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The interplay of polar effects in controlling the selectivity of radical reactions

Abstract

Radical reactivity is a powerful tool for molecular construction that often provides bond-forming strategies and retrosynthetic disconnections complementary to those available through ionic and metal-mediated approaches. Understanding reactivity and selectivity patterns in radical chemistry is crucial to harness and develop the full potential of open-shell species in synthetic settings. Polar effects operate at the transition-state level of all radical reactions and have important implications in controlling their outcomes. The recognition of the key factors that respond to polar effects can be used to understand reactivity trends and also to rationally enhance (or mute) the intrinsic reactivity of specific molecular sites over others. These features render radical reactivity easy to predict and, therefore, programmable. In this Review we highlight some of the key underlining mechanistic features associated with polar effects and we accompany our discussion with representative synthetic examples.

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Fig. 1: Polar effects control the outcome of radical reactions.
Fig. 2: Synthetic examples of site-selective C(sp3)–H functionalization by HAT.
Fig. 3: Synthetic examples of selective late-stage C(sp3)–H functionalizations of complex and bioactive materials.
Fig. 4: Difference in HAT reactivity upon amine protonation.
Fig. 5: Strategies to increase the reactivity of C(sp3)–H bonds in HAT processes.
Fig. 6: Example of polar effects in strategies for XAT.
Fig. 7: Site selectivity controlled by polar effects in homolytic aromatic substitutions with electrophilic radicals and electron-rich arenes.
Fig. 8: Site selectivity in Minisci reactions.

References

  1. Zard, S. Z. Radicals in action: a festival of radical transformations. Org. Lett. 19, 1257–1269 (2017).

    Article  CAS  Google Scholar 

  2. Beckwith, A. L. J. Centenary lecture. The pursuit of selectivity in radical reactions. Chem. Soc. Rev. 22, 143–151 (1993).

    Article  CAS  Google Scholar 

  3. Dixon, D. A. & Garrett, B. C. Role of water in electron-initiated processes and radical chemistry: issues and scientific advances. Chem. Rev. 105, 355–390 (2005).

    Article  PubMed  CAS  Google Scholar 

  4. Héberger, K. & Lopata, A. Assessment of nucleophilicity and electrophilicity of radicals, and of polar and enthalpy effects on radical addition reactions. J. Org. Chem. 63, 8646–8653 (1998).

    Article  Google Scholar 

  5. Tedder, J. M. Which factors determine the reactivity and regioselectivity of free radical substitution and addition reactions? Angew. Chem. Int. Ed. 21, 401–410 (1982).

    Article  Google Scholar 

  6. Parsaee, F. et al. Radical philicity and its role in selective organic transformations. Nat. Rev. Chem. 5, 486–499 (2021).

    Article  CAS  Google Scholar 

  7. Wong, M. W., Pross, A. & Radom, L. Are polar interactions important in the addition of methyl radical to alkenes? J. Am. Chem. Soc. 115, 11050–11051 (1993).

    Article  CAS  Google Scholar 

  8. Tedder, J. M. & Walton, J. C. The importance of polarity and steric effects in determining the rate and orientation of free radical addition to olefins: rules for determining the rate and preferred orientation. Tetrahedron 36, 701–707 (1980).

    Article  CAS  Google Scholar 

  9. Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–135 (1999).

    Article  CAS  Google Scholar 

  10. Rüchardt, C. Relations between structure and reactivity in free-radical chemistry. Angew. Chem. Int. Ed. 9, 830–843 (1970).

    Article  Google Scholar 

  11. Chan, B., Easton, C. J. & Radom, L. Outcome-changing effect of polarity reversal in hydrogen-atom-abstraction reactions. J. Phys. Chem. A 119, 3843–3847 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Finn, M., Friedline, R., Suleman, N. K., Wohl, C. J. & Tanko, J. M. Chemistry of the t-butoxyl radical: evidence that most hydrogen abstractions from carbon are entropy-controlled. J. Am. Chem. Soc. 126, 7578–7584 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Jones, M. J., Moad, G., Rizzardo, E. & Solomon, D. H. The philicity of tert-butoxy radicals. What factors are important in determining the rate and regiospecificity of tert-butoxy radical addition to olefins? J. Org. Chem. 54, 1607–1611 (1989).

