Unraveling the Importance of Noncovalent Interactions in Asymmetric Hydroformylation Reactions

Abstract

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)-YanPhoscatalyzed AHF of α-methylstyrene, as obtained through a comprehensive DFT (ω-B97XD and M06) study. The challenges with the double axially chiral YanPhos, bearing an N-benzyl BINOL-phosphoramidite and a BINAP-bis(3,5-t-Bu-aryl)phosphine, are addressed through exhaustive conformational sampling. The C−H•••π, π•••π, and lone pair•••π noncovalent interactions (NCIs) between the N-benzyl and the rest of the chiral ligand limit the N-benzyl conformers. Similarly, the C−H•••π and π•••π NCIs between the chiral catalyst and α-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 α-carbon is 3.6 kcal/mol lower than that to the β-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.

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids

“…The two diastereomers of the Yanphos ligand gave the opposite enantioselectivity (entry 4 and 5 in Table 1 ), which indicate the decisive role of the chiral BINOL frame of the phosphoramidite moiety. Based on our DFT calculations (see the ESI † ) and Sunoj's computational research, 52 we tentatively proposed the enantioinduction model as depicted in Fig. 4c .…”

Iridium-Catalyzed Regioselective Borylation through C–H Activation and the Origin of Ligand-Dependent Regioselectivity Switching

“…To understand the energetic origin of the regioselectivity switching, from an exclusive ortho borylation with 8-AQ to a predominant meta borylation with the TMP ligand, we have examined the stereoelectronic features of the regiocontrolling OA TS . A combination of (i) topological analysis of the electron density using the atoms in molecule formalism to map out the NCI and (ii) distortion–interaction/activation-strain (DI–AS) analyses on these TSs is employed for this purpose …”

“…The energetic span (δ E ) of the catalytic cycle was determined as the energy difference between the turnover-determining TS (TDTS) and the turnover-determining intermediate (TDI) in accordance with the Shaik–Kozuch recommendation . The weak NCIs in the TSs, generally traced by identifying the closest interatomic nonbonded contacts, were examined by performing the topological analyses of the electron densities using the atoms-in-molecule formalism as implemented in the AIM2000 program . The strength of these NCIs was further evaluated using the topological parameters such as the electron density at the bond critical point (ρ bcp ), the corresponding Laplacian of the electron density (∇ 2 ρ), kinetic energy ( G ), and potential energy densities ( V ) as per the Espinosa’s formulation …”

Evolution in the metal-catalyzed asymmetric hydroformylation of 1,1′-disubstituted alkenes

“…Dangat and Sunoj have recently performed a comprehensive DFT study on the asymmetric hydroformylation of α-methylstyrene catalyzed by the Rh/(S,S)-DTB-YanPhos (L22) system, with the aim to unravel the origin of the attained high regio-and enantioselectivities (39). These calculations pointed out that non-covalent interactions (NCI) between the N-benzyl group and the other aromatic moieties in the ligand backbone are crucial for reaching good enantioselectivities (Fig.…”