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 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.