Energetics of Dynamic Kinetic Asymmetric Transformation in Suzuki–Miyaura Coupling

Abstract

The enantioselective cross-coupling reactions that transform a racemic mixture into an enantio-enriched product are in high contemporary demand. Elucidation of mechanism involving catalytic enantioselective transformation with racemic substrates is often challenging. Herein, we provide mechanistic insights derived through a comprehensive density functional theory (B3LYP-D3) investigation, on the origin of stereoinduction in a Rh-catalyzed asymmetric allylic arylation of racemic 3-chlorocyclohex-1-ene by using arylboronic acid. Energetically most preferred pathway is found to proceed through (a) a transmetalation wherein aryl group gets transferred from the boron of arylboronic acid to the Rh center of the catalyst, (b) an oxidative addition (OA) of Rh to the C–Cl bond of cyclohexenyl chloride, and (c) a reductive elimination (RE) leading to the bond formation between the Rh-bound phenyl and cyclohexenyl moiety to furnish the final arylated product. We note that each enantiomer of the substrate follows different OA modes, which is highly suggestive of a dynamic kinetic asymmetric transformation (DYKAT). Although the likelihood of DYKAT has been routinely invoked in the literature, quantitative energetic details, as well as mechanistic underpinnings such as the identity of the common intermediate, generally remain scarce. The R enantiomer of cyclohexenyl chloride is found to undergo an anti-SN2′ OA, whereas the S enantiomer prefers an anti-SN2 route to the common prochiral η3-Rh-π-allyl intermediate. High enantioselectivity in the ensuing RE, favoring the S enantiomer of the product, is traced to the lower activation barrier, which, in turn, arises from the lower distortion energy in the RE transition state when the si face of Rh-bound cyclohexenyl forms the bond with the phenyl group than when the re face is involved. The mechanistic insights presented herein are expected to be valuable toward understanding the DYKAT mechanism of conversion of racemic substrates to an enantiopure product.