Geminal Atom Catalysts with Minimized d-Orbital Holes Enable β-Elimination-Resistant C(sp2)–C(sp3) Cross-Coupling

Geminal Atom Catalysts with Minimized d-Orbital Holes Enable β-Elimination-Resistant C(sp2)–C(sp3) Cross-Coupling

Journal of the American Chemical Society

10.1021/jacs.6c00936

https://doi.org/10.1021/jacs.6c00936

Qiang Wang, Tan Li, Pengru Huang, Qi Yu, Kun Fu, Shibo Xi, Xiaocang Han, Jingcong Hu, Xiaoxu Zhao, Haipei Shao, Ming Lin, Yang Meng, Jinxing Chen, Jiali Li, Caozheng Diao, Xiao Hai, Yulin Wang, Xingjie Fu, Jialu Sun, Kostya S. Novoselov, Richard Y. Liu, Jun LI, Jiong Lu

Geminal Atom Catalysts

09 April 2026

Wang, Q., Li, T., Huang, P., Yu, Q., Fu, K., Xi, S., Han, X., Hu, J., Zhao, X., Shao, H., Lin, M., Meng, Y., Chen, J., Li, J., Diao, C., Hai, X., Wang, Y., Fu, X., Sun, J., et al. (2026). Geminal Atom Catalysts with Minimized d-Orbital Holes Enable β-Elimination-Resistant C(sp2)–C(sp3) Cross-Coupling. Journal of the American Chemical Society, 148(15), 16138–16150. https://doi.org/10.1021/jacs.6c00936

Heterogeneous C(sp2)−C(sp3) Suzuki−Miyaura coupling offers an attractive route for the large-scale and sustainable synthesis of structurally complex and pharmaceutically relevant molecules that are otherwise difficult to access. However, the low reactivity of unactivated alkyl electrophiles and the intrinsic instability of alkyl metal intermediates, particularly their propensity for β-hydride elimination, render selective C(sp2)−C(sp3) bond formation exceptionally challenging. Here, we integrate high throughput density functional theory (DFT) screening with quantum-chemical calculations to identify Cu-based geminal atom catalysts as optimal candidates and uncover the critical role of d-orbital holes that promote agostic interactions, leading to undesired β-hydride elimination. Guided by these insights, we developed a d-orbital hole passivation strategy to fabricate a class of high-fidelity Cu-based geminal-atom catalysts (HF−Cu/GACs), simultaneously accelerating oxidative addition and suppressing β-hydride elimination, enabling broad-scope and highly selective C(sp2)−C(sp3) cross-coupling between aryl boronic esters and alkyl (pseudo)halides. These catalysts enable the synthesis of diverse pharmaceutically relevant intermediates in fewer steps, with higher yields and using safer, more sustainable conditions compared to traditional routes. Mechanistic studies reveal that the HF−Cu/GACs feature paired, low-valent Cu centers with minimal d-orbital holes, and that C−Br bond activation proceeds through a surface-mediated single-electron transfer between coadsorbed reactants, rather than free-radical rebound pathways. The findings here establish a generalizable strategy for electronic-state engineering of geminal metal sites to overcome long-standing challenges in cross-coupling chemistry and highlight the potential of heterogeneous Cu catalysts for the sustainable synthesis of fine chemicals and pharmaceuticals.

Publisher Copyright

This research / project is supported by the National Research Foundation - Competitive Research Program
Grant Reference no. : NRF-CRP29-2022-0004

This research / project is supported by the A*STAR - Manufacturing, Trade, and Connectivity Individual Research Grants
Grant Reference no. : M22K2c0082

This research / project is supported by the the Science and Technology Project of Jiangsu Province - BZ2022056
Grant Reference no. : NA

This research / project is supported by the SUSTech- NUS joint research program - A-8002269-00-00, A-8002269- 01-00, A-8002269-02-00
Grant Reference no. : NA

This research / project is supported by the the National Natural Science Foundation of China - 22033005, 22076095, 22222605
Grant Reference no. : NA

This research / project is supported by the National Key R&D Program of China - 2022YFA1503900
Grant Reference no. : NA

This research / project is supported by the NSFC Center for Single-Atom Catalysis - 22388102
Grant Reference no. : NA

This research / project is supported by the National Natural Science Foundation of China - 22473071
Grant Reference no. : NA

This research / project is supported by the Ministry of Education - Research Centre of Excellence Institute for Functional Intelligent Materials
Grant Reference no. : EDUNC-33-18-279-V12

This research / project is supported by the National Research Foundation - AI Singapore Program
Grant Reference no. : AISG3-RP-2022-028

This research / project is supported by the Ministry of Education - Academic Research Fund Tier 3 Grant
Grant Reference no. : MOET32024-0002

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see 10.1021/jacs.6c00936.

https://oar.a-star.edu.sg/communities-collections/articles/23142

0002-7863
1520-5126

Institute of Materials Research and Engineering