A Method of Calculating the Kamlet–Abboud–Taft Solvatochromic Parameters Using COSMO-RS (original) (raw)
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Journal of Chemical & Engineering Data, 2014
In the present work, the free energy solvation of H + , ΔG sol H + , is estimated in various important nonaqueous solvents including alcohols and polar aprotic solvents, semiempirically. The selected solvents are methanol, ethanol, 2-propanol, 2-methyl-2-propanol, dimethyl sulfoxide, dimethylformamide, and acetonitrile. The value of ΔG sol H + in 2-propanol and 2-methyl-2-propanol were reported for the first time. The estimated values of ΔG sol H + were used to predict the acidity constants (pK a) of different compounds in the selected solvents. These pK a values had better agreement with the experimental values than the corresponding values obtained using the other ΔG sol H + reported in literature. This confirmed that the values of ΔG sol H + , predicted in this work, are reasonable. The calculated pK a values of selected compounds in nonaqueous solvents were further corrected by accounting for the error of the applied computational method for predicting the pK a values of the compounds in water. New correlation equations were proposed and used to estimate the pK a values of carboxylic acids (aliphatic and aromatic derivatives), phenol derivatives, a series of active pharmaceutical ingredients, and some anti-inflammatory agents in the considered solvents when their experimental pK a values are known in water. The calculations presented in this work were performed at four different levels of theory including B3LYP, M062X, MP2, and CCSD using 6-311++G(d,p) basis set, separately.
Accurate determination of absolute solvation free energy plays a critical role in numerous areas of biomolecular modeling and drug discovery. A quantitative representation of ligand and receptor desolvation, in particular, is an essential component of current docking and scoring methods. Furthermore, the partitioning of a drug between aqueous and nonpolar solvents is one of the important factors considered in pharmacokinetics. In this study, the absolute hydration free energy for a set of 239 neutral ligands spanning diverse chemical functional groups commonly found in drugs and drug-like candidates is calculated using the molecular dynamics free energy perturbation method (FEP/MD) with explicit water molecules, and compared to experimental data as well as its counterparts obtained using implicit solvent models. The hydration free energies are calculated from explicit solvent simulations using a staged FEP procedure permitting a separation of the total free energy into polar and nonpolar contributions. The nonpolar component is further decomposed into attractive (dispersive) and repulsive (cavity) components using the Weeks-Chandler-Anderson (WCA) separation scheme. To increase the computational efficiency, all of the FEP/MD simulations are generated using a mixed explicit/implicit solvent scheme with a relatively small number of explicit TIP3P water molecules, in which the influence of the remaining bulk is incorporated via the spherical solvent boundary potential (SSBP). The performances of two fixed-charge force fields designed for small organic molecules, the General Amber force field (GAFF), and the all-atom CHARMm-MSI, are compared. Because of the crucial role of electrostatics in solvation free energy, the results from various commonly used charge generation models based on the semiempirical (AM1-BCC) and QM calculations [charge fitting using ChelpG and RESP] are compared. In addition, the solvation free energies of the test set are also calculated using Poisson-Boltzmann (PB) and Generalized Born model of solvation (GB), which are two widely used continuum electrostatic implicit solvent models. The protocol for running the absolute solvation free energy calculations used throughout is automated as much as possible, with minimum user intervention, so that it can be used in large-scale analysis and force field optimization. Figure 2. Average unsigned error [AUE] in the absolute solvation free energies. The AUE is shown in the y-axis, and the chemical functionalities in the small molecules are plotted in the x-axis. The solid bars represent the solvation free energies calculated using explicit solvent/FEP method in CHARMM. The bars with dotted line and stripes represent the solvation free energy calculated using GB and PB model in Amber9.