    Article  CAS  Google Scholar 

  14. Kamigata, N., Udodaira, K. & Shimizu, T. Reactions of perfluoroalkane-sulfonyl chlorides with silyl enol ethers catalyzed by a ruthenium(II) phosphine complex. Phosphorus Sulfur Silicon Relat. Elem. 129, 155–168 (1997).

    Article  CAS  Google Scholar 

  15. Koike, T. & Akita, M. New horizons of photocatalytic fluoromethylative difunctionalization of alkenes. Chem. 4, 409–437 (2018).

    Article  CAS  Google Scholar 

  16. Zipse, H. in Radicals in Synthesis I, Vol. 263 (ed. Gansäuer, A.) 163–189 (Springer, 2006).

  17. Ni, C. & Hu, J. The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. Chem. Soc. Rev. 45, 5441–5454 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Bietti, M. Activation and deactivation strategies promoted by medium effects for selective aliphatic C–H bond functionalization. Angew. Chem. Int. Ed. 57, 16618–16637 (2018).

    Article  CAS  Google Scholar 

  19. Asensio, G., Gonzalez-Nunez, M. E., Bernardini, C. B., Mello, R. & Adam, W. Regioselective oxyfunctionalization of unactivated tertiary and secondary carbon–hydrogen bonds of alkylamines by methyl(trifluoromethyl)dioxirane in acid medium. J. Am. Chem. Soc. 115, 7250–7253 (1993).

    Article  CAS  Google Scholar 

  20. Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. White, M. C. & Zhao, J. Aliphatic C–H oxidations for late-stage functionalization. J. Am. Chem. Soc. 140, 13988–14009 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds 1st edn (CRC, 2002).

  23. Newhouse, T. & Baran, P. S. If C–H bonds could talk: selective C–H bond oxidation. Angew. Chem. Int. Ed. 50, 3362–3374 (2011).

    Article  CAS  Google Scholar 

  24. Hartwig, J. F. Evolution of C–H bond functionalization from methane to methodology. J. Am. Chem. Soc. 138, 2–24 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Zielinski, Z. A. M. & Pratt, D. A. Lipid peroxidation: kinetics, mechanisms, and products. J. Org. Chem. 82, 2817–2825 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Genovino, J., Sames, D., Hamann, L. G. & Touré, B. B. Accessing drug metabolites via transition-metal catalyzed C–H oxidation: the liver as synthetic inspiration. Angew. Chem. Int. Ed. 55, 14218–14238 (2016).

    Article  CAS  Google Scholar 

  27. Mayer, J. M. Understanding hydrogen atom transfer: from bond strengths to Marcus theory. Acc. Chem. Res. 44, 36–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Paul, V. & Roberts, B. P. Polarity reversal catalysis of hydrogen atom abstraction reactions. J. Chem. Soc. Chem. Commun. 1322–1324 (1987).

  29. Cao, H., Tang, X., Tang, H., Yuan, Y. & Wu, J. Photoinduced intermolecular hydrogen atom transfer reactions in organic synthesis. Chem Catal. 1, 523–598 (2021).

    Article  Google Scholar 

  30. Griffin, J. D., Vogt, D. B., Du Bois, J. & Sigman, M. S. Mechanistic guidance leads to enhanced site-selectivity in C–H oxidation reactions catalyzed by ruthenium bis(bipyridine) complexes. ACS Catal. 11, 10479–10486 (2021).

