Electronic absorption spectra and solvatochromic shifts by the vertical excitation model: solvated clusters and molecular dynamics sampling.

A physically realistic treatment of solvatochromic shifts in liquid-phase electronic absorption spectra requires a proper account for various short- and long-range equilibrium and nonequilibrium solute-solvent interactions. The present article demonstrates that such a treatment can be accomplished using a mixed discrete-continuum approach based on the two-time-scale self-consistent state-specific vertical excitation model (called VEM) for electronic excitation in solution. We apply this mixed approach in combination with time-dependent density functional theory to compute UV/vis absorption spectra in solution for the n → π* ((1)A2) transition for acetone in methanol and in water, the π → π* ((1)A1) transition for para-nitroaniline (PNA) in methanol and in water, the n → π* ((1)B1) transition for pyridine in water, and the n → π* ((1)B1) transition for pyrimidine in water. Hydrogen bonding and first-solvation-shell-specific complexation are included by means of explicit solvent molecules, and solute-solvent dispersion is included by using the solvation model with state-specific polarizability (SMSSP). Geometries of microsolvated clusters were treated in two different ways, (i) using single liquid-phase global-minimum solute-solvent clusters containing up to two explicit solvent molecules and (ii) using solute-solvent cluster snapshots derived from molecular dynamics (MD) trajectories. The calculations in water involve using VEM/TDDFT excitation energies and oscillator strengths computed over 200 MD-derived solute-solvent clusters and convoluted with Gaussian functions. We also calculate ground- and excited-state dipole moments for interpretation. We find that inclusion of explicit solvent molecules generally improves the agreement with experiment and can be recommended as a way to include the effect of hydrogen bonding in solvatochromic shifts.

Computational electrochemistry: prediction of liquid-phase reduction potentials.

This article reviews recent developments and applications in the area of computational electrochemistry. Our focus is on predicting the reduction potentials of electron transfer and other electrochemical reactions and half-reactions in both aqueous and nonaqueous solutions. Topics covered include various computational protocols that combine quantum mechanical electronic structure methods (such as density functional theory) with implicit-solvent models, explicit-solvent protocols that employ Monte Carlo or molecular dynamics simulations (for example, Car-Parrinello molecular dynamics using the grand canonical ensemble formalism), and the Marcus theory of electronic charge transfer. We also review computational approaches based on empirical relationships between molecular and electronic structure and electron transfer reactivity. The scope of the implicit-solvent protocols is emphasized, and the present status of the theory and future directions are outlined.

Configuration Interaction-Corrected Tamm-Dancoff Approximation: A Time-Dependent Density Functional Method with the Correct Dimensionality of Conical Intersections.

Linear response (LR) Kohn-Sham (KS) time-dependent density functional theory (TDDFT), or KS-LR, has been widely used to study electronically excited states of molecules and is the method of choice for large and complex systems. The Tamm-Dancoff approximation to TDDFT (TDDFT-TDA or KS-TDA) gives results similar to KS-LR and alleviates the instability problem of TDDFT near state intersections. However, KS-LR and KS-TDA share a debilitating feature; conical intersections of the reference state and a response state occur in F - 1 instead of the correct F - 2 dimensions, where F is the number of internal degrees of freedom. Here, we propose a new method, named the configuration interaction-corrected Tamm-Dancoff approximation (CIC-TDA), that eliminates this problem. It calculates the coupling between the reference state and an intersecting response state by interpreting the KS reference-state Slater determinant and linear response as if they were wave functions. Both formal analysis and test results show that CIC-TDA gives similar results to KS-TDA far from a conical intersection, but the intersection occurs with the correct dimensionality. We anticipate that this will allow more realistic application of TDDFT to photochemistry.

Calculation of the Gibbs free energy of solvation and dissociation of HCl in water via Monte Carlo simulations and continuum solvation models.

The Gibbs free energy of solvation and dissociation of hydrogen chloride in water is calculated through a combined molecular simulation/quantum chemical approach at four temperatures between T = 300 and 450 K. The Gibbs free energy is first decomposed into the sum of two components: the Gibbs free energy of transfer of molecular HCl from the vapor to the aqueous liquid phase and the standard-state Gibbs free energy of acid dissociation of HCl in aqueous solution. The former quantity is calculated using Gibbs ensemble Monte Carlo simulations using either Kohn-Sham density functional theory or a molecular mechanics force field to determine the system's potential energy. The latter Gibbs free energy contribution is computed using a continuum solvation model utilizing either experimental reference data or micro-solvated clusters. The predicted combined solvation and dissociation Gibbs free energies agree very well with available experimental data.

