Discovery of Switchable Metal‐ and Ligand‐Centered Reactivity via Mechanistic Studies on CO Activation of Pyridines

Metal–ligand cooperation (MLC) reaction revolutionizes the boundaries of homogeneous catalysis by permitting ligand‐centered reactivity beyond traditional metal‐orientated reactivity. Pyridine is key motif in many pharmaceuticals and agrochemical products, but it also shows promise in participating MLC reaction for further derivatization. However, such unique reaction integration into CO bond functionalization remains underexplored, largely due to poorly understood reactivity profiles. In this work, a mechanistic investigation into nickel‐catalyzed CO bond activation of pyridine‐based aryl ethers is reported to elucidate the electronic and structural features of the active species and MLC/metal–ligand role reversal (MLRR) pathway. With detailed mechanistic studies including density functional theory calculation, X‐ray absorption spectroscopy, electron spin resonance, and model catalyst, two distinct catalytic cycles are elucidated: 1) a two‐electron‐based CO arylation at nickel center and 2) a single‐electron‐driven pyridine homocoupling reaction via MLC and MLRR manifolds. These insights subsequently allow establishment of a synthetic methodology for switchable CO bond cleavage and homocoupling in substrate scope studies.