Are thermodynamic cycles necessary for continuum solvent calculation of pK_as and reduction potentials?

Abstract

Continuum solvent calculations of pKas and reduction potentials usually entail the use of a thermodynamic cycle to express the reaction free energy in terms of gas phase energies and free energies of solvation. In this work, we present a systematic study comparing the solution phase free energy changes obtained in this manner with those directly computed within the SMD solvation model against a large test set of 117 pKas and 42 reduction potentials in water and DMSO. The inclusion of vibrational contributions in the free energy of solvation has a negligible impact on the accuracy of thermodynamic cycle predictions of pKas and reduction potentials. Additionally, when gas phase energies in the thermodynamic cycle are computed at more accurate levels of theory, very similar results (mean unsigned difference of 0.5 kcal mol(-1)) can be achieved when the high-level computations (MP2/GTMP2Large and G3(MP2)-RAD(+)) are directly carried out within the continuum model. Increasing the accuracy of the electronic structure theory may or may not improve the agreement with experiment suggesting that the error is largely in the solvation model. For amino acids where their gas and solution phase species exist as different tautomers, the direct approach provided a significant improvement in calculated pKas. These results demonstrate that direct calculation of solution phase pKas and reduction potentials within the SMD model provides a general and reliable approximation to corresponding thermodynamic cycle based protocols, and is recommended for systems where solvation induced changes in geometry are significant. Further studies are necessary to ascertain whether the results are generalisable to other continuum solvation models.

Prediction of the reduction potential in transition‐metal containing complexes: How expensive? For what accuracy?

“…Results (Supporting Information Tables S8 andS9, Figs. S3–S6) showed solvation models played an important role in the computations of reduction potentials and SMD and IEFPCM‐Bondi models produced better results compared to IEFPCM‐Pauling model, which was in agreement with Ho's conclusion on the solvation model based on the computed results of the 117 p K a 's and 42 reduction potentials of the nontransition metal‐containing molecules …”

“…Density functional theory (DFT) has proven to be a reliable, convenient, and advantageous tool for computing reduction potentials . Although many studies have utilized DFT, the absolute deviations between the experimental data and computed values are still quite large for some transition metal‐containing complexes (including both inorganic and organometallic complexes) compared with simple organic molecules.…”

Systematic microsolvation approach with a cluster‐continuum scheme and conformational sampling

“…With this partitioning scheme, however, free energies cannot be straightforwardly calculated because vibrational modes cannot (easily) be attributed to the solute and its direct surrounding (see also the recent comparison of finite‐temperature models for solution in Reference and references therein). We note that a recent study showed that the inclusion of vibrational contributions in the free energy of solvation can have a negligible effect on the accuracy of thermodynamic cycle predictions of pK a 's and reduction potentials.…”

Large‐Sized Ammonia Clusters and Solvation Energies of the Proton in Ammonia

“…Several investigations have been performed to determine the solvation energies of the proton in water . Besides, only few authors have been interested in the solvation energies of the proton in other solvents such as methanol, acetonitrile, dimethyl sulfoxide, acetone, benzene, ethanol, and ammonia .…”