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Deuterium Isotope Effects on Acid-Base Equilibrium of Organic Compounds - PubMed

  • ️Fri Jan 01 2021

Deuterium Isotope Effects on Acid-Base Equilibrium of Organic Compounds

Meiyi Liu et al. Molecules. 2021.

Abstract

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=pKaD2O-pKaH2O versus pKaH2O, 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 ΔpKa change from Model 1 was found to be in reasonable agreement with the experimental average result, the pKaH2O 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.

Keywords: KIE on pKa; deuterium isotope effects; nuclear quantum effects; path integral free-energy simulations.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Experimental and computed deuterium isotope effects on acidity constants. The computational results determined by using density functional theory and polarizable continuum solvation model with B3LYP-PCM/6-311++G(d,p) are taken from reference [19].

Scheme 1
Scheme 1

Thermodynamic cycle depicting acid–base equilibrium in water and in D2O.

Figure 2
Figure 2

Experimental and computed isotope effects on acidity using Model 1 and path integral-free energy perturbation simulations.

Figure 3
Figure 3

Experimental and computed isotope effects on acidity using Model 2 and path integral-free energy perturbation simulations. Medium isotope effects on specific acid–base interactions with the solvent are included in Model 2.

Figure 4
Figure 4

Correlation of the total isotope medium effects (∆GME) on acid and base equilibrium with the difference in hydrogen-bonding energies between the conjugate base and acid, ∆∆Eint = ∆EHB(A−…HOH)—∆EHB(AH…OH2), due to the replacement of a water (H2O) by a heavy water (D2O) molecule. Energies are given in kcal/mol.

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