Unraveling the Importance of Noncovalent Interactions in Asymmetric Hydroformylation Reactions

For catalytic asymmetric hydroformylation (AHF) of alkenes to chiral aldehydes, though a topic of high interest, the contemporary developments remain largely empirical owing to rather limited molecular insights on the origin of enantioselectivity. Given this gap, herein, we present the mechanistic details of Rh-(S,S)-YanPhos-catalyzed AHF of alpha-methylstyrene, as obtained through a comprehensive DFT (omega-B97XD and M06) study. The challenges with the double axially chiral YanPhos, bearing an N-benzyl BINOL-phosphoramidite and a BINAP-bis(3,54-Bu-aryl)phosphine, are addressed through exhaustive conformational sampling. The C-H center dot center dot center dot pi, pi center dot center dot center dot pi, and lone pair center dot center dot center dot pi it noncovalent interactions (NCIs) between the N-benzyl and the rest of the chiral ligand limit the N-benzyl conformers. Similarly, the C-H center dot center dot center dot pi and pi center dot center dot center dot pi - NCIs between the chiral catalyst and alpha-methylstyrene render the siface binding to the Rh-center more preferred over the re-face. The transition state (TS) for the regiocontrolling migratory insertion, triggered by the Rh-hydride addition to the alkene, to the more substituted alpha-carbon is 3.6 kcal/mol lower than that to the beta-carbon, thus favoring the linear chiral aldehyde over the achiral branched alternative. In the linear pathway, the TS for the hydride addition to the si-face is 1.5 kcal/mol lower than that to the re-face, with a predicted ee of 85% for the S aldehyde (expt. 87%). The energetic span analysis reveals the reductive elimination as the turnover determining step for the preferred S linear aldehyde. These molecular insights could become valuable for exploiting AHF reactions for substituted alkenes and for eventual industrial implementation.