Uniform Treatment of Solute-Solvent Dispersion in the Ground and Excited Electronic States of the Solute Based on a Solvation Model with State-Specific Polarizability.

We present a new kind of treatment of the solute-solvent dispersion contribution to the free energy of solvation using a solvation model with state-specific polarizability (SMSSP). To evaluate the solute-solvent dispersion contribution, the SMSSP model utilizes only two descriptors, namely, the spherically averaged dipole polarizability of the solute molecule (either in its ground or excited electronic state) and the refractive index of the solvent. The model was parametrized over 643 ground-state solvation free energy data for 231 solutes in 14 nonpolar, non-hydrogen-bonding solvents. We show that the SMSSP model is applicable to solutes in both the ground and the excited electronic state. For example, in comparison to available experimental data, the model yields qualitatively accurate predictions of the solvatochromic shifts for a number of systems where solute-solvent dispersion is the dominant contributor to the shift.

Generalized Born Solvation Model SM12.

We present a new self-consistent reaction-field implicit solvation model that employs the generalized Born approximation for the bulk electrostatic contribution to the free energy of solvation. The new solvation model (SM) is called SM12 (where ″12″ stands for 2012), and it is available with two sets of parameters, SM12CM5 and SM12ESP. The SM12CM5 parametrization is based on CM5 partial atomic charges, and the SM12ESP parametrization is based on charges derived from a quantum-mechanically calculated electrostatic potential (ESP) (in particular, we consider ChElPG and Merz-Kollman-Singh charges). The model was parametrized over 10 combinations of theoretical levels including the 6-31G(d) and MG3S basis sets and the B3LYP, mPW1PW, M06-L, M06, and M06-2X density functionals against 2979 reference experimental data. The reference data include 2503 solvation free energies and 144 transfer free energies of neutral solutes composed of H, C, N, O, F, Si, P, S, Cl, Br, and I in water and in 90 organic solvents as well as 332 solvation free energies of singly charged anions and cations in acetonitrile, dimethyl sulfoxide, methanol, and water. The advantages of the new solvation model over our previous generalized Born model (SM8) and all other previous generalized Born solvation models are (i) like the SMD model based on electron density distributions, it may be applied with a single set of parameters with arbitrary extended basis sets, whereas the SM8 model involves CM4 or CM4M charges that become unstable for extended basis sets, (ii) it is parametrized against a more diverse training sets than any previous solvation model, and (iii) it is defined for the entire periodic table.

Quantum mechanical continuum solvation models for ionic liquids.

The quantum mechanical SMD continuum universal solvation model can be applied to predict the free energy of solvation of any solute in any solvent following specification of various macroscopic solvent parameters. For three ionic liquids where these descriptors are readily available, the SMD solvation model exhibits a mean unsigned error of 0.48 kcal/mol for 93 solvation free energies of neutral solutes and a mean unsigned error of 1.10 kcal/mol for 148 water-to-IL transfer free energies. Because the necessary solvent parameters are not always available for a given ionic liquid, we determine average values for a set of ionic liquids over which measurements have been made in order to define a generic ionic liquid solvation model, SMD-GIL. Considering 11 different ionic liquids, the SMD-GIL solvation model exhibits a mean unsigned error of 0.43 kcal/mol for 344 solvation free energies of neutral solutes and a mean unsigned error of 0.61 kcal/mol for 431 water-to-IL transfer free energies. As these errors are similar in magnitude to those typically observed when applying continuum solvation models to ordinary liquids, we conclude that the SMD universal solvation model may be applied to ionic liquids as well as ordinary liquids.

Resolution of a Challenge for Solvation Modeling: Calculation of Dicarboxylic Acid Dissociation Constants Using Mixed Discrete-Continuum Solvation Models.

First and second dissociation constants (pKa values) of oxalic acid, malonic acid, and adipic acid were computed by using a number of theoretical protocols based on density functional theory and using both continuum solvation models and mixed discrete-continuum solvation models. We show that fully implicit solvation models (in which the entire solvent is represented by a dielectric continuum) fail badly for dicarboxylic acids with mean unsigned errors (averaged over six pKa values) of 2.4-9.0 log units, depending on the particular implicit model used. The use of water-solute clusters and accounting for multiple conformations in solution significantly improve the performance of both generalized Born solvation models and models that solve the nonhomogeneous dielectric Poisson equation for bulk electrostatics. The four most successful models have mean unsigned errors of only 0.6-0.8 log units.