    Article  CAS  Google Scholar 

  31. Sun, W. & Sun, Q. Bioinspired manganese and iron complexes for enantioselective oxidation reactions: ligand design, catalytic activity, and beyond. Acc. Chem. Res. 52, 2370–2381 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 547, 79–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Salamone, M. et al. Bimodal Evans–Polanyi relationships in hydrogen atom transfer from C(sp3)–H bonds to the cumyloxyl radical. A combined time-resolved kinetic and computational study. J. Am. Chem. Soc. 143, 11759–11776 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shaw, M. H., Shurtleff, V. W., Terrett, J. A., Cuthbertson, J. D. & MacMillan, D. W. Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles. Science 352, 1304–1308 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kamijo, S., Hoshikawa, T. & Inoue, M. Photochemically induced radical transformation of C(sp3)–H bonds to C(sp3)–CN bonds. Org. Lett. 13, 5928–5931 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lei, G., Xu, M., Chang, R., Funes-Ardoiz, I. & Ye, J. Hydroalkylation of unactivated olefins via visible-light-driven dual hydrogen atom transfer catalysis. J. Am. Chem. Soc. 143, 11251–11261 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Leibler, I. N.-M., Tekle-Smith, M. A. & Doyle, A. G. A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor. Nat. Commun. 12, 6950–6959 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim, K. E., Adams, A. M., Chiappini, N. D., Du Bois, J. & Stoltz, B. M. Cyanthiwigin natural product core as a complex molecular scaffold for comparative late-stage C–H functionalization studies. J. Org. Chem. 83, 3023–3033 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Kim, K. E., Kim, A. N., McCormick, C. J. & Stoltz, B. M. Late-stage diversification: a motivating force in organic synthesis. J. Am. Chem. Soc. 143, 16890–16901 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. McNeill, E. & Du Bois, J. Ruthenium-catalyzed hydroxylation of unactivated tertiary C–H bonds. J. Am. Chem. Soc. 132, 10202–10204 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Adams, A. M. & Du Bois, J. Organocatalytic C–H hydroxylation with Oxone® enabled by an aqueous fluoroalcohol solvent system. Chem. Sci. 5, 656–665 (2014).

    Article  CAS  Google Scholar 

  43. Curci, R., D’Accolti, L. & Fusco, C. A novel approach to the efficient oxygenation of hydrocarbons under mild conditions. Superior oxo transfer selectivity using dioxiranes. Acc. Chem. Res. 39, 1–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Sharma, A. & Hartwig, J. F. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Prat, I. et al. The mechanism of stereospecific C–H oxidation by Fe(Pytacn) complexes: bioinspired non-heme iron catalysts containing cis-labile exchangeable sites. Chem. Eur. J. 19, 6724–6738 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, K. & Que, L. Stereospecific alkane hydroxylation by non-heme iron catalysts: mechanistic evidence for an FeV=O active species. J. Am. Chem. Soc. 123, 6327–6337 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Yang, Z., Yu, P. & Houk, K. N. Molecular dynamics of dimethyldioxirane C–H oxidation. J. Am. Chem. Soc. 138, 4237–4242 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Quinn, R. K. et al. Site-selective aliphatic C–H chlorination using N-chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc. 138, 696–702 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135, 14052–14055 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, X., Yang, H. & Tang, P. Transition-metal-free oxidative aliphatic C–H azidation. Org. Lett. 17, 5828–5831 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Bovicelli, P., Lupattelli, P., Mincione, E., Prencipe, T. & Curci, R. Oxidation of natural targets by dioxiranes. 2. Direct hydroxylation at the side-chain C-25 of cholestane derivatives and of vitamin D3 Windaus–Grundmann ketone. J. Org. Chem. 57, 5052–5054 (1992).

    Article  CAS  Google Scholar 

  53. Wender, P. A., Hilinski, M. K. & Mayweg, A. V. W. Late-stage intermolecular C–H activation for lead diversification: a highly chemoselective oxyfunctionalization of the C-9 position of potent bryostatin analogues. Org. Lett. 7, 79–82 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Mack, J. B. C., Gipson, J. D., Du Bois, J. & Sigman, M. S. Ruthenium-catalyzed C–H hydroxylation in aqueous acid enables selective functionalization of amine derivatives. J. Am. Chem. Soc. 139, 9503–9506 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Zhao, J., Nanjo, T., de Lucca, E. C. & White, M. C. Chemoselective methylene oxidation in aromatic molecules. Nat. Chem. 11, 213–221 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Mukherjee, S., Maji, B., Tlahuext-Aca, A. & Glorius, F. Visible-light-promoted activation of unactivated C(sp3)–H bonds and their selective trifluoromethylthiolation. J. Am. Chem. Soc. 138, 16200–16203 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Meyer, T. H., Samanta, R. C., Del Vecchio, A. & Ackermann, L. Mangana(III/IV)electro-catalyzed C(sp3)–H azidation. Chem. Sci. 12, 2890–2897 (2021).

