Issue 24, 2016

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

Abstract

The mechanism of the dipeptide (S)-pro-(S)-asp catalyzed intermolecular aldol reaction with acetone as the donor and three aromatic aldehydes (benzaldehyde, p-methyl benzaldehyde and p-nitrobenzaldehyde) as the acceptors was studied by means of density functional theory (DFT) at the level of B3LYP/6-31G(d,p). The calculated results showed that there were four steps in the reaction path: (i) the nucleophilic attack of an amino group on carbonyl for the formation of intermediate A, which was the rate-determining step due to it having the largest energy barrier of 44.33 kcal mol−1; (ii) the dehydration process to form an s-cis- or s-trans-enamine through an imine-generating step; (iii) the electrophilic addition of aldehyde, which decided the stereoselectivity of the product because of the steric repulsion interactions between the enamine and aldehyde; (iv) the removal of the dipeptide to generate the final products. According to the results analysis, it was found that the dipeptide-catalyzed aldol reaction via an s-trans-enamine was more energetically favorable to obtain the R-product (with an ee value > 99%). The energy variations in the reaction path were verified using CAM-B3LYP and M06-2X methods in the same basis set. The solvation effects were explored based on B3LYP/6-31G(d,p) combined with a polarizable continuum model (PCM), the substituent effects of aromatic aldehydes were also considered. The computed results provided a reference for experiments that DMSO and H2O as the solvents could decrease the energy barriers in the reaction path and the impact of substituent effects might be small. The feasibility of the dipeptide provided a possibility for proteins to act as catalysts which are green and nontoxic.

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

Supplementary files

Article information

Article type
Paper
Submitted
15 Dec 2015
Accepted
09 Feb 2016
First published
09 Feb 2016

RSC Adv., 2016,6, 19742-19750

Author version available

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

X. Zhang and M. Pu, RSC Adv., 2016, 6, 19742 DOI: 10.1039/C5RA26808G

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