Charge Model 5: An Extension of Hirshfeld Population Analysis for the Accurate Description of Molecular Interactions in Gaseous and Condensed Phases.

We propose a novel approach to deriving partial atomic charges from population analysis. The new model, called Charge Model 5 (CM5), yields class IV partial atomic charges by mapping from those obtained by Hirshfeld population analysis of density functional electronic charge distributions. The CM5 model utilizes a single set of parameters derived by fitting to reference values of the gas-phase dipole moments of 614 molecular structures. An additional test set (not included in the CM5 parametrization) contained 107 singly charged ions with nonzero dipole moments, calculated from the accurate electronic charge density, with respect to the center of nuclear charges. The CM5 model is applicable to any charged or uncharged molecule composed of any element of the periodic table in the gas phase or in solution. The CM5 model predicts dipole moments for the tested molecules that are more accurate on average than those from the original Hirshfeld method or from many other popular schemes including atomic polar tensor and Löwdin, Mulliken, and natural population analyses. In addition, the CM5 charge model is essentially independent of a basis set. It can be used with larger basis sets, and thereby this model significantly improves on our previous charge models CMx (x = 1-4 or 4M) and other methods that are prone to basis set sensitivity. CM5 partial atomic charges are less conformationally dependent than those derived from electrostatic potentials. The CM5 model does not suffer from ill conditioning for buried atoms in larger molecules, as electrostatic fitting schemes sometimes do. The CM5 model can be used with any level of electronic structure theory (Hartree-Fock, post-Hartree-Fock, and other wave function correlated methods or density functional theory) as long as an accurate electronic charge distribution and a Hirshfeld analysis can be computed for that level of theory.

Use of solution-phase vibrational frequencies in continuum models for the free energy of solvation.

We find that vibrational contributions to a solute's free energy are in general insensitive to whether the solute vibrational frequencies are computed in the gas phase or in solution. In most cases, the difference is smaller than the intrinsic error in solvation free energies associated with the continuum approximation to solvation modeling, although care must be taken to avoid spurious results associated with limitations in the quantum-mechanical harmonic-oscillator approximation for very low-frequency molecular vibrations. We compute solute vibrational partition functions in aqueous and carbon tetrachloride solution and compare them to gas-phase molecular partition functions computed with the same level of theory and the same quasiharmonic approximation for the diverse and extensive set of molecules and ions included in the training set of the SMD continuum solvation model, and we find mean unsigned differences in vibrational contributions to the solute free energy of only about 0.2 kcal/mol. On the basis of these results and a review of the theory, we conclude, in contrast to previous work (Ho, J.; Klamt, H.; Coote, M. L. J. Phys. Chem. A 2010, 114, 13442), that using partition functions computed for molecules optimized in solution is a correct and useful approach for averaging over solute degrees of freedom when computing free energies of solutes in solution, and it is moreover recommended for cases where liquid and gas-phase solute structures differ appreciably or when stationary points present in liquid solution do not exist in the gas phase, for which we provide some examples. When gas-phase and solution-phase geometries and frequencies are similar, the use of gas-phase geometries and frequencies is a useful approximation.

The solvation, partitioning, hydrogen bonding, and dimerization of nucleotide bases: a multifaceted challenge for quantum chemistry.

We present M06-2X density functional calculations of the chloroform/water partition coefficients of cytosine, thymine, uracil, adenine, and guanine and calculations of the free energies of association of selected unsubstituted and alkylated nucleotide base pairs in chloroform and water. Both hydrogen bonding and π-π stacking interactions are considered. Solvation effects are treated using the continuum solvent models SM8, SM8AD, and SMD, including geometry optimization in solution. Comparison of theoretical results with available experimental data indicates that all three of these solvation models predict the chloroform-water partition coefficients for the studied nucleobases qualitatively well, with mean unsigned errors in the range of 0.4-1.3 log units. All three models correctly predict the preference for hydrogen bonding over stacking for nucleobase pairs solvated in chloroform, and SM8, SM8AD, and SMD show similar accuracy in predicting the corresponding free energies of association. The agreement between theory and experiment for the association free energies of the dimers in water is more difficult to assess, as the relevant experimental data are indirect. Theory predicts that the stacking interaction of nucleobases in water is more favorable than hydrogen bonding for only two out of three tested hetero-dimers.

Free Energies of Solvation with Surface, Volume, and Local Electrostatic Effects and Atomic Surface Tensions to Represent the First Solvation Shell.

