Mechanism and Origins of Regioselectivity in the Catalytic C(sp2)–H Borylation of Arenes by Cobalt and Iron Complexes

Abstract

The generation of synthetically versatile organoboronate products is among the most valuable C–H functionalizations. In most cases, arene C(sp2)–H borylations are catalyzed by bipyridine iridium catalysts and proceed with predictable sterically-driven regioselectivity which disfavors activation of C(sp2)–H sites ortho to a methyl group or any larger substituent. In contrast, the iridium catalysts fail to discriminate between accessible arene C–H sites which differ in terms of their electronic properties, resulting in statistical product mixtures. The advent of cobalt precatalysts for C(sp2)–H borylation offers promise to address this limitation, as regioselective C(sp2)–H borylations of fluoroarenes have been reported, ostensibly owing to an enhanced ability for electronic site discrimination. These advances highlight the potential of first-row metals to exhibit complementary performance in catalysis compared to their precious metal counterparts, but an understanding of the origins of these unique regioselectivities is needed to extend this concept past these early successes. In this dissertation, investigations into the operative mechanisms of catalytic C(sp2)–H borylation by cobalt and iron complexes are described, and the insights obtained from these studies are used to construct rationale for the regioselectivity observed with each catalyst system. Initial studies focused on the mechanism of the ortho-selective borylation of fluorinated arenes by bis(phosphino)pyridine cobalt [(PNP)Co] complexes, where experimental results supported a mechanism featuring a fast and reversible C–H activation event, enabling thermodynamic control of this step. In subsequent studies, it was found that changes in regioselectivity can result from changes in the turnover-limiting step of the catalytic reaction due to subtle changes in substrate electronics. This concept inspired pursuits of catalyst-controlled regioselectivity in fluoroarene borylation, where the PNP ligand was replaced by a less electron-donating terpyridine ligand to slow the C–H activation step and invert regioselectivity. A highly meta-selective catalyst for fluoroarene borylation was developed, and mechanistic investigations supported a kinetically-controlled C–H activation as the rate- and selectivity-determining step in catalysis. Finally, studies of iron-based precatalysts provided insights into possible mechanisms and revealed that iron catalysts, like known cobalt systems, can discriminate between fluoroarene sites to affect regioselective C(sp2)–H functionalization.