode passivation analysis and gram-scale synthesis.

Data availability

All data supporting the findings of this work are available within the paper and its Supplementary Information.


  1. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Everson, D. A. & Weix, D. J. Cross-electrophile coupling: principles of reactivity and selectivity. J. Org. Chem. 79, 4793–4798 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang, X., Dai, Y. & Gong, H. Nickel-catalyzed reductive couplings. Top. Curr. Chem. 374, 43 (2016).

    Article  CAS  Google Scholar 

  5. Lucas, E. L. & Jarvo, E. R. Stereospecific and stereoconvergent cross-couplings between alkyl electrophiles. Nat. Rev. Chem. 1, 0065 (2017).

    Article  CAS  Google Scholar 

  6. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weix, D. J. Methods and mechanisms for cross-electrophile coupling of Csp2 halides with alkyl electrophiles. Acc. Chem. Res. 48, 1767–1775 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cherney, A. H. & Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles. J. Am. Chem. Soc. 136, 14365–14368 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, P., Le, C. C. & MacMillan, D. W. C. Silyl radical activation of alkyl halides in metallaphotoredox catalysis: a unique pathway for cross-electrophile coupling. J. Am. Chem. Soc. 138, 8084–8087 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ackerman, L. K. G., Lovell, M. W. & Weix, D. J. Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates. Nature 524, 454–457 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sanford, A. B. et al. Nickel-catalyzed alkyl−alkyl cross-electrophile coupling reaction of 1,3-dimesylates for the synthesis of alkylcyclopropanes. J. Am. Chem. Soc. 142, 5017–5023 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qian, X., Auffrant, A., Felouat, A. & Gosmini, C. Cobalt-catalyzed reductive allylation of alkyl halides with allylic acetates or carbonates. Angew. Chem. Int. Ed. 50, 10402–10405 (2011).

    Article  CAS  Google Scholar 

  13. Liu, J.-H. et al. Copper-catalyzed reductive cross-coupling of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides. Chem. Eur. J. 20, 15334–15338 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Yu, X., Yang, T., Wang, S., Xu, H. & Gong, H. Nickel-catalyzed reductive cross-coupling of unactivated alkyl halides. Org. Lett. 13, 2138–2141 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Xu, H., Zhao, C., Qian, Q., Deng, W. & Gong, H. Nickel-catalyzed cross-coupling of unactivated alkyl halides using bis(pinacolato)diboron as reductant. Chem. Sci. 4, 4022–4029 (2013).

    Article  CAS  Google Scholar 

  16. Smith, R. T. et al. Metallaphotoredox-catalyzed cross-electrophile Csp3−Csp3 coupling of aliphatic bromides. J. Am. Chem. Soc. 140, 17433–17438 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Diccianni, J. B., Katigbak, J., Hu, C. & Diao, T. Mechanistic characterization of (xantphos)Ni(I)-mediated alkyl bromide activation: oxidative addition, electron transfer, or halogen-atom abstraction. J. Am. Chem. Soc. 141, 1788–1796 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Wang, J., Gong, Y., Sun, D. & Gong, H. Nickel-catalyzed reductive benzylation of tertiary alkyl halides with benzyl chlorides and chloroformates. Org. Chem. Front. 8, 2944–2948 (2021).

    Article  CAS  Google Scholar 

  19. Chen, H., Jia, X., Yu, Y., Qian, Q. & Gong, H. Nickel-catalyzed reductive allylation of tertiary alkyl halides with allylic carbonates. Angew. Chem. Int. Ed. 56, 13103–13106 (2017).

    Article  CAS  Google Scholar 

  20. Xue, W. et al. Nickel-catalyzed formation of quaternary carbon centers using tertiary alkyl electrophiles. Chem. Soc. Rev. 50, 4162–4184 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Clayden, J., Greeves, N. & Warren, S. Organic Chemistry 2nd edn (Oxford Univ. Press, 2012).

  22. Vasudevan, D. Direct and indirect electrochemical reduction of organic halides in aprotic media. Russ. J. Electrochem. 41, 310–314 (2005).

    Article  CAS  Google Scholar 

  23. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moeller, K. D. Synthetic applications of anodic electrochemistry. Tetrahedron 56, 9527–9554 (2000).

    Article  CAS  Google Scholar 

  25. Cleary, J. A., Mubarak, M. S., Vieira, K. L., Anderson, M. R. & Peters, D. G. Electrochemical reduction of alkyl halides at vitreous carbon cathodes in dimethylformamide. J. Electroanal. Chem. Interfacial Electrochem. 198, 107–124 (1986).

    Article  CAS  Google Scholar 

  26. Chaussard, J. et al. Use of sacrificial anodes in electrochemical functionalization of organic halides. Synthesis 1990, 369–381 (1990).

    Article  Google Scholar 

  27. Nedelec, J. Y., Ait-Haddou-Mouloud, H., Folest, J. C. & Perichon, J. Electrochemical cross-coupling of alkyl halides in the presence of a sacrificial anode. J. Org. Chem. 53, 4720–4724 (1988).

    Article  CAS  Google Scholar 

  28. Andrieux, C. P., Gallardo, I. & Saveant, J. M. Outer-sphere electron-transfer reduction of alkyl halides. A source of alkyl radicals or of carbanions? Reduction of alkyl radicals. J. Am. Chem. Soc. 111, 1620–1626 (1989).

