Mechanism-Based Classification of Carbon–Oxygen Bond Functionalization by Transition Metal Catalysis

Abstract

In this review, we categorize C–O bond functionalization reactions according to their underlying mechanisms, encompassing both C(sp²)–O and C(sp³)–O bond activations. While nickel-based catalysts have dominated the early and continuing developments in this area, recent efforts have expanded the scope to include a broader range of transition metals. Although molecular transformations catalyzed by these alternative metals are still in their infancy, they have yielded valuable mechanistic insights that are essential for future advancements. Moreover, it has become increasingly clear that traditional mechanistic frameworks are insufficient to fully explain the activation of inherently unreactive C–O bonds. This has led to a surge of interest in alternative activation paradigms, particularly dual activation strategies that exploit the synergistic roles of multiple catalytic components. By systematically summarizing current strategies for C–O bond activation, this review seeks to accelerate progress in the field and offer conceptual guidance for the broader activation of otherwise inert bonds.

Keywords

C(sp²)–O bond activation - C(sp³)–O bond activation - Transition metal - Catalysis - Reaction mechanism - Dual activation

Publication History

Received: 12 June 2025

Accepted after revision: 11 August 2025

Accepted Manuscript online:
11 August 2025

Article published online:
03 November 2025

• References

• 1a Zhou T, Szostak M. Catal Sci Technol 2020; 10: 5702
• 1b Han F-S. Chem Soc Rev 2013; 42: 5270
• 1c Rosen BM, Quasdorf KW, Wilson DA. et al. Chem Rev 2011; 111: 1346
• 1d Cornella J, Zarate C, Martin R. Chem Soc Rev 2014; 43: 8081
• 1e Zhang SQ, Hong X. Acc Chem Res 2021; 54: 2158
• 1f Bisz E, Szostak M. ChemSusChem 2017; 10: 3964
• 2a McMurry J. Organic Chemistry. 9th ed Boston, MA: Cengage Learning; 2016. ISBN: ISBN: 978-1-305-58035-0
• 2b Weissman SA, Zewge D. Tetrahedron 2005; 61: 7833
• 3 Appel R. Angew Chem Int Ed 1975; 14: 801
• 4a Pound SM, Watson MP. Chem Commun 2018; 54: 12286
• 4b Zhang H, Gu Q, You S-L. Chin J Org Chem 2019; 39: 15
• 4c Furniel LG, Corrêa AG. ChemPhotoChem 2024; 8: e202400120
• 4d Bull JA, Croft RA, Davis OA, Doran R, Morgan KF. Chem Rev 2016; 116: 12150
• 4e Villo P, Shatskiy A, Kärkäs MD, Lundberg H. Angew Chem Int Ed 2023; 62: e202211952
• 5a Jones CE, Shaw BL, Turtle BLJ. Chem Soc: Dalton Trans 1974; 992
• 5b Empsall HD, Hyde EM, Jones CE, Shaw BL. J Chem Soc, Dalton Trans 1974; 1974: 1980
• 5c Ittel SD, Tolman CA, English AD, Jesson JP. J Am Chem Soc 1978; 100: 7577
• 5d Tolman CA, Ittel SD, English AD, Jesson JP. J Am Chem Soc 1979; 101: 1742
• 5e Dunbar KR, Haefner SC, Uzelmeier CE, Howard A. Inorg Chim Acta 1995; 240: 527
• 5f Van Der Boom ME, Liou SY, Ben-David Y, Vigalok A, Milstein D. Angew Chem Int Ed 1997; 36: 625
• 5g Kundu S, Choi J, Wang DY. et al. J Am Chem Soc 2013; 135: 5127
• 6 Wenkert E, Michelotti EL, Swindell CS. J Am Chem Soc 1979; 101: 2246
• 7 Bartmann E. J Organomet Chem 1985; 284: 149
• 8a Qiu Z, Li C-J. Chem Rev 2020; 120: 10454
• 8b Cornella J, Zarate C, Martin R. Chem Soc Rev 2014; 43: 8081
• 8c Tobisu M, Chatani N. Acc Chem Res 2015; 48: 1717
• 8d Tobisu M, Chatani N. Top Curr Chem 2016; 374: 41
• 8e Li B-J, Yu D-G, Sun C-L, Shi Z-J. Chem Eur J 2011; 17: 1728
• 8f Li WN, Wang ZL. RSC Adv 2013; 3: 25565