Building on the SVPE (surface and volume polarization for electrostatics) model for electrostatic contributions to the free energy of solvation with explicit consideration of both surface and volume polarization effects, on the SMx approach to including first-solvation-shell contributions, and on the linear relationship between the electric field and short-range electrostatic contributions found by Chipman, we have developed a new method for computing absolute aqueous solvation free energies by combining the SVPE method with semiempirical terms that account for effects beyond bulk electrostatics. The new method is called SMVLE, and the elements it contains are denoted by SVPE-CDSL where SVPE denotes accounting for bulk electrostatic interactions between solute and solvent with both surface and volume contributions, CDS denotes the inclusion of solvent cavitation, changes in dispersion energy, and possible changes in local solvent structure by a semiempirical term utilizing geometry-dependent atomic surface tensions as implemented in SMx models, and L represents the local electrostatic effect derived from the outward-directed normal electric field on the cavity surface. The semiempirical CDS and L terms together represent the deviation of short-range contributions to the free energy of solvation from those accounted for by the SVPE term based on the bulk solvent dielectric constant. A solute training set containing a broad range of molecules used previously in the development of SM6 is used here for SMVLE model calibration. The aqueous solvation free energies predicted by the parameterized SMVLE model correlate exceedingly well with experimental values. The square of the correlation coefficient is 0.9949 and the slope is 1.0079. Comparison of the final SMVLE model against the earlier SMx solvation model shows that the parameterized SMVLE model not only yields good accuracy for neutrals but also significantly increases the accuracy for ions, making it the best implicit solvation model to date for aqueous solvation free energies of ions. The semiempirical terms associated with the outward-directed electric field account in a physical way for the improvement in the predictive accuracy for ions. The SMVLE method greatly decreases the need to include explicit water molecules for accurate modeling of solvation free energies of ions.

Prediction of SAMPL2 aqueous solvation free energies and tautomeric ratios using the SM8, SM8AD, and SMD solvation models.

We applied the solvation models SM8, SM8AD, and SMD in combination with the Minnesota M06-2X density functional to predict vacuum-water transfer free energies (Task 1) and tautomeric ratios in aqueous solution (Task 2) for the SAMPL2 test set. The bulk-electrostatic contribution to the free energy of solvation is treated as follows: SM8 employs the generalized Born model with the Coulomb field approximation, SM8AD employs the generalized Born approximation with asymmetric descreening, and SMD solves the nonhomogeneous Poisson equation. The non-bulk-electrostatic contribution arising from short-range interactions between the solute and solvent molecules in the first solvation shell is treated as a sum of terms that are products of geometry-dependent atomic surface tensions and solvent-accessible surface areas of the individual atoms of the solute. On average, three models tested in the present work perform similarly. In particular, we achieved mean unsigned errors of 1.3 (SM8), 2.0 (SM8AD), and 2.6 kcal/mol (SMD) for the aqueous free energies of 30 out of 31 compounds with known reference data involved in Task 1 and mean unsigned errors of 2.7 (SM8), 1.8 (SM8AD), and 2.4 kcal/mol (SMD) in the free energy differences (tautomeric ratios) for 21 tautomeric pairs in aqueous solution involved in Task 2.

Sorting Out the Relative Contributions of Electrostatic Polarization, Dispersion, and Hydrogen Bonding to Solvatochromic Shifts on Vertical Electronic Excitation Energies.

Conventional polarized continuum model calculations of solvatochromic shifts on electronic excitation energies using popular quantum chemical programs (e.g., Gaussian or Turbomole) include the noninertial and inertial bulk-solvent polarization, which will be called electrostatics, but not dispersion interactions and specific effects like hydrogen bonding. For the n→π* excitation of acetone in several solvents, we estimated the nonelectrostatic contributions in two ways: (i) the vertical excitation model (VEM) of Li et al. (Int. J. Quantum Chem. 2000, 77, 264), but updated to use TD-DFT corrected linear response with SMD atomic radii, and (ii) in the case of acetone in water, ensemble averaging over supermolecule calculations with up to 12 explicit solvent molecules selected from a molecular dynamics trajectory, with the explicit solvent surrounded by a continuum solvent. The TD-DFT VEM calculations carried out with the M06 density functional for 23 solvents result in a dispersion contribution to the red of 261-356 cm(-1) and a hydrogen-bonding contribution to the blue of up to 289 cm(-1).

Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions.