    Article  CAS  Google Scholar 

  29. Knochel, P. New approach to boron-stabilized organometallics. J. Am. Chem. Soc. 112, 7431–7433 (1990).

    Article  CAS  Google Scholar 

  30. Matteson, D. S. α-Halo boronic esters: intermediates for stereodirected synthesis. Chem. Rev. 89, 1535–1551 (1989).

    Article  CAS  Google Scholar 

  31. Schmidt, J., Choi, J., Liu, A. T., Slusarczyk, M. & Fu, G. C. A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters. Science 354, 1265–1269 (2016).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sun, S.-Z., Börjesson, M., MartinMontero, R. & Martin, R. Site-selective Ni-catalyzed reductive coupling of α-haloboranes with unactivated olefins. J. Am. Chem. Soc. 140, 12765–12769 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).

    Article  CAS  Google Scholar 

  34. Li, C. et al. Decarboxylative borylation. Science 356, eaam7355 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fawcett, A. et al. Photoinduced decarboxylative borylation of carboxylic acids. Science 357, 283–286 (2017).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Yang, Y. et al. Practical and modular construction of C(sp3)‑rich alkyl boron compounds. J. Am. Chem. Soc. 143, 471–480 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Bera, S., Mao, R. & Hu, X. Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis. Nat. Chem. 13, 270–277 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Hong, K., Liu, X. & Morken, J. P. Simple access to elusive α-boryl carbanions and their alkylation: an umpolung construction for organic synthesis. J. Am. Chem. Soc. 136, 10581–10584 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kischkewitz, M., Okamoto, K., Mück-Lichtenfeld, C. & Studer, A. Radical-polar crossover reactions of vinylboron ate complexes. Science 355, 936–938 (2017).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Collins, B. S. L., Wilson, C. M., Myers, E. L. & Aggarwal, V. K. Asymmetric synthesis of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 56, 11700–11733 (2017).

    Article  CAS  Google Scholar 

  41. Hofstra, J. L., Cherney, A. H., Ordner, C. M. & Reisman, S. E. Synthesis of enantioenriched allylic silanes via nickel-catalyzed reductive cross-coupling. J. Am. Chem. Soc. 140, 139–142 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, L. et al. C–O functionalization of α-oxyboronates: a deoxygenative gem-diborylation and gem-silylborylation of aldehydes and ketones. J. Am. Chem. Soc. 139, 5257–5264 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Hazrati, H. & Oestreich, M. Copper-catalyzed double C(sp3)–Si coupling of geminal dibromides: ionic-to-radical switch in the reaction mechanism. Org. Lett. 20, 5367–5369 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Vasilopoulos, A., Krska, S. W. & Stahl, S. S. C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling. Science 372, 398–403 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. McMillan, A. J. et al. Practical and selective sp3 C−H bond chlorination via aminium radicals. Angew. Chem. Int. Ed. 60, 7132–7139 (2021).

    Article  CAS  Google Scholar 

  46. Bishop, J. L., Quinn, R. & Dyar, M. D. Spectral and thermal properties of perchlorate salts and implications for Mars. Am. Mineral. 99, 1580–1592 (2014).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  47. Xue, W., Shishido, R. & Oestreich, M. Bench-stable stock solutions of silicon Grignard reagents: application to iron- and cobalt-catalyzed radical C(sp3)–Si cross-coupling reactions. Angew. Chem. Int. Ed. 57, 12141–12145 (2018).

    Article  CAS  Google Scholar 

  48. Chan, C.-Y., Lepeshkov, I. N. & Khoo, K. H. (eds) Alkaline Earth Metal Perchlorates (Solubility Data Series, Pergamon, 1989).

  49. Okoshi, M., Yamada, Y., Yamada, A. & Nakai, H. Theoretical analysis on de-solvation of lithium, sodium, and magnesium cations to organic electrolyte solvents. J. Electrochem. Soc. 160, A2160–A2165 (2013).

    Article  CAS  Google Scholar 

  50. Shao, Y. et al. Coordination chemistry in magnesium battery electrolytes: how ligands affect their performance. Sci. Rep. 3, 3130 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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Financial support was provided by NIGMS (R01GM134088; to S.L.), NSF Center for Synthetic Organic Electrochemistry (CHE-2002158; to K.A.S.), and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S.L. is grateful to the Research Corporation for Science Advancement for a Cottrell Scholar Award. This study made use of the NMR facility supported by the NSF (CHE-1531632). XPS data were collected at the Molecular Materials Research Center in the Beckman Institute of the California Institute of Technology. We thank C. Yang for providing propargylic chloride substrates.

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Authors and Affiliations



S.L. and K.A.S. supervised the project. N.S. and D.L. provided guidance on the project. Wen Zhang and S.L. conceived the work. Wen Zhang, L.L., N.S., D.L. and S.L. designed the experiments. Wen Zhang. and L.L. conducted the synthetic experiments and mechanism studies. Wendy Zhang, S.D.W. and K.A.S. conducted the analysis of electrode passivation. Y.W., J.M. and J.R. conducted the density functional theory calculations. Wen Zhang, L.L., Wendy Zhang, K.A.S. and S.L. wrote the manuscript. N.S., D.L. and S.D.W. edited the manuscript.

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Correspondence to Kimberly A. See or Song Lin.

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This file contains Supplementary Sections 1–20, including Supplementary text, data, tables and figures and NMR spectra data—see contents page for details.

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Zhang, W., Lu, L., Zhang, W. et al. Electrochemically driven cross-electrophile coupling of alkyl halides. Nature 604, 292–297 (2022).

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