Andreas Klamt

COSMO-RS: a novel and efficient method for the a priori prediction of thermophysical data of liquids

A novel and very efficient method for the a priori prediction of thermophysical data of liquids is presented. It is based on unimolecular quantum chemical calculations that provide the necessary information for the evaluation of molecular interactions in liquids. Combined with a very fast and accurate statistical thermodynamics, the new method is an alternative to structure-interpolating group contribution methods (GCMs). The most important advantages are the essentially general applicability, the sound physical basis, and the graphicness of the procedure, which easily allows for chemical interpretation and understanding of thermophysical behaviour. A methodological comparison with GCMs is given. Example applications are presented.

Treatment of the outlying charge in continuum solvation models

Continuum solvation models have proven to yield very valuable information about solvation effects, if cavities close to the van der Waals surface of the solutes are used for the calculation of the screening charges. Unfortunately, such cavity size implies that a small but significant portion of the solute electron density reaches out of the cavity. This outlying charge causes serious problems in the context of the dielectric continuum treatment of the solvent. The present paper presents a critical consideration of the origin, the magnitude, and the different strategies for treatment of this problem. Finally, a novel ansatz using an additional, outer cavity is presented which provides rather accurate correction of the corresponding error.

Incorporation of solvent effects into density functional calculations of molecular energies and geometries

In this paper, we present the implementation of the ‘‘conductorlike screening model’’ (COSMO) into the density functional program DMol. The electronic structure and geometry of the solute are described by a density functional method (DFT). The solute is placed into a cavity which has the shape of the solute molecule. Outside of the cavity, the solvent is represented by a homogeneous dielectric medium. The electrostatic interaction between solute and solvent is modeled through cavity surface charges induced by the solvent. The COSMO theory, based on the screening in conductors, allows for the direct determination of the surface charges within the SCF procedure using only the electrostatic potentials. This represents the major computational advantage over many of other reaction field methods. Since the DMol/COSMO energy is fully variational, accurate gradients with respect to the solute coordinates can be calculated for the first time, without any restriction on the shape of the cavity. The solvation energi...

COSMO Implementation in TURBOMOLE: Extension of an efficient quantum chemical code towards liquid systems

The most recent algorithmic enhancements of the COSMO solvation model are presented and the implementation in the TURBOMOLE program package is described. Three demonstrative applications covering homogeneous catalysis, tautomeric equilibria, and binary phase diagrams show the efficiency and general applicability of the approach. Especially when combined with the COSMO-RS extension, the method very reliably predicts thermodynamic properties of liquid mixtures.

The COSMO and COSMO-RS solvation models

The conductor‐like screening model COSMO, a variant of the dielectric continuum solvation models, has become very popular due to its algorithmic simplicity, numerical stability, and its great insensitivity with respect to outlying charge errors. The advanced model COSMO‐RS, i.e., COSMO for realistic solvation, is a statistical thermodynamics theory based on COSMO polarization charge densities, which overcomes many of the limitations and theoretical shortcomings of dielectric continuum models. Due to its ability to treat mixtures at variable temperatures, it has become very popular in chemical engineering and in wide areas of physical and medicinal chemistry. COSMO‐RS currently may be considered as the most accurate model for the prediction of solvation energies. This article provides a short description of the basic concepts of both the models, of the differences with other solvation models and of their application areas. Finally, direct COSMO‐RS, a recent direct integration of the COSMO‐RS concept into quantum chemical calculations, is briefly described.

COSMO-RS: An Alternative to Simulation for Calculating Thermodynamic Properties of Liquid Mixtures

The conductor-like screening model for realistic solvation (COSMO-RS) method has been established as a novel way to predict thermophysical data for liquid systems and has become a frequently used alternative to force field-based molecular simulation methods on one side and group contribution methods on the other. Through its unique combination of a quantum chemical treatment of solutes and solvents with an efficient statistical thermodynamics procedure for the molecular surface interactions, it enables the efficient calculation of many properties that other methods can barely predict. This review presents a short delineation of the theory, the application potential and limitations of COSMO-RS, and its most important application areas.

