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.

活化熵（Activation entropy，ΔS‡）通常不被视作决定单分子反应反应活性的核心因素。本研究发现，六元环化合物的分子内降解主要由活化熵变（ΔS‡）主导，而活化熵变受环翻转运动与取代基几何构型的显著调控。我们从1,2-环己烷甲酰胺（1,2-CHCAA）几何异构体的pH依赖降解动力学的独特差异切入——仅顺式异构体可在弱酸性环境（pH < 5.5）下快速降解——发现该差异源于二者间16.02 cal·mol–1·K–1的活化熵变差值。顺式-1,2-环己烷甲酰胺始终维持对经典环己烷椅式构象的偏好，而反式-1,2-环己烷甲酰胺则可在椅式与扭船式构象间发生动态互变，该结论得到了分子动力学（MD）模拟与变温核磁共振（VT-NMR）分析的佐证。反式异构体1,2位大体积取代基之间的空间位阻斥力，是降低环构象间能垒、促进动态环翻转运动的关键诱因之一。因此，相较于顺式异构体，动态性更强的反式异构体在活化过程中因反应物预定位引发的熵减更为显著，其pH依赖降解过程也得到有效抑制。当通过在环己烷环上引入额外甲基取代基抑制环翻转运动时，即使是反式异构体，其pH依赖降解能力也可得到显著提升。本研究揭示了空间排布与动态特性可显著影响单分子反应中分子反应活性的独特案例，可为未来基于动态构象变化的反应性结构设计提供重要参考。