A proline mimetic for enantioselective aldol reaction: a quantum chemical study of a catalytic reaction with a sterically hindered l‐prolinamide derivative

Abstract

The direct aldol reaction between acetone and 4‐nitrobenzaldehyde catalyzed by sterically hindered l‐prolinamide derivative (64 atoms) of the (11S,12S)‐9,10‐dihydro‐9,10‐ethanoanthracene‐11,12‐diamine molecule has been investigated using density functional theory at the B3LYP/6‐31G(d) level of theory. The reliability of the B3LYP/6‐31G(d) calculations to elucidate the reaction mechanism and estimate activation and reaction energies was confirmed by energy calculation of the net reaction with full geometry optimizations of the reactants and product at the B3LYP/6‐311++G(2d,2p) as well as B2PLYP/def2‐TZVPP levels with correction to Van der Waals interaction. The calculations reveal that the l‐prolinamide derivative catalyzes the reaction according to a multistep enamine mechanism with highly activated C–C bond and/or enamine formation in the proposed mechanism. The final elementary reaction – the C–N bond cleavage in the chiral diol adduct – is accompanied by a very large barrier, which may inhibit further progression of the reaction. The origin of the enantioselectivity and the corresponding reaction paths to a chiral product were unambiguously identified. Copyright © 2012 John Wiley & Sons, Ltd.

Density functional theory study of the mechanism of a dipeptide-catalyzed intermolecular aldol reaction—the effects of steric repulsion interactions on stereoselectivity

“…Theoretically, the Rproduct was found to be the major product, with an enantiomeric excess >99%, which translated approximately to an energy difference of 6.65 kcal mol À1 between the TS3-tR and TS3-tS transition states. 41 This was due to the steric repulsion interaction between the carbonyl of the benzyl substituent and enamine terminus in the S-face attack. This also explained why the R-face transition state was preferred over the S-face for electrophilic attack.…”

Investigation of Thermochemistry Associated with the Carbon–Carbon Coupling Reactions of Furan and Furfural Using ab Initio Methods

“…These interactions often require sophisticated calculations that take well-balanced account of electron correlation . Recent computational studies have frequently utilized density functional (DFT) methods, especially B3LYP, , to investigate the thermochemistry of C–C coupling reactions (e.g., Diels–Alder and aldol reactions). − Although B3LYP is accurate for the prediction of ground-state geometric parameters, it has sometimes shown large errors in the prediction of relative energies of isomers of hydrocarbons and other main group element containing compounds. − Some recent studies , have also suggested that B3LYP gives poor reaction enthalpies for Diels–Alder reactions compared with high level G3 and CBS-QB3 − methods. Both G3 and CBS-QB3 have shown good agreement with the experimental reaction enthalpies of Diels–Alder reactions .…”