Electrostatic Switching of Stereoselectivity in Aldol Reactions

Li-Juan Yu, Michelle L. Coote

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1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)9076-9083
Number of pages8
JournalJournal of Organic Chemistry
Volume86
Issue number13
DOIs
Publication statusPublished - 2 Jul 2021
Externally publishedYes

Keywords

  • Electrostatic
  • Stereoselectivity
  • Aldol
  • Reactions
  • Density functional theory
  • DFT
  • enantioselectivity
  • acetone
  • p-nitrobenzaldehyd
  • proline
  • Electron

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