Journal of Solution Chemistry, 2018
Solvent basicity is recognized as playing a major role in solvation and is included, through empirical basicity parameters, in linear free energy relationships that account for the effects of changes in solvent on chemical reactions. It is reasonable to postulate that the basicity of a solvent molecule reflects some combination of its molecular properties. In the present study, density functional calculations using the B3LYP functional, and Hartree-Fock calculations have been used to calculate the partial atomic charges (using the Hirshfeld and CM5 models), orbital energies, polarizabilities, dipole moments and quadrupolar amplitudes for over one hundred molecules for which there are experimental values for two basicity parameters, Kamlet and Taft's hydrogen bond acceptor strength, β, and Gutmann's donor number, DN, a measure of Lewis basicity. Regression of the experimental β and DN values against molecular descriptors reflecting the above molecular properties yields a remarkably consistent picture. For both parameters the values for alcohols and amines lie systematically off of the regression lines through the remaining compounds, which include alkanes, aromatics, halogenated alkanes and aromatics, esters, carbonates, carboxylic acids, ketones, ethers, nitriles, phosphates, sulfides and sulfates. Independent of the calculation method or method of estimating the partial atomic charges, both experimental β and DN are essentially determined by two molecular properties: the charge on the most negative atom of the molecule and the molecular orbital from which charge donation would occur. The regression results using any of the fours sets of descriptors (reflecting the two calculation methods and two methods of charge estimation) are remarkably similar for β and DN supporting the view that these are measures of the same "basicity".
Journal of chemical information and modeling, 2018
To describe the physically realistic solvation free energy surface of a molecule in a solvent, a generalized version of the solvation free energy density (G-SFED) calculation method has been developed. In the G-SFED model, the contribution from the hydrogen bond (HB) between a solute and a solvent to the solvation free energy was calculated as the product of the acidity of the donor and the basicity of the acceptor of an HB pair. The acidity and basicity parameters of a solute were derived using the summation of acidities and basicities of the respective acidic and basic functional groups of the solute, and that of the solvent was experimentally determined. Although the contribution of HBs to the solvation free energy could be evenly distributed to grid points on the surface of a molecule, the G-SFED model was still inadequate to describe the angle dependency of the HB of a solute with a polarizable continuum solvent. To overcome this shortcoming of the G-SFED model, the contributio...
Journal of Solution Chemistry, 2020
Reichardt's normalized E N T (30) parameter for solvent polarity has been analyzed in terms of properties of solvent molecules estimated from quantum-mechanical calculations of isolated solvent molecules. The analyses show that E N T (30) has a strong dependence on the partial charge on the most positive hydrogen atom in the solvent molecule, reflecting hydrogen bonding at the pendant oxygen atom of the betaine dye used to define the E T (30) scale. There are smaller, and roughly equal, dependences on the dipole moments and quadrupolar amplitudes of the solvent molecules and an inverse dependence on the solvent polarizability. These three dependences reflect the solvent polarity, that is, the ability to stabilize charge through longer-range interactions. The reason for the inverse dependence on the solvent polarizability is unclear, but a similar dependence was found previously in the analysis of the Kamlet, Abboud and Taft π * scale. The resulting equation for E N T (30) reproduces the experimental values for around 160 solvents, representing most classes of organic solvents, with a standard deviation of around 0.07 { E N T (30) values range from 0 to 1}. The Kamlet and Taft α scale of hydrogen bond donor acidities, which is, in effect, derived from the differences between the E N T (30) and π * values for a solvent, is discussed. The results of the present analyses of E N T (30) and earlier analyses of π * indicate that, while the α values capture the effect of solvent hydrogen bond donor acidity, it also contains residual dependences on other molecular properties. These residual dependences result from the differences in the dependences of the E N T (30) and π * on solvent properties.
J
The three-dimensional reference interaction site model of the molecular solvation theory with the Kovalenko–Hirata closure is used to calculate the free energy of solvation of organic solutes in liquid aliphatic ketones. The ketone solvent sites were modeled using a modified united-atom force field. The successful application of these solvation models in calculating ketone–water partition coefficients of a large number of solutes supports the validation and benchmarking reported here.
Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules
The Journal of Physical Chemistry B, 2008
Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TΔS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R 2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid. *Corresponding author. dmobley@gmail.com. Supporting Information Available: Coordinate files (mol2) with AM1-BCC partial charges for the small molecules in the test set used here; list of computed values for each compound with each of the implicit solvent models, and for the model of Onufriev, Bashford, and Case, using different conformations and different analysis methods; experimental solvation free energies (1M vacuum to 1M water) and references for the molecules in the test set; histograms of molecular weight and number of rotatable bonds for the test set; an alternative version of ; and a table of the 17 small molecules with TΔS larger than 0.5 kcal/mol. This information is available free of charge via the Internet at
Journal of Chemical Information and Modeling, 2006
In a recent paper appearing in this Journal Laffort and Héricourt 1 presented a generalized method to establish the numerical values of the solvation parameters of solutes. The solvation parameters, when combined with the five solvent solvation parameters, describe the intermolecular forces present in fluid solutions. As part of their discussion the authors suggested two sets of optimized values of solute solvation parameters. The first set of parameters was based on the published Abraham solute descriptors (E, S, A, B, and L), modified by the authors to include scaling factors and greater independence (orthogonality). In eqs 1-5, δ 2 denotes the solute's Laffort et al. dispersion parameter, ω 2 is the solute's orientation factor, 2 refers to the polarizability-induction parameter of the solute, and R 2 and 2 represent the solute's acidity and basicity parameters, respectively. Laffort et al. 1,2 deduced their second set of solvation parameters from experimental gas-liquid chromatographic retention indices of the solute on five selected stationary phases. The selected stationary phases were prepared in limited quantity and are not commercially available. Numerical solvation parameters were reported for 133 substances for the second of the two
Kamlet-Taft .pi.* polarizability/dipolarity of mixtures of water with various organic solvents
Analytical Chemistry, 1988
The Kamlet-Taft a" values of mldures of water with four organlc solvents over the entlre range d composition have been estknated by solvatochromk measurements wlth a serles of carefully selected Indkators. The measured a* value of each lndlcator is colllnear wlth the average a* value. We Interpret these resutts as IndkaUng that the Indicators sense the polarlzaMUty/dlpolarity and not the hydrogen bond acldlty of the solvent. Examhation of relatlonshlps between a* and c and between E , and a* and excess properties of a*, E,, and t with respect to volume fraction of the organk cosolvent leads to the conclusion that the principal effect of changlng the solvent composltkn on the observed a" values operates through the dlelectrk properties of the local medtum about the solute. Thls also supports the prevlous observatlon that soivatochromlc shifts of the Indicators used In this study are not very sensitive to solvent hydrogen bond acidity. The measured a* values together with literature E , values were used to estimate a values, the hydrogen bond acldity parameter, of aqueous organic solvents.
International Journal of Quantum Chemistry, 2014
This article reviews different formulations of the thermodynamic cycles used for the prediction of pK a values, their advantages, and disadvantages with special emphasis on the limitations resulting from the necessity of gas-phase calculations, which allow introducing some difficult cases that motivated alternative strategies. Before introducing the protocols that do not consider gas-phase calculations, the two current opinions available in the literature on the debate about the correct formalism for the calculation of free energies in solution are briefly introduced. Then, the isodesmic proton exchange reaction in solution is reviewed by analyzing its performance on difficult cases for thermodynamic cycles such as carbon acids and amino acids. The pK a values predicted by the isodesmic reaction for common acid species are also reviewed to compare their accuracy results in relation with those of thermodynamic cycles. Linear regressions between experimental pK a values and the calculated free energies obtained with the isodesmic reaction provide expressions for the dependence of the error in the calculated pK a s on the pK a difference between the studied acid and the reference species. Finally, it is shown that linear regressions correct the calculated free energies of the isodesmic reaction, when high constant precision is required in a large pK a range. The deviations from the expected behavior are equivalent to those reported previously for different pK a calculation protocols and are determined by the inaccuracies of continuum solvent models on the interactions with ionic species.