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

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 develope 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.