Density functional theory (DFT) has been employed in predicting the enantioselectivity of the aldol reaction between acetone and p-nitrobenzaldehyde catalyzed by proline and its derivatives Me2bdc-Pro (bdc = 1,4-benzenedicarboxylate) and Me2bpdc-Pro (bpdc = 4,4′-biphenyldicarboxylate). For each catalyst, our computationally predicted values at the M062X/6-31+G(d) level of theory with the SMD solvent model are in excellent agreement with experimental results reported in the literature. Electron-donating and electron-withdrawing groups (viz., SO3-, NMe2, SO3H, and NMe3+) were installed at the C4 position of the proline-based catalysts to study the impact of electrostatic effects on stereoselectivity. The electron-donating groups decrease and even invert the enantioselectivity, while the electron-withdrawing ones increase it. Enantiomeric excesses in the range of 49-71 and 59-68% are predicted for Me2bdc-Pro and Me2bpdc-Pro catalysts with the electron-withdrawing SO3H and NMe3+ installed respectively, values much higher than those of the corresponding unmodified catalysts. More interestingly, enantiomeric excesses decrease and, in the case of SO3-, are even inverted in favor of the other enantiomer when the electron-donating groups are installed. These results highlight the importance of electrostatic effects, and polar effects more generally, in optimal organocatalyst design for stereoselective C-C bond-forming reactions.
- Density functional theory