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.

  • Perspective
  • Published:

Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization

Nature Synthesis volume 3, pages 568–575 (2024)Cite this article

Subjects

Abstract

Photoinduced C(sp3)–H functionalization through hydrogen atom transfer (HAT) processes is pivotal in organic synthesis because of the mild reaction conditions and applicability to late-stage functionalization of complex molecules, such as pharmaceuticals and agrochemicals. Despite promise, achieving precise site-selectivity and overcoming the high bond dissociation energy (BDE) of unactivated aliphatic C–H bonds in photoinduced C(sp3)–H functionalization reactions, through HAT, are challenging. In this landscape, pyridine N-oxides have emerged as potent HAT reagents due to their easily tunable nature. This Perspective highlights studies showcasing the potential of pyridine N-oxides as HAT reagents in site-selective hydrogen atom abstraction from unactivated C(sp3)–H bonds and explores their structure–activity relationship with multiple hydrocarbon substrates. Pyridine N-oxides have become promising reagents in environmentally friendly synthesis owing to their cost-effectiveness, tunability and applicability in (heterogeneous) catalysis. Ongoing research on the use of pyridine N-oxides as HAT reagents will probably offer additional avenues for efficient and selective C(sp3)–H bond functionalization.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Photoinduced direct C(sp3)–H functionalization through HAT chemistry.
Fig. 2: Pyridine N-oxides as a versatile reagent in radical chemistry.
Fig. 3: Screening of pyridine N-oxides as HAT catalysts in photocatalysed C(sp3)–H functionalizations.
Fig. 4: Structure–activity relationships of pyridine N-oxides in photoinduced C(sp3)–H functionalizations.
Fig. 5: The use of pyridine N-oxide-embedded COFs as HAT reagents.

Similar content being viewed by others

References

  1. Hanukoglu, I. Steroidogenic enzymes: structure, function and role in regulation of steroid hormone biosynthesis. J. Steroid Biochem. Mol. Biol. 43, 779–804 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Kaspera, R. & Croteau, R. Cytochrome P450 oxygenases of taxol biosynthesis. Phytochem. Rev. 5, 433–444 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lewis, J. C., Coelho, P. S. & Arnold, F. H. Enzymatic functionalization of carbon-hydrogen bonds. Chem. Soc. Rev. 40, 2003–2021 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Darcy, J. W., Koronkiewicz, B., Parada, G. A. & Mayer, J. M. A continuum of proton-coupled electron transfer reactivity. Acc. Chem. Res. 51, 2391–2399 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yi, H. et al. Recent advances in radical C-H activation/radical cross-coupling. Chem. Rev. 117, 9016–9085 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Wang, X. & Studer, A. Iodine(III) reagents in radical chemistry. Acc. Chem. Res. 50, 1712–1724 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kärkäs, M. D. Electrochemical strategies for C-H functionalization and C-N bond formation. Chem. Soc. Rev. 47, 5786–5865 (2018).

    Article  PubMed  Google Scholar 

  8. 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 

  9. 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  CAS  Google Scholar 

  10. Capaldo, L., Ravelli, D. & Fagnoni, M. Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C-H bonds elaboration. Chem. Rev. 122, 1875–1924 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Chang, L. et al. Resurgence and advancement of photochemical hydrogen atom transfer processes in selective alkane functionalizations. Chem. Sci. 14, 6841–6859 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Galli, C., Gentili, P. & Lanzalunga, O. Hydrogen abstraction and electron transfer with aminoxyl radicals: synthetic and mechanistic issues. Angew. Chem. Int. Ed. 47, 4790–4796 (2008).

    Article  CAS  Google Scholar 

  14. Wu, Z.-X., Hu, G.-W. & Luan, Y.-X. Development of N-hydroxy catalysts for C-H functionalization via hydrogen atom transfer: challenges and opportunities. ACS Catal. 12, 11716–11733 (2022).

    Article  CAS  Google Scholar 

  15. Yang, C., Arora, S., Maldonado, S., Pratt, D. A. & Stephenson, C. R. J. The design of PINO-like hydrogen-atom-transfer catalysts. Nat. Rev. Chem. 7, 653–666 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. Leifert, D. & Studer, A. Organic synthesis using nitroxides. Chem. Rev. 123, 10302–10380 (2023).

