Improved pK_a Prediction of Substituted Alcohols, Phenols, and Hydroperoxides in Aqueous Medium Using Density Functional Theory and a Cluster-Continuum Solvation Model

Abstract

Acid dissociation constants (pK's) are key physicochemical properties that are needed to understand the structure and reactivity of molecules in solution. Theoretical pK's have been calculated for a set of 72 organic compounds with -OH and -OOH groups (48 with known experimental pK's). This test set includes 17 aliphatic alcohols, 25 substituted phenols, and 30 hydroperoxides. Calculations in aqueous medium have been carried out with SMD implicit solvation and three hybrid DFT functionals (B3LYP, ωB97XD, and M06-2X) with two basis sets (6-31+G(d,p) and 6-311++G(d,p)). The effect of explicit water molecules on calculated pK's was assessed by including up to three water molecules. pK's calculated with only SMD implicit solvation are found to have average errors greater than 6 pK units. Including one explicit water reduces the error by about 3 pK units, but the error is still far from chemical accuracy. With B3LYP/6-311++G(d,p) and three explicit water molecules in SMD solvation, the mean signed error and standard deviation are only -0.02 ± 0.55; a linear fit with zero intercept has a slope of 1.005 and R = 0.97. Thus, this level of theory can be used to calculate pK's directly without the need for linear correlations or thermodynamic cycles. Estimated pK values are reported for 24 hydroperoxides that have not yet been determined experimentally.

Determination of the Bridging Ligand in the Active Site of Tyrosinase

“…The p K a could be accurately determined by first-principles QM calculations employing the continuum/cluster model. For example, it was found that the SMD solvation method incorporating three explicit water molecules in the first solvation shell produced accurate p K a for molecules with hydroxyl and hydroperoxyl functional groups [ 27 ]. In the present study, the oxygen of the bridging ligand binds with the two copper ions, leaving the hydrogens of the bridging ligand pointing towards the outside of the active site.…”

“…1 M and 1atm refer to the standard states for the aqueous solution and gas phase, respectively. G gas,H + is the gas-phase free energy of the proton with the value of −6.28 kcal/mol at the 1 atm standard state and 298.15 K [ 27 ]. ΔG 1atm→1 M is the free energy change from the standard state of 1 atm to 1 M, of which the value is 1.89 kcal/mol [ 33 ].…”

“…For example, the absolute hydration free energy of the proton was determined in such a way by including the water clusters in the first and second solvation shells [ 25 ]. In addition, a recent study showed that the average error for p K a prediction on molecules with hydroxyl and hydroperoxyl functional groups was about 0.02 p K a units by employing the SMD solvation model [ 26 ] at the B3LYP/6-311++G** level, in which the continuum/cluster model was used with three explicit water molecules in the first solvation shell [ 27 ]. Accordingly, the ΔG model(expt) for the model systems here could be calculated by using the same method.…”

Hybrid discrete‐continuum solvation methods

“…More recent examples of the merits of a hybrid type of approach can be illustrated by a series papers by Thapa and Schlegel . For a series of alcohols, phenols, hydroperoxides, thiols, and selenols, p K a calculations were carried out with different functionals and the SMD solvation model.…”

Relative pKa of some anilinium derivatives in methanol, acetonitrile, and tetrahydrofurane solvents

“…Along this line, several works have been performed on proton‐transfer reactions in the gas phase as well as aqueous and non‐aqueous solution. For instance, Poliak applied the B3LYP/6–311++G(d,p) level of theory and IEF‐PCM/UFF solvation model to calculate the p K a values of the cationic acid aniline and pyridine derivatives in common solvents with the root‐mean‐squared (RMS) error of less than 2.0 p K a units .…”