Mechanism and Selectivity Control in Ni- and Pd-Catalyzed Cross-Couplings Involving Carbon–Oxygen Bond Activation

Conspectus Transition-metal-catalyzed C–O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C–O bond activation and functionalization methods. Toward the rational design of C–O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C­(sp2)–O and C­(sp3)–O bond activations. We found that the nickel catalyst cleaves the benzylic and allylic C­(sp3)–O bonds via two general mechanisms: the stereoinvertive SN2 back-side attack model and the stereoretentive chelation-assisted model. These two models control the stereochemistry in a wide array of stereospecific Ni-catalyzed cross-coupling reactions with benzylic or allylic alcohol derivatives. Because of the catalyst distortion, the ligands can differentiate the competing stereospecific C­(sp3)–O bond activations. The PCy3 ligand interacts with nickel mainly through σ-donation, and the Ni­(PCy3) catalyst can undergo facile bending of the substrate–nickel–ligand angle, which favors the stereoretentive benzylic C–O bond activation. The N-heterocyclic carbene SIMes ligand has additional d­(metal)–p­(ligand) back-donation with nickel, which leads to an extra energy penalty for the same angle bending. This results in the preference of stereoinvertive benzylic C–O bond activation under Ni/SIMes catalysis. In addition to ligand control, a Lewis acid can increase the selectivity for stereoinvertive C­(sp3)–O activation by stabilizing the SN2 back-side attack transition state. The oxygen leaving group complexes with the MgI2 Lewis acid in the stereoinvertive activation, leading to the exclusive stereoinvertive Kumada coupling of benzylic ethers. We also identified that the competing C­(sp3)–O bond activation models have noticeable differences in charge separation. This leads to the solvent polarity control of the stereospecificity in C­(sp3)–O activations. Low-polarity solvents favor the neutral stereoretentive C–O bond activation, while high-polarity solvents favor the zwitterionic stereoinvertive cleavage. In sharp contrast to the nickel catalysts, the C­(sp2)–O bond activation under palladium catalysis mainly proceeds via the classic three-memb