    Article  CAS  Google Scholar 

  59. Niu, L. et al. Manganese-catalyzed oxidative azidation of C(sp3)–H bonds under electrophotocatalytic conditions. J. Am. Chem. Soc. 142, 17693–17702 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Chen, K., Eschenmoser, A. & Baran, P. S. Strain release in C–H bond activation? Angew. Chem. Int. Ed. 48, 9705–9708 (2009).

    Article  CAS  Google Scholar 

  61. Guo, S., Zhang, X. & Tang, P. Silver-mediated oxidative aliphatic C–H trifluoromethylthiolation. Angew. Chem. Int. Ed. 54, 4065–4069 (2015).

    Article  CAS  Google Scholar 

  62. Kee, C. W., Chin, K. F., Wong, M. W. & Tan, C.-H. Selective fluorination of alkyl C–H bonds via photocatalysis. Chem. Commun. 50, 8211–8214 (2014).

    Article  CAS  Google Scholar 

  63. Halperin, S. D., Fan, H., Chang, S., Martin, R. E. & Britton, R. A convenient photocatalytic fluorination of unactivated C–H bonds. Angew. Chem. Int. Ed. 53, 4690–4693 (2014).

    Article  CAS  Google Scholar 

  64. Ravelli, D., Fagnoni, M., Fukuyama, T., Nishikawa, T. & Ryu, I. Site-selective C–H functionalization by decatungstate anion photocatalysis: synergistic control by polar and steric effects expands the reaction scope. ACS Catal. 8, 701–713 (2018).

    Article  CAS  Google Scholar 

  65. Liu, W. et al. Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin. Science 337, 1322–1325 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Huang, X., Bergsten, T. M. & Groves, J. T. Manganese-catalyzed late-stage aliphatic C–H azidation. J. Am. Chem. Soc. 137, 5300–5303 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Bloom, S., Knippel, J. L. & Lectka, T. A photocatalyzed aliphatic fluorination. Chem. Sci. 5, 1175–1178 (2014).

    Article  CAS  Google Scholar 

  68. Saito, M. et al. N-Ammonium ylide mediators for electrochemical C–H oxidation. J. Am. Chem. Soc. 143, 7859–7867 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Perry, I. B. et al. Direct arylation of strong aliphatic C–H bonds. Nature 560, 70–75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schmidt, V. A., Quinn, R. K., Brusoe, A. T. & Alexanian, E. J. Site-selective aliphatic C–H bromination using N-bromoamides and visible light. J. Am. Chem. Soc. 136, 14389–14392 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Czaplyski, W. L., Na, C. G. & Alexanian, E. J. C–H xanthylation: a synthetic platform for alkane functionalization. J. Am. Chem. Soc. 138, 13854–13857 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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 

  73. Mbofana, C. T., Chong, E., Lawniczak, J. & Sanford, M. S. Iron-catalyzed oxyfunctionalization of aliphatic amines at remote benzylic C–H sites. Org. Lett. 18, 4258–4261 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pal, U., Sen, S. & Maiti, N. C. Cα–H carries information of a hydrogen bond involving the geminal hydroxyl group: a case study with a hydrogen-bonded complex of 1,1,1,3,3,3-hexafluoro-2-propanol and tertiary amines. J. Phys. Chem. A 118, 1024–1030 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Gawlita, E. et al. H-bonding in alcohols is reflected in the Cα–H bond strength: variation of C–D vibrational frequency and fractionation factor. J. Am. Chem. Soc. 122, 11660–11669 (2000).