We present a new continuum solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent. The model is called SMD, where the "D" stands for "density" to denote that the full solute electron density is used without defining partial atomic charges. "Continuum" denotes that the solvent is not represented explicitly but rather as a dielectric medium with surface tension at the solute-solvent boundary. SMD is a universal solvation model, where "universal" denotes its applicability to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known (in particular, dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters). The model separates the observable solvation free energy into two main components. The first component is the bulk electrostatic contribution arising from a self-consistent reaction field treatment that involves the solution of the nonhomogeneous Poisson equation for electrostatics in terms of the integral-equation-formalism polarizable continuum model (IEF-PCM). The cavities for the bulk electrostatic calculation are defined by superpositions of nuclear-centered spheres. The second component is called the cavity-dispersion-solvent-structure term and is the contribution arising from short-range interactions between the solute and solvent molecules in the first solvation shell. This contribution is a sum of terms that are proportional (with geometry-dependent proportionality constants called atomic surface tensions) to the solvent-accessible surface areas of the individual atoms of the solute. The SMD model has been parametrized with a training set of 2821 solvation data including 112 aqueous ionic solvation free energies, 220 solvation free energies for 166 ions in acetonitrile, methanol, and dimethyl sulfoxide, 2346 solvation free energies for 318 neutral solutes in 91 solvents (90 nonaqueous organic solvents and water), and 143 transfer free energies for 93 neutral solutes between water and 15 organic solvents. The elements present in the solutes are H, C, N, O, F, Si, P, S, Cl, and Br. The SMD model employs a single set of parameters (intrinsic atomic Coulomb radii and atomic surface tension coefficients) optimized over six electronic structure methods: M05-2X/MIDI!6D, M05-2X/6-31G, M05-2X/6-31+G, M05-2X/cc-pVTZ, B3LYP/6-31G, and HF/6-31G. Although the SMD model has been parametrized using the IEF-PCM protocol for bulk electrostatics, it may also be employed with other algorithms for solving the nonhomogeneous Poisson equation for continuum solvation calculations in which the solute is represented by its electron density in real space. This includes, for example, the conductor-like screening algorithm. With the 6-31G basis set, the SMD model achieves mean unsigned errors of 0.6-1.0 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 4 kcal/mol on average for ions with either Gaussian03 or GAMESS.

Performance of SM6, SM8, and SMD on the SAMPL1 test set for the prediction of small-molecule solvation free energies.

The SM6, SM8, and SMD quantum mechanical aqueous continuum solvation models are applied to predict free energies of aqueous solvation for 61 molecules in the SAMPL1 test set described elsewhere (Guthrie. J. Phys. Chem. B 2009, 113, 4501-4507). For direct comparison to other models, frozen geometries, provided by Guthrie, were used together with the M06-2X density functional and the 6-31G(d) basis set. For the bulk electrostatic component of the solvation free energy, SM6 and SM8 employ a generalized Born model that uses polarized discrete partial atomic charges to model the electron density, with these charges being calculated by the CM4 and CM4M class IV charge models, respectively; SMD uses the polarized continuous quantum mechanical charge density. If five sulfonylureas are removed from the SAMPL1 set, the root-mean-square deviations (RMSDs) of SM6, SM8, and SMD on the remaining 56 molecules are 2.4, 2.6, and 2.5 kcal mol(-1), respectively. The SM6, SM8, and SMD RMSDs on the five sulfonylureas are 14.2, 12.6, and 11.1 kcal mol(-1), respectively; however, we suggest that the uncertainty in the target solvation free energies for these molecules may be quite large.

Mechanistic Analysis of the Base-Catalyzed HF Elimination from 4-Fluoro-4-(4'-nitrophenyl)butane-2-one Based on Liquid-Phase Kinetic Isotope Effects Calculated by Dynamics Modeling with Multidimensional Tunneling.

The primary and secondary deuterium kinetic isotope effects as well as leaving-group fluorine kinetic isotope effects have been calculated for the base-promoted elimination of hydrogen fluoride from 4-fluoro-4-(4'-nitrophenyl)butane-2-one in 75% aqueous methanol solution. The elimination was studied for both formate and imidazole as the catalytic base; and reactant and transition state structures and vibrational frequencies have been calculated by including the base explicitly and by including the solvent by an implicit solvation model that includes both electrostatics by class IV charges and first-solvation-shell effects by atomic surface tensions. We used the M06-L density functional for all calculations. The optimized stationary points, the geometry changes along the solution-phase minimum free energy path, and the solution-phase free energy profile indicate that the elimination reaction occurs concertedly but asynchronously via an E1cb-like transition state. Reaction rates were calculated by the equilibrium solvation path method, using variational transition state theory with multidimensional tunneling. The primary deuterium kinetic isotope effects are calculated to be large: 1.67 and 5.13 for formate and imidazole, respectively. The corresponding C4-secondary deuterium kinetic isotope effects are 1.044 and 1.044, and the leaving group fluorine kinetic isotope effects are respectively 1.020 and 1.015.