• 8g Zeng H, Qiu Z, Domínguez-Huerta A, Hearne Z, Chen Z, Li C-J. ACS Catal 2017; 7: 510
• 9 Borys AM, Hevia E. Synthesis 2022; 54: 2976
• 10 Sergeev AG, Hartwig JF. Science 2011; 332: 439
• 11 Sawatlon B, Wititsuwannakul T, Tantirungrotechai Y, Surawatanawong P. Dalton Trans 2014; 43: 18123
• 12 Wititsuwannakul T, Tantirungrotechai Y, Surawatanawong P. ACS Catal 2016; 6: 1477
• 13 Xu L, Chung LW, Wu YD. ACS Catal 2016; 6: 483
• 14 Tobisu M, Shimasaki T, Chatani N. Angew Chem Int Ed 2008; 47: 4866
• 15 Tobisu M, Yasutome A, Kinuta H, Nakamura K, Chatani N. Org Lett 2014; 16: 5572
• 16 Schwarzer MC, Konno R, Hojo T. et al. J Am Chem Soc 2017; 139: 10347
• 17 Kakiuchi F, Usui M, Ueno S, Chatani N, Murai S. J Am Chem Soc 2004; 126: 2706
• 18 Ueno S, Mizushima E, Chatani N, Kakiuchi F. J Am Chem Soc 2006; 128: 16516
• 19 Kusumoto S, Nozaki K. Nat Commun 2015; 6: 6296
• 20 Gjermestad CS, Kusumoto S, Flores-Linares I. et al. Organometallics 2025; 44: 536
• 21 Hibe Y, Ebe Y, Nishimura T, Yorimitsu H. Chem Lett 2017; 46: 953
• 22 Chen K, Kang QK, Li Y, Wu WQ, Zhu H, Shi H. J Am Chem Soc 2022; 144: 1144
• 23 Chen K, Ma Y, Lin Y, Li JY, Shi H. J Am Chem Soc 2024; 146: 15833
• 24 Mkrtchyan S, Jakubczyk M, Sarfaraz S, Ayub K, Iaroshenko VO. Chem Sci 2024; 14798
• 25 Mkrtchyan S, Jakubczyk M, Sarfaraz S. et al. Cell Rep Phys Sci 2024; 5: 102062
• 26 Mkrtchyan S, Purohit VB, Jakubczyk M. et al. Molecules 2025; 30: 1835
• 27 Jin J, MacMillan DWC. Nature 2015; 525: 87
• 28 Suga Y, Takahashi Y, Miki C, Ukaji Y. Angew Chem Int Ed 2022; 61: e202112533
• 29 Suga T, Shimazu S, Ukaji Y. Org Lett 2018; 20: 5389
• 30 Guo P, Song X, Huang B, Zhang R, Zhao J. Angew Chem Int Ed 2024; 63: e202405449
• 31 Ogawa H, Minami H, Ozaki T, Komagawa S, Wang C, Uchiyama M. Chem Eur J 2015; 21: 13904
• 32a Yoshikai N, Mashima H, Nakamura E. J Am Chem Soc 2005; 127: 17978
• 32b Yoshikai N, Matsuda H, Nakamura E. J Am Chem Soc 2009; 131: 9590
• 33 Álvarez-Bercedo P, Martin R. J Am Chem Soc 2010; 132: 17352
• 34 Cornella J, Gómez-Bengoa E, Martin R. J Am Chem Soc 2013; 135: 1997
• 35a Zarate C, Nakajima M, Martin R. J Am Chem Soc 2017; 139: 1191
• 35b Somerville RJ, Hale LVA, Gómez-Bengoa E, Burés J, Martin R. J Am Chem Soc 2018; 140: 8771
• 36 Kelley P, Edouard GA, Lin S, Agapie T. Chem Eur J 2016; 22: 17173
• 37 Cornella J, Martin R. Org Lett 2013; 15: 6298
• 38 Liu X, Hsiao CC, Kalvet I. et al. Angew Chem Int Ed 2016; 55: 6093
• 39 Borys AM, Hevia E. Angew Chem Int Ed 2021; 60: 24659
• 40 Liang H, Borys AM, Hevia E, Perrin MEL, Payard PA. J Am Chem Soc 2023; 145: 19989
• 41 Borys AM, Hevia E. Chem Commun 2024; 60: 11052
• 42 Iwasaki T, Miyata Y, Akimoto R, Fujii Y, Kuniyasu H, Kambe N. J Am Chem Soc 2014; 136: 9260
• 43 Iwasaki T, Ishiga W, Pal S, Nozaki K, Kambe N. ACS Catal 2022; 12: 7936
• 44 Kinuta H, Tobisu M, Chatani N. J Am Chem Soc 2015; 137: 1593
• 45 Seki R, Hara N, Saito T, Nakao Y. J Am Chem Soc 2021; 143: 6388
• 46a Kuriakose N, Shaik S. Chem Eur J 2023; 29: e202300977
• 46b Kumawat J, Macias ID, Ess DH. Organometallics 2023; 42: 1890
• 47 Fujii I, Seki R, Kido H, Jauffret L, Semba K, Nakao Y. ChemRxiv. 2025
• 48 Fujii I, Semba K, Li Q-Z, Sakaki S, Nakao Y. J Am Chem Soc 2020; 142: 11647
• 49 Seki R, Takaya H, Nakao Y. ChemRxiv. 2023
• 50 Brown RK, Hooper TN, Rekhroukh F, White AJP, Costa PJ, Crimmin MR. Chem Commun 2021; 57: 11673
• 51 Lyu H, Kevlishvili I, Yu X, Liu P, Dong G. Science 2021; 372: 175