    Article  CAS  Google Scholar 

  76. Salamone, M., Giammarioli, I. & Bietti, M. Tuning hydrogen atom abstraction from the aliphatic C–H bonds of basic substrates by protonation. Control over selectivity by C–H deactivation. Chem. Sci. 4, 3255–3262 (2013).

    Article  CAS  Google Scholar 

  77. 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  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jeffrey, J. L., Terrett, J. A. & MacMillan, D. W. C. O–H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols. Science 349, 1532–1536 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cradlebaugh, J. A. et al. Rate constants for hydrogen abstraction from alkoxides by a perfluoroalkyl radical. An oxyanion accelerated process. Org. Biomol. Chem. 2, 2083–2086 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Dimakos, V., Su, H. Y., Garrett, G. E. & Taylor, M. S. Site-selective and stereoselective C–H alkylations of carbohydrates via combined diarylborinic acid and photoredox catalysis. J. Am. Chem. Soc. 141, 5149–5153 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. Dimakos, V. et al. Site-selective redox isomerizations of furanosides using a combined arylboronic acid/photoredox catalyst system. Chem. Sci. 11, 1531–1537 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Borrell, M., Gil-Caballero, S., Bietti, M. & Costas, M. Site-selective and product chemoselective aliphatic C–H bond hydroxylation of polyhydroxylated substrates. ACS Catal. 10, 4702–4709 (2020).

    Article  CAS  Google Scholar 

  83. Jasperse, C. P., Curran, D. P. & Fevig, T. L. Radical reactions in natural product synthesis. Chem. Rev. 91, 1237–1286 (2002).

    Article  Google Scholar 

  84. Juliá, F., Constantin, T. & Leonori, D. Applications of halogen-atom transfer (XAT) for the generation of carbon radicals in synthetic photochemistry and photocatalysis. Chem. Rev. 122, 2292–2352 (2022).

    Article  PubMed  CAS  Google Scholar 

  85. Baguley, P. A. & Walton, J. C. Flight from the tyranny of tin: the quest for practical radical sources free from metal encumbrances. Angew. Chem. Int. Ed. 37, 3072–3082 (1998).

    Article  CAS  Google Scholar 

  86. Chatgilialoglu, C., Ferreri, C., Landais, Y. & Timokhin, V. I. Thirty years of (TMS)3SiH: a milestone in radical-based synthetic chemistry. Chem. Rev. 118, 6516–6572 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Ingold, K. U., Lusztyk, J. & Scaiano, J. C. Absolute rate constants for the reactions of tributylgermyl and tributylstannyl radicals with carbonyl compounds, other unsaturated molecules, and organic halides. J. Am. Chem. Soc. 106, 343–348 (1984).

    Article  CAS  Google Scholar 

  88. Walton, J. C. et al. EPR studies of the generation, structure, and reactivity of N-heterocyclic carbene borane radicals. J. Am. Chem. Soc. 132, 2350–2358 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Wu, C., Hou, X., Zheng, Y., Li, P. & Lu, D. Electrophilicity and nucleophilicity of boryl radicals. J. Org. Chem. 82, 2898–2905 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Bitterwolf, T. E. Photochemistry and reaction intermediates of the bimetallic group VIII cyclopentadienyl metal carbonyl compounds, (η5-C5H5)2M2(CO)4 and their derivatives. Coord. Chem. Rev. 206–207, 419–450 (2000).

    Article  Google Scholar 

  91. Bitterwolf, T. E. Mechanisms and intermediates in the photochemistry of M2(CO)65-C5H5)2, where M = Cr, Mo and W, and their ring-coupled analogs. Coord. Chem. Rev. 211, 235–254 (2001).

    Article  CAS  Google Scholar 

  92. Wang, L., Lear, J. M., Rafferty, S. M., Fosu, S. C. & Nagib, D. A. Ketyl radical reactivity via atom transfer catalysis. Science 362, 225–229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Constantin, T. et al. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 367, 1021–1026 (2020).

