Calculating pK_a values for substituted phenols and hydration energies for other compounds with the first‐order fuzzy‐border continuum solvation model

Abstract

We have computed pKa values for eleven substituted phenol compounds using the continuum Fuzzy-Border (FB) solvation model. Hydration energies for 40 other compounds, including alkanes, alkenes, alkynes, ketones, amines, alcohols, ethers, aromatics, amides, heterocycles, thiols, sulfides and acids have been calculated. The overall average unsigned error in the calculated acidity constant values was equal to 0.41 pH units and the average error in the solvation energies was 0.076 kcal/mol. We have also reproduced pKa values of propanoic and butanoic acids within ca. 0.1 pH units from the experimental values by fitting the solvation parameters for carboxylate ion carbon and oxygen atoms. The FB model combines two distinguishing features. First, it limits the amount of noise which is common in numerical treatment of continuum solvation models by using fixed-position grid points. Second, it employs either second- or first-order approximation for the solvent polarization, depending on a particular implementation. These approximations are similar to those used for solute and explicit solvent fast polarization treatment which we developed previously. This article describes results of employing the first-order technique. This approximation places the presented methodology between the Generalized Born and Poisson-Boltzmann continuum solvation models with respect to their accuracy of reproducing the many-body effects in modeling a continuum solvent.

Phosphate‐Based Self‐Immolative Linkers for Tuneable Double Cargo Release

“…[18] SI was slower in 4 than in 3, the intermediate 4-I was detected, and the corresponding phenol was released in 24 h. The relative concentration of products 3-P2 and 4-P2 was significantly higher than that of their unsubstituted phenol counterpart 5. The SI reaction in 3, 4 and 5 matches the corresponding pK a values of p-NO 2 , p-F, and p-H phenols (7.15, [28] 9.95, and 9.98, respectively). The lower the pK a of phenol is, the faster SI will be.…”

An Experimental Validated Computational Method for pKa Determination of Substituted 1,2-Dihydroxybenzenes

“…Computational methods have the advantage of having relatively good accuracy, low cost (Pathare et al, 2014 ), and facilitate determinations of pKa values at pH ranges where the compound lose solubility. However, to obtain good results, it is highly important to perform calculations using an adequate model of solvation (Sharma and Kaminski, 2012 ) and possess experimental data to validate the computational results.…”

Origin of pKa Shifts of Internal Lysine Residues in SNase Studied Via Equal-Molar VMMS Simulations in Explicit Water

“…33,36,38–40,50–63 A series of computational methods have been developed for p K a calculation. 12–14,16,18–21,23–26,28,30–32,34–38,40,41,59, 64–70 For buried ionizable groups, it has been realized that explicit water molecules are needed to accurately describe the microenvironment; 23,48,71,72 this presents challenges for most of the p K a calculation methods.…”