Dynamics and Entropy of Cyclohexane Rings Control pH-Responsive Reactivity

Activation entropy
(ΔS‡) is not normally considered
the main factor in determining the reactivity
of unimolecular reactions. Here, we report that the intramolecular
degradation of six-membered ring compounds is mainly determined by
the ΔS‡, which is strongly
influenced by the ring-flipping motion and substituent geometry. Starting
from the unique difference between the pH-dependent degradation kinetics
of geometric isomers of 1,2-cyclohexanecarboxylic acid amide (1,2-CHCAA),
where only the cis isomer can readily degrade under
weakly acidic conditions (pH < 5.5), we found that the difference
originated from the large difference in ΔS‡ of 16.02 cal·mol–1·K–1. While cis-1,2-CHCAA maintains a
preference for the classical chair cyclohexane conformation, trans-1,2-CHCAA shows dynamic interconversion between the
chair and twisted boat conformations, which was supported by both
MD simulations and VT-NMR analysis. Steric repulsion between the bulky
1,2-substituents of the trans isomer is one of the
main reasons for the reduced energy barrier between ring conformations
that facilitates dynamic ring inversion motions. Consequently, the
more dynamic trans isomer exhibits much a larger
loss in entropy during the activation process due to the prepositioning
of the reactant than the cis isomer, and the pH-dependent
degradation of the trans isomer is effectively suppressed.
When the ring inversion motion is inhibited by an additional methyl
substituent on the cyclohexane ring, the pH degradability can be dramatically
enhanced for even the trans isomer. This study shows
a unique example in which spatial arrangement and dynamic properties
can strongly influence molecular reactivity in unimolecular reactions,
and it will be helpful for the future design of a reactive structure
depending on dynamic conformational changes.