    Article  CAS  PubMed  Google Scholar 

  94. Neff, R. K. et al. Generation of halomethyl radicals by halogen atom abstraction and their addition reactions with alkenes. J. Am. Chem. Soc. 141, 16643–16650 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Nakajima, K., Miyake, Y. & Nishibayashi, Y. Synthetic utilization of α-aminoalkyl radicals and related species in visible light photoredox catalysis. Acc. Chem. Res. 49, 1946–1956 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Sakai, H. A., Liu, W., Le, C. C. & MacMillan, D. W. C. Cross-electrophile coupling of unactivated alkyl chlorides. J. Am. Chem. Soc. 142, 11691–11697 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rossi, R. A., Budén, M. E. & Guastavino, J. F. in Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds (ed. Mortier, J.) 219–242 (Wiley, 2015).

  98. Minisci, F. in Synthetic and Mechanistic Organic Chemistry Vol. 62 (eds Minisci, F. et al.) 1–48 (Springer, 1976).

  99. Nagib, D. A. & MacMillan, D. W. C. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480, 224–228 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Allen, L. J., Cabrera, P. J., Lee, M. & Sanford, M. S. N-Acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C–H amination of arenes and heteroarenes. J. Am. Chem. Soc. 136, 5607–5610 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yuan, C. et al. Metal-free oxidation of aromatic carbon–hydrogen bonds through a reverse-rebound mechanism. Nature 499, 192–196 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Ruffoni, A. et al. Practical and regioselective amination of arenes using alkylamines. Nat. Chem. 11, 426–433 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitutionenables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Legnani, L., Cerai, G. P. & Morandi, B. Direct and practical synthesis of primary anilines through iron-catalyzed C–H bond amination. ACS Catal. 6, 8162–8165 (2016).

    Article  CAS  Google Scholar 

  106. Rössler, S. L. et al. Pyridyl radical cation for C–H amination of arenes. Angew. Chem. Int. Ed. 58, 526–531 (2019).

    Article  CAS  Google Scholar 

  107. Ham, W. S., Hillenbrand, J., Jacq, J., Genicot, C. & Ritter, T. Divergent late-stage (hetero)aryl C–H amination by the pyridinium radical cation. Angew. Chem. Int. Ed. 58, 532–536 (2019).

    Article  CAS  Google Scholar 

  108. Sánchez-Márquez, J. Correlations between Fukui indices and reactivity descriptors based on Sanderson’s principle. J. Phys. Chem. A 123, 8571–8582 (2019).

    Article  PubMed  CAS  Google Scholar 

  109. Kwan, E. E., Zeng, Y., Besser, H. A. & Jacobsen, E. N. Concerted nucleophilic aromatic substitutions. Nat. Chem. 10, 917–923 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Minisci, F. Novel applications of free-radical reactions in preparative organic chemistry. Synthesis 1973, 1–24 (1973).

    Article  Google Scholar 

  111. Duncton, M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal chemists. MedChemComm 2, 1135–1161 (2011).

    Article  CAS  Google Scholar 

  112. Proctor, R. S. J. & Phipps, R. J. Recent advances in Minisci-type reactions. Angew. Chem. Int. Ed. 58, 13666–13699 (2019).

    Article  CAS  Google Scholar 

  113. Fujiwara, Y. et al. A new reagent for direct difluoromethylation. J. Am. Chem. Soc. 134, 1494–1497 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Proctor, R. S. J., Chuentragool, P., Colgan, A. C. & Phipps, R. J. Hydrogen atom transfer-driven enantioselective Minisci reaction of amides. J. Am. Chem. Soc. 143, 4928–4934 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. DiRocco, D. A. et al. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Ed. 53, 4802–4806 (2014).