    Article  CAS  PubMed  Google Scholar 

  17. Youssif, S. Recent trends in the chemistry of pyridine N-oxides. Arkivoc 1, 242–268 (2001).

    Article  Google Scholar 

  18. Li, D. et al. The diversity of heterocyclic N-oxide molecules: highlights on their potential in organic synthesis, catalysis and drug applications. Curr. Org. Chem. 23, 616–627 (2019).

    Article  CAS  Google Scholar 

  19. Habib, I., Singha, K. & Hossain, M. Recent progress on pyridine N-oxide in organic transformations: a review. ChemistrySelect 8, e202204099 (2023).

    Article  CAS  Google Scholar 

  20. Wang, D., Désaubry, L., Li, G., Huang, M. & Zheng, S. Recent advances in the synthesis of C2-functionalized pyridines and quinolines using N-oxide chemistry. Adv. Synth. Catal. 363, 2–39 (2021).

    Article  CAS  Google Scholar 

  21. Wang, Y. & Zhang, L. Recent developments in the chemistry of heteroaromatic N-oxides. Synthesis 47, 289–305 (2015).

    Article  CAS  Google Scholar 

  22. Xu, J., Wu, W. & Wu, J. Photoinduced divergent alkylation/acylation of pyridine N-oxides with alkynes under anaerobic and aerobic conditions. Org. Lett. 21, 5321–5325 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Kim, I. et al. Site-selective functionalization of pyridinium derivatives via visible-light-driven photocatalysis with quinolinone. J. Am. Chem. Soc. 141, 9239–9248 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Markham, J. P., Wang, B., Stevens, E. D., Burris, S. C. & Deng, Y. ortho-Alkylation of pyridine N-oxides with alkynes by photocatalysis: pyridine N-oxide as a redox auxiliary. Chem. Eur. J. 25, 6638–6644 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Li, D. et al. Visible-light-promoted C2 selective arylation of quinoline and pyridine N-oxides with diaryliodonium tetrafluoroborate. J. Org. Chem. 85, 2733–2742 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Mathi, G. R. et al. H functionalization of heteroarene N-oxides enabled by a traceless nucleophile. Angew. Chem. Int. Ed. 59, 22675–22683 (2020).

    Article  CAS  Google Scholar 

  27. Beatty, J. W., Douglas, J. J., Cole, K. P. & Stephenson, C. R. J. A scalable and operationally simple radical trifluoromethylation. Nat. Commun. 6, 7919 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kim, I., Min, M., Kang, D., Kim, K. & Hong, S. Direct phosphonation of quinolinones and coumarins driven by the photochemical activity of substrates and products. Org. Lett. 19, 1394–1397 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Capaldo, L. & Ravelli, D. Alkoxy radicals generation: facile photocatalytic reduction of N-alkoxyazinium or azolium salts. Chem. Commun. 55, 3029–3032 (2019).

    Article  CAS  Google Scholar 

  30. He, F.-S., Ye, S. & Wu, J. Recent advances in pyridinium salts as radical reservoirs in organic synthesis. ACS Catal. 9, 8943–8960 (2019).

    Article  CAS  Google Scholar 

  31. McClain, J. E., Wortman, A. K. & Stephenson, C. R. J. Radical generation enabled by photoinduced N-O bond fragmentation. Chem. Sci. 13, 12158–12163 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schlegel, M., Qian, S. & Nicewicz, D. A. Aliphatic C–H functionalization using pyridine N-oxides as H-atom abstraction agents. ACS Catal. 12, 10499–10505 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, B. et al. Photoinduced site-selective functionalization of aliphatic C-H bonds by pyridine N-oxide based HAT catalysts. ACS Catal. 12, 10441–10448 (2022).

    Article  CAS  Google Scholar 

  34. Ciszewski, Ł. W. & Gryko, D. Pyridine N-oxides as HAT reagents for photochemical C-H functionalization of electron-deficient heteroarenes. Chem. Commun. 58, 10576–10579 (2022).

    Article  CAS  Google Scholar 

  35. Mech, P., Bogunia, M., Nowacki, A. & Makowski, M. Calculations of pKa values of selected pyridinium and its N-oxide ions in water and acetonitrile. J. Phys. Chem. A 124, 538–551 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Teufel, R. et al. Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement. Nature 503, 552–556 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Miyazaki, H., Kubota, T. & Yamakawa, M. The characterization of the electronic spectra of heterocyclic amine N-oxides by means of the non-aqueous oxidation and reduction potentials and the substituent effects on them. Bull. Chem. Soc. Jpn 45, 780–785 (1972).

