Increasing Complexity in a Conformer Space Step-by-Step: Weighing London Dispersion against Cation−π Interactions

We
report an evaluation of the importance of London dispersion
in moderately large (up to 36 heavy atoms) organic molecules by means
of a molecular torsion balance whose conformations “weigh”
one interaction against another in the absence of solvents. The experimental
study, with gas-phase cryogenic ion vibrational predissociation (CIVP)
spectroscopy, solid-state Fourier transfer infrared (FT-IR), and single-crystal
X-ray crystallography, is accompanied by density functional theory
calculations, including an extensive search and analysis of accessible
conformations. We begin with the unsubstituted molecular torsion balance,
and then step up the complexity systematically by adding alkyl groups
incrementally as dispersion energy donors (DEDs) to achieve a degree
of chemical complexity comparable to what is typically found in transition
states for many regio- and stereoselective reactions in organic and
organometallic chemistry. We find clear evidence for the small attractive
contribution by DEDs, as had been reported in other studies, but we
also find that small individual contributions by London dispersion,
when they operate in opposition to other weak noncovalent interactions,
produce composite effects on the structure that are difficult to predict
intuitively, or by modern quantum chemical calculations. The experimentally
observed structures, together with a reasonable value for a reference
cation−π interaction, indicate that the pairwise interaction
between two tert-butyl groups, in the best case,
is modest. Moreover, the visualization of the conformational space,
and comparison to spectroscopic indicators of the structure, as one
steps up the complexity of the manifold of noncovalent interactions,
makes clear that in silico predictive ability for the structure of
moderately large, flexible, organic molecules falters sooner than
one might have expected.