Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5‑Phenyl-1,3-dioxane

Anancomeric
5-phenyl-1,3-dioxanes provide a unique opportunity
to study factors that control conformation. Whereas one might expect
an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation
similar to that in axial phenylcyclohexane, a series of studies including
X-ray crystallography, NOE measurements, and DFT calculations demonstrate
that the phenyl prefers to lie over the dioxane ring in order to position
an ortho-hydrogen to participate in a stabilizing,
nonclassical CH···O hydrogen bond with a ring oxygen
of the dioxane. Acid-catalyzed equilibration of a series of anancomeric
2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates
that remote substituents on the phenyl ring affect the conformational
energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents
decrease the conformational energy of the aryl group, while electron-donating
substituents increase the conformational energy of the group. This
effect is correlated in a very linear way to Hammett substituent parameters.
In short, the strength of the CH···O hydrogen bond
may be tuned in a predictable way in response to the electron-withdrawing
or electron-donating ability of substituents positioned remotely on
the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference
for the axial orientation. The results are relevant to broader conformational
issues involving heterocyclic systems bearing aryl substituents.