Additivity of Substituent Effects in Aromatic Stacking Interactions

The goal of this
study was to experimentally test the additivity
of the electrostatic substituent effects (SEs) for the aromatic stacking
interaction. The additivity of the SEs was assessed using a small
molecule model system that could adopt an offset face-to-face aromatic
stacking geometry. The intramolecular interactions of these molecular
torsional balances were quantitatively measured via the changes in
a folded/unfolded conformational
equilibrium. Five different types of substituents were examined (CH3, OCH3, Cl, CN, and NO2) that ranged
from electron-donating to electron-withdrawing. The strength of the
intramolecular stacking interactions was measured for 21 substituted
aromatic stacking balances and 21 control balances in chloroform solution.
The observed stability trends were consistent with additive SEs. Specifically,
additive SE models could predict SEs with an accuracy from ±0.01
to ±0.02 kcal/mol. The additive SEs were consistent with Wheeler
and Houk’s direct SE model. However, the indirect or polarization
SE model cannot be ruled out as it shows similar levels of additivity
for two to three substituent systems, which were the number of substituents
in our model system. SE additivity also has practical utility as the
SEs can be accurately predicted. This should aid in the rational design
and optimization of systems that utilize aromatic stacking interactions.