Influence of inter- and intramolecular hydrogen bonding on kemp decarboxylations from QM/MM simulations

Orlando Acevedo, William L. Jorgensen

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

The Kemp decarboxylation reaction for benzisoxazole-3-carboxylic acid derivatives has been investigated using QM/MM calculations in protic and dipolar aprotic solvents. Aprotic solvents have been shown to accelerate the rates of reaction by 7-8 orders of magnitude over water; however, the inclusion of an internal hydrogen bond effectively inhibits the reaction with near solvent independence. The effects of solvation and intramolecular hydrogen bonding on the reactants, transition structures, and the rate of reaction are elucidated using two-dimensional potentials of mean force (PMF) derived from free energy perturbation calculations in Monte Carlo simulations (MC/FEP). Free energies of activation in six solvents have been computed to be in close agreement with experiment. Solute-solvent interaction energies show that poorer solvation of the reactant anion in the dipolar aprotic solvents is primarily responsible for the observed rate enhancements over protic media. In addition, a discrepancy for the experimental rate in chloroform has been studied in detail with the conclusion that ion-pairing between the reactant anion and tetramethylguanidinium counterion is responsible for the anomalously slow reaction rate. The overall quantitative success of the computations supports the present QM/MM/MC approach, which features PDDG/PM3 as the QM method.

Original languageEnglish (US)
Pages (from-to)8829-8834
Number of pages6
JournalJournal of the American Chemical Society
Volume127
Issue number24
DOIs
StatePublished - Jun 22 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'Influence of inter- and intramolecular hydrogen bonding on kemp decarboxylations from QM/MM simulations'. Together they form a unique fingerprint.

  • Cite this