First Principles Calculations of Aqueous pKa Values for Organic and Inorganic Acids Using COSMO−RS Reveal an Inconsistency in the Slope of the pKa Scale

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for more realistic solvation (RS) simulations, has been used for the direct prediction of pKa constants of a large variety of 64 organic and inorganic acids. A highly significant correlation of r(2) = 0.984 with a standard deviation of only 0.49 between the calculated values of the free energies of dissociation and the experimental pKa values was found, without any special adjustment of the method. Thus, we have a theoretical a priori prediction method for pKa, which has the regression constant and the slope as only adjusted parameters. Such a method can be of great value in many areas of physical chemistry, especially in pharmaceutical and agrochemical industry. To our surprise, the slope of pKa vs ΔGdiss is only 58% of the theoretically expected value of 1/RTln(10). A careful analysis with respect to different contributions as well as a comparison with the work of other authors excludes the possibility that the discrepancy is due to weaknesses of the calculation method. Hence, we must conclude that the experimental pKa scale depends differently on the free energy of dissociation than generally assumed.

Prediction of aqueous solubility of drugs and pesticides with COSMO-RS.

The COSMO‐RS method, originally developed for the prediction of liquid–liquid and liquid–vapor equilibrium constants based on quantum chemical calculations, has been extended to solid compounds by addition of a heuristic expression for the Gibbs free energy of fusion. By this addition, COSMO‐RS is now capable of a priori prediction of aqueous solubilities of a wide range of typical neutral drug and pesticide compounds. Only three parameters in the heuristic expression have been fitted on a data set of 150 drug‐like compounds. On these data an rms deviation of 0.66 log‐units was achieved. Later, the model was tested on a set of 107 pesticides, which have been critically selected based on two experimental data sources and by a crosscheck with an independent HQSAR model. On this data set an rms of 0.61 log‐units was achieved, without any adjustments to the structurally extremely diverse pesticides. This result verifies the ability of this extended COSMO‐RS to predict aqueous solubilities of drugs and pesticides of almost arbitrary structural classes. The new method is COSMO‐RSol.

First principles implementation of solvent effects without outlying charge error

In this work, we present a sound modified implementation of the noniterative approach for the inclusion of solvent effects for molecular-shaped cavities in conventional ab initio gas phase computations. This model will serve as the starting point from which to add additional influences such as nonelectrostatic and correlation effects, as well as optimization of cavity radii. The improvement over recent dielectric continuum models is (a) the utilization of distributed multipoles up to hexadecapoles for the generation of the potential on the cavity boundary to the dielectric and the calculation of surface charges, and (b) an accurate assessment of outlying charge effects. The new method is tested in calculations of solvation energies and geometries for a number of neutral and charged molecules.

Prediction of acidity in acetonitrile solution with COSMO-RS

The COSMO‐RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of pKa values in acetonitrile. For a variety of 93 organic acids, the directly calculated values of the free energies of dissociation in acetonitrile showed a very good correlation with the pKa values (r2 = 0.97) in acetonitrile, corresponding to a standard deviation of 1.38 pKa units. Thus, we have a prediction method for acetonitrile pKa with the intercept and the slope as the only adjusted parameters. Furthermore, the pKa values of CH acids yielding large anions with delocalized charge can be predicted with a rmse of 1.12 pKa units using the theoretical values of slope and intercept resulting in truly ab initio pKa prediction. In contrast to our previous findings on aqueous acidity predictions the slope of the experimental pKa versus theoretical ΔGdiss was found to match the theoretical value 1/RT ln (10) very well. The predictivity of the presented method is general and is not restricted to certain compound classes. However, a systematic correction of −7.5 kcal mol−1 is required for compounds that do not allow electron‐delocalization in the dissociated anion. The prediction model was tested on a diverse test set of 129 complex multifunctional compounds from various sources, reaching a root mean square deviation of 2.10 pKa units.