Dynamics and Entropy of Cyclohexane Rings Control pH-Responsive Reactivity

Sunyoung Kang, Chanwoo Noh, Hyosik Kang, Ji Yeon Shin, So Young Kim, Seulah Kim, Moon Gi Son, Eunseok Park, Hyun Kyu Song, Seokmin Shin, Sanghun Lee, Nak Kyoon Kim, Younjoon Jung, Yan Lee

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2070-2079
Number of pages10
JournalJACS Au
Volume1
Issue number11
DOIs
Publication statusPublished - 2021 Nov 22

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Keywords

  • Amide degradation
  • Cyclohexane
  • Dynamics
  • Entropy
  • Ring inversion
  • pH-Responsive reactivity

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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