    Article  CAS  Google Scholar 

  38. Koldasheva, E. M., Geletii, Y. V., Yanilkin, V. V. & Strelets, V. V. Electrogenerated cation radicals of heteroaromatic N-oxides and oxidation of cyclohexane induced by them. Bull. Acad. Sci. USSR Div. Chem. Sci. 39, 886–890 (1990).

    Article  Google Scholar 

  39. Sako, M., Shimada, K., Hirota, K. & Maki, Y. Photochemical oxygen-atom transfer reaction by heterocycle N-oxides involving a single-electron transfer process: oxidative demethylation of N,N-dimethylaniline. J. Am. Chem. Soc. 108, 6039–6041 (1986).

    Article  CAS  PubMed  Google Scholar 

  40. Nakanishi, I. et al. Hydroxyl radical generation via photoreduction of a simple pyridine N-oxide by an NADH analogue. Org. Biomol. Chem. 3, 3263–3265 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Li, H., Xie, F. & Zhang, M.-T. Metal-free electrocatalyst for water oxidation initiated by hydrogen atom transfer. ACS Catal. 11, 68–73 (2021).

    Article  CAS  Google Scholar 

  42. Laze, L., Quevedo-Flores, B., Bosque, I. & Gonzalez-Gomez, J. C. Alkanes in minisci-type reaction under photocatalytic conditions with hydrogen evolution. Org. Lett. 25, 8541–8546 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Yamada, K. et al. Photocatalyzed site-selective C-H to C-C conversion of aliphatic nitriles. Org. Lett. 17, 1292–1295 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Fukuyama, T. et al. Site-selectivity in TBADT-photocatalyzed C(sp3)-H functionalization of saturated alcohols and alkanes. Chem. Lett. 47, 207–209 (2018).

    Article  CAS  Google Scholar 

  46. Zhi, Y., Wang, Z., Zhang, H.-L. & Zhang, Q. Recent progress in metal-free covalent organic frameworks as heterogeneous catalysts. Small 16, 2001070 (2020).

    Article  CAS  Google Scholar 

  47. Mak, C. H. et al. Heterogenization of homogeneous photocatalysts utilizing synthetic and natural support materials. J. Mater. Chem. A 9, 4454–4504 (2021).

    Article  CAS  Google Scholar 

  48. López-Magano, A. et al. Recent advances in the use of covalent organic frameworks as heterogenous photocatalysts in organic synthesis. Adv. Mater. 35, 2209475 (2023).

    Article  Google Scholar 

  49. Pang, H. et al. Embedding hydrogen atom transfer moieties in covalent organic frameworks for efficient photocatalytic C-H functionalization. Angew. Chem. Int. Ed. 62, e202313520 (2023).

    Article  CAS  Google Scholar 

  50. Li, X. et al. Chemically robust covalent organic frameworks: progress and perspective. Matter 3, 1507–1540 (2020).

    Article  Google Scholar 

Download references

Acknowledgements

J.W. acknowledges financial support provided by the National Research Foundation, the Prime Minister’s Office of Singapore, under its NRF-CRP Programme (award no. NRFCRP25-2020RS-0002), Pfizer (A-8000004-00-00) and the NUS (Chongqing) Research Institute, National Natural Science Foundation of China (grant nos. 22071170 and 22371200). D.R. acknowledges support from the Ministero dell’Università e della Ricerca (MUR) and the University of Pavia through the program ‘Dipartimenti di Eccellenza 2023–2027’.

Author information

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Hwee Ting Ang, Yidan Miao & Jie Wu

  2. Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, Fuzhou, P. R. China

    Yidan Miao

  3. PhotoGreen Lab, Department of Chemistry, University of Pavia, Pavia, Italy

    Davide Ravelli

  4. National University of Singapore (Chongqing) Research Institute, Chongqing, China

    Jie Wu

Authors
  1. Hwee Ting Ang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yidan Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Davide Ravelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.T.A., Y.M., D.R. and J.W. contributed to discussions and wrote the manuscript.

Corresponding authors

Correspondence to Davide Ravelli or Jie Wu.

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.

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

Ang, H.T., Miao, Y., Ravelli, D. et al. Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization. Nat. Synth 3, 568–575 (2024). https://doi.org/10.1038/s44160-024-00528-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-024-00528-2

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