Solvent Dependence of (14)N Nuclear Magnetic Resonance Chemical Shielding Constants as a Test of the Accuracy of the Computed Polarization of Solute Electron Densities by the Solvent.

Although continuum solvation models have now been shown to provide good quantitative accuracy for calculating free energies of solvation, questions remain about the accuracy of the perturbed solute electron densities and properties computed from them. Here we examine those questions by applying the SM8, SM8AD, SMD, and IEF-PCM continuum solvation models in combination with the M06-L density functional to compute the (14)N magnetic resonance nuclear shieldings of CH3CN, CH3NO2, CH3NCS, and CH3ONO2 in multiple solvents, and we analyze the dependence of the chemical shifts on solvent dielectric constant. We examine the dependence of the computed chemical shifts on the definition of the molecular cavity (both united-atom models and models based on superposed individual atomic spheres) and three kinds of treatments of the electrostatics, namely the generalized Born approximation with the Coulomb field approximation, the generalized Born model with asymmetric descreening, and models based on approximate numerical solution schemes for the nonhomogeneous Poisson equation. Our most systematic analyses are based on the computation of relative (14)N chemical shifts in a series of solvents, and we compare calculated shielding constants relative to those in CCl4 for various solvation models and density functionals. While differences in the overall results are found to be reasonably small for different solvation models and functionals, the SMx models SM8, and SM8AD, using the same cavity definitions (which for these models means the same atomic radii) as those employed for the calculation of free energies of solvation, exhibit the best agreement with experiment for every functional tested. This suggests that in addition to predicting accurate free energies of solvation, the SM8 and SM8AD generalized Born models also describe the solute polarization in a manner reasonably consistent with experimental (14)N nuclear magnetic resonance spectroscopy. Models based on the nonhomogeneous Poisson equation show slightly reduced accuracy. Scaling the intrinsic Coulomb radii to larger values (as has sometimes been suggested in the past) does not uniformly improve the results for any kind of solvent model; furthermore it uniformly degrades the results for generalized Born models. Use of a basis set that increases the outlying charge diminishes the accuracy of continuum models that solve the nonhomogeneous Poisson equation, which we ascribe to the inability of the numerical schemes for approximately solving the nonhomogeneous Poisson equation to fully account for the effects of electronic charge outside the solute cavity.

Universal Solvation Model Based on the Generalized Born Approximation with Asymmetric Descreening.

We present a new self-consistent reaction field continuum solvation model based on the generalized Born (GB) approximation for the bulk electrostatic contribution to the free energy of solvation. The new model improves on the earlier SM8 model by using the asymmetric descreening algorithm of Grycuk to treat dielectric descreening effects rather than the Coulomb field approximation; it will be called Solvation Model 8 with asymmetric descreening (SM8AD). The SM8AD model is applicable to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known, in particular dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign molecular mechanics types to an atom or a group; all parameters are unique and continuous functions of geometry. This model employs a single set of parameters (solvent acidity-dependent intrinsic Coulomb radii for the treatment of bulk electrostatics and solvent description-dependent atomic surface tensions coefficients for the treatment of nonelectrostatic and short-range electrostatic effects). The SM8AD model was optimized over 26 combinations of theoretical levels including various basis sets (MIDI!, 6-31G*, 6-31+G*, 6-31+G**, 6-31G**, cc-pVDZ, DZVP, 6-31B*) and electronic structure methods (M05-2X, M05, M06-2X, M06, M06-HF, M06-L, mPW1PW, mPWPW, B3LYP, HF). It may be used with confidence with any level of electronic structure theory as long as self-consistently polarized Charge Model 4 or other self-consistently polarized charges compatible with CM4 charges are used, for example, CM4M charges can be used. With M05-2X/6-31G*, the SM8AD model achieves a mean unsigned error of 0.6 kcal/mol on average over 2 560 solvation free energies of tested aqueous and nonaqueous neutral solutes and a mean unsigned error of 3.9 kcal/mol on average over 332 solvation free energies of aqueous and nonaqueous ions.