    Article  CAS  Google Scholar 

  116. O’Hara, F., Blackmond, D. G. & Baran, P. S. Radical-based regioselective C–H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability. J. Am. Chem. Soc. 135, 12122–12134 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Seiple, I. B. et al. Direct C–H arylation of electron-deficient heterocycles with arylboronic acids. J. Am. Chem. Soc. 132, 13194–13196 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Li, G.-X. et al. Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine. Chem. Sci. 7, 6407–6412 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Perkins, J. J., Schubert, J. W., Streckfuss, E. C., Balsells, J. & ElMarrouni, A. Photoredox catalysis for silyl-mediated C–H alkylation of heterocycles with non-activated alkyl bromides. Eur. J. Org. Chem. 2020, 1515–1522 (2020).

    Article  CAS  Google Scholar 

  121. Nuhant, P. et al. Visible-light-initiated manganese catalysis for C–H alkylation of heteroarenes: applications and mechanistic studies. Angew. Chem. Int. Ed. 56, 15309–15313 (2017).

    Article  CAS  Google Scholar 

  122. Fontana, F., Minisci, F. & Vismara, E. New general and convenient sources of alkyl radicals, useful for selective syntheses. Tetrahedron Lett. 29, 1975–1978 (1988).

    Article  CAS  Google Scholar 

  123. McCallum, T. & Barriault, L. Direct alkylation of heteroarenes with unactivated bromoalkanes using photoredox gold catalysis. Chem. Sci. 7, 4754–4758 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Citterio, A., Gentile, A., Minisci, F., Serravalle, M. & Ventura, S. Redox-chain decomposition of hydroxylamine-O-sulphonic acid. A novel general source of nucleophilic radicals for the functionalization of heteroaromatic bases. J. Chem. Soc. Chem. Commun. 916–917 (1983)

  125. Capaldo, L. & Ravelli, D. Hydrogen atom transfer (HAT): a versatile strategy for substrate activation in photocatalyzed organic synthesis. Eur. J. Org. Chem. 2017, 2056–2071 (2017).

    Article  CAS  Google Scholar 

  126. Quattrini, M. C. et al. Versatile cross-dehydrogenative coupling of heteroaromatics and hydrogen donors via decatungstate photocatalysis. Chem. Commun. 53, 2335–2338 (2017).

    Article  CAS  Google Scholar 

  127. Kim, J. H. et al. A radical approach for the selective C–H borylation of azines. Nature 595, 677–683 (2021).

    Article  CAS  PubMed  Google Scholar 

  128. Aynetdinova, D. et al. Installing the ‘magic methyl‘ – C–H methylation in synthesis. Chem. Soc. Rev. 50, 5517–5563 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Jin, J. & MacMillan, D. W. C. Alcohols as alkylating agents in heteroarene C–H functionalization. Nature 525, 87–90 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Duncton, M. A. J. et al. Preparation of heteroaryloxetanes and heteroarylazetidines by use of a Minisci reaction. J. Org. Chem. 74, 6354–6357 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Börgel, J., Tanwar, L., Berger, F. & Ritter, T. Late-stage aromatic C–H oxygenation. J. Am. Chem. Soc. 140, 16026–16031 (2018).

    Article  PubMed  CAS  Google Scholar 

  132. Margrey, K. A., McManus, J. B., Bonazzi, S., Zecri, F. & Nicewicz, D. A. Predictive model for site-selective aryl and heteroaryl C–H functionalization via organic photoredox catalysis. J. Am. Chem. Soc. 139, 11288–11299 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Foo, K., Sella, E., Thomé, I., Eastgate, M. D. & Baran, P. S. A mild, ferrocene-catalyzed C–H imidation of (hetero)arenes. J. Am. Chem. Soc. 136, 5279–5282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

D.L. would like to thank the EPSRC for a Fellowship (EP/P004997/1), the European Research Council for a research grant (758427) and the Leverhulme Trust for additional support (Philip Leverhulme Prize). R.M. would like to thank the EPSRC for a Doctoral Prize Fellowship (EP/T517823/1).

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Ruffoni, A., Mykura, R.C., Bietti, M. et al. The interplay of polar effects in controlling the selectivity of radical reactions. Nat. Synth 1, 682–695 (2022). https://doi.org/10.1038/s44160-022-00108-2

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