Electrostatic Switching of Stereoselectivity in Aldol Reactions
Density functional theory (DFT) has been employed in predicting the enantioselectivity of the aldol reaction between acetone and <i>p</i>-nitrobenzaldehyde catalyzed by proline and its derivatives Me<sub>2</sub>bdc-Pro (bdc = 1,4-benzenedicarboxylate) and Me<sub>2</s...
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2021
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| Summary: | Density functional theory (DFT) has been employed in predicting the enantioselectivity of the aldol reaction between acetone and <i>p</i>-nitrobenzaldehyde catalyzed by proline and its derivatives Me<sub>2</sub>bdc-Pro (bdc = 1,4-benzenedicarboxylate) and Me<sub>2</sub>bpdc-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., SO<sub>3</sub><sup>–</sup>, NMe<sub>2</sub>, SO<sub>3</sub>H, and NMe<sub>3</sub><sup>+</sup>) 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 Me<sub>2</sub>bdc-Pro and Me<sub>2</sub>bpdc-Pro catalysts with the electron-withdrawing SO<sub>3</sub>H and NMe<sub>3</sub><sup>+</sup> installed respectively, values much higher than those of the corresponding unmodified catalysts. More interestingly, enantiomeric excesses decrease and, in the case of SO<sub>3</sub><sup>–</sup>, 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. |
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