Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp²)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity

The mechanism of C(sp²)-H borylation of fluorinated arenes with B₂Pin₂ (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (^iPrPNP) cobalt complexes was studied to understand the origins of the uniquely high ortho-to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp²)-H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)-aryl complex that was generated with the same high ortho-to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp²)-H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of ortho-fluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal-carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in (^iPrPNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp²)-H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.