Importance of Long-Range Noncovalent Interactions in the Regioselectivity of Rhodium-Xantphos-Catalyzed Hydroformylation

M06-L-based quantum chemical calculations were performed to examine two key elementary steps in rhodium (Rh)-xantphos-catalyzed hydroformylation: carbonyl ligand (CO) dissociation and the olefin insertion into the Rh–H bond. For the resting state of the Rh-xantphos catalyst, HRh­(xantphos)­(CO)₂, our M06-L calculations were able to qualitatively reproduce the correct ordering of the equatorial–equatorial (<i>ee</i>) and equatorial–axial (<i>ea</i>) conformers of the phosphorus ligands for 16 derivatives of the xantphos ligand, implying that the method is sufficiently accurate for capturing the subtle energy differences associated with various conformers involved in Rh-catalyzed hydroformylation. The calculated CO dissociation energy from the <i>ea</i> conformer (Δ<i>E</i> = 21–25 kcal/mol) was 10–12 kcal/mol lower than that from the <i>ee</i> conformer (Δ<i>E</i> = 31–34 kcal/mol), which is consistent with prior experimental and theoretical studies. The calculated regioselectivities for propene insertion into the Rh–H bond of the <i>ee</i>-HRh­(xantphos)­(propene)­(CO) complexes were in good agreement with the experimental l:b ratios. The comparative analysis of the regioselectivities for the pathways originating from the <i>ee</i>-HRh­(xantphos)­(propene)­(CO) complexes with and without diphenyl substituents yielded useful mechanistic insight into the interactions that play a key role in regioselectivity. Complementary computations featuring xantphos ligands lacking diphenyl substituents implied that the long-range noncovalent ligand–ligand and ligand–substrate interactions, but not the bite angles per se, control the regioselectivity of Rh-diphosphine-catalyzed hydroformylation of simple terminal olefins for the <i>ee</i> isomer. Additional calculations with longer chain olefins and the simplified structural models, in which the phenyl rings of the xantphos ligands were selectively removed to eliminate either substrate–ligand or ligand–ligand noncovalent interactions, suggested that ligand–substrate π-HC interactions play a more dominant role in the regioselectivity of Rh-catalyzed hydroformylation than ligand–ligand π–π interactions. The present calculations may provide foundational knowledge for the rational design of ligands aimed at optimizing hydroformylation regioselectivity