Deuterium isotope effects on acid-base equilibrium of organic compounds

Meiyi Liu, Jiali Gao

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Deuterium isotope effects on acid-base equilibrium have been investigated using a combined path integral and free-energy perturbation simulation method. To understand the origin of the linear free-energy relationship of ΔpKa = pKD α 2O a - pKα H2O a versus pKαH2 O a, we examined two theoretical models for computing the deuterium isotope effects. In Model 1, only the intrinsic isotope exchange effect of the acid itself in water was included by replacing the titratable protons with deuterons. Here, the dominant contribution is due to the difference in zero-point energy between the two isotopologues. In Model 2, the medium isotope effects are considered, in which the free energy change as a result of replacing H2O by D2O in solute-solvent hydrogen-bonding complexes is determined. Although the average DpKa change from Model 1 was found to be in reasonable agreement with the experimental average result, the pKH2O a dependence of the solvent isotope effects is absent. A linear free-energy relationship is obtained by including the medium effect in Model 2, and the main factor is due to solvent isotope effects in the anion-water complexes. The present study highlights the significant roles of both the intrinsic isotope exchange effect and the medium solvent isotope effect.

Original languageEnglish (US)
Article number7687
Issue number24
StatePublished - Dec 1 2021

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© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Deuterium isotope effects
  • KIE on pK
  • Nuclear quantum effects
  • Path integral free-energy simulations


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