António J. Queimada

1-Octanol/water partition coefficients of n-Alkanes from molecular simulations of absolute solvation free energies

The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1-Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C1-C8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS-AA/TraPPE force field for the organic phase can give excellent predictions for n-alkanes up to C8 with an absolute average deviation of 0.1 log P units to the experimental data.

Solubilities of Biologically Active Phenolic Compounds: Measurements and Modeling

Aqueous solubilities of natural phenolic compounds from different families (hydroxyphenyl, polyphenol, hydroxybenzoic, and phenylpropenoic) were experimentally obtained. Measurements were performed on tyrosol and ellagic, protocatechuic, syringic, and o-coumaric acids, at five different temperatures (from 288.2 to 323.2 K), using the standard shake-flask method, followed by compositional analysis using UV spectrophotometry. To verify the accuracy of the spectrophotometric method, some data points were measured by gravimetry, and in general, the values obtained with the two methods are in good agreement (deviations lower than 11%). To adequately understand the solubilization process, melting properties of the pure phenolics were obtained by differential scanning calorimetry (DSC), and apparent acid dissociation constants were measured by potentiometry titration. The aqueous solubilities followed the expected general exponential trend. The melting temperatures did not follow the same solubility tendency, and for tyrosol and ellagic acid, not only the size and extent of hydrogen bonding, but also the energy associated with their crystal structures, determine the solubility. For these binary systems, acid dissociation is not important. Approaches for modeling the measured data were evaluated. These included an excess Gibbs energy equation, the modified UNIQUAC model, and the cubic-plus-association (CPA) equation of state. Particularly for the CPA approach, a new methodology that explicitly takes into account the number and nature of the associating sites and the prediction of the pure-component parameters from molecular structure is proposed. The results indicate that these are appropriate tools for representing the water solubilities of these molecules.

Viscosity and Liquid Density of Asymmetric Hydrocarbon Mixtures

Although a large body of viscosity data exists for simple mixtures of lighter n-alkanes, available information for heavy or asymmetric systems is scarce. Experimental measurements of viscosity and liquid densities were performed, at atmospheric pressure, in pure and mixed n-heptane, n-hexadecane, n-eicosane, n-docosane, and n-tetracosane from 293.15 K, or above the melting point, up to 343.15 K. The measured densities were correlated using the Peng–Robinson equation of state, and viscosities were modelled using the friction theory.

Measurement and Modeling of Surface Tensions of Asymmetric Systems: Heptane, Eicosane, Docosane, Tetracosane and their Mixtures

To extend the surface tension database for heavy or asymmetric n-alkane mixtures, measurements were performed using the Wilhelmy plate method. Measured systems included the binary mixtures heptane + eicosane, heptane + docosane and heptane + tetracosane and the ternary mixture heptane + eicosane + tetracosane at temperatures from 313.15 K (or above the melting point of the mixture) up to 343.15 K. All the measurements were performed at atmospheric pressure. Using these data, along with data previously measured by us and collected from the literature, a recently proposed corresponding states model was assessed. It is shown that using a new generalized combining rule for the critical temperature, the data can be described with deviations of about 1% that is within the experimental uncertainty of the measurements.

Surface tension of pure heavy n-alkanes: a corresponding states approach

The surface tension of heavy n-alkanes is a poorly studied subject. Few data exist and the predictive methods used for their estimation are rather complex or show considerable errors for the higher members of the series. In this work, the corresponding states theory is used to predict the surface tension of the series of the n-alkanes. Two approaches have been followed: the first is a second-order perturbation model based on a Taylor series expansion of the surface tension using the Pitzer acentric factor; the second approach uses shape factors to account for the non-conformalities. Comparisons of the two models with experimental data and other available predictive methods are presented.

A new Corresponding States model for the estimation of thermophysical properties of long chain n-alkanes☆

The interest in phase equilibrium and thermophysical properties of mixtures containing long chain hydrocarbons is increasing. Despite the industrial interest of these systems, the available experimental data are scarce, while new models are required. Corresponding States Theoryhas been used with success for the estimation of properties of pure components and mixtures of small molecules. This work shows how this theory can be extended to the evaluation of liquid density, vapour pressure and viscosity of long chain molecules in a broad temperature range, based on information of lower members of the same homologous series. Results for the n-alkane series showed that this new model is able to predict liquid density, vapour pressure and viscosity with percent average absolute deviations of 0.44, 0.52, and 3.15%, respectively.

Low temperature behaviour of refined products from DSC measurements and their thermodynamical modelling

Abstract The low temperature behaviour of five distillation cuts (230–375°C) from crude oil from different sources (North Sea, Africa and Middle East) provided by the Portuguese refinery Petrogal, was studied. Precipitation curves for these cuts, showing the evolution of the fraction of solid n -alkanes with temperature, were measured by DSC and the compositions of the cuts were analysed by gas chromatography (GC). The measured precipitation curves have been compared with the predictions from a thermodynamical model using the compositional analysis. The model results agree well with the experimental data indicating that the model used can be an adequate tool to predict the low temperature behaviour of refined oil products.

Using molecular simulation to predict solute solvation and partition coefficients in solvents of different polarity

A methodology is proposed for the prediction of the Gibbs energy of solvation (Δ(Solv)G) based on MD simulations. The methodology is then used to predict Δ(Solv)G of four solutes (namely propane, benzene, ethanol and acetone) in several solvents of different polarities (including n-hexane, n-hexadecane, ethylbenzene, 1-octanol, acetone and water) while testing the validity of the TraPPE force field parameters. Excellent agreement with experimental data is obtained, with average deviations of 0.2, 1.1, 0.8 and 1.2 kJ mol(-1), for the four solutes respectively. Subsequently, partition coefficients (log P) for forty different solute/solvent systems are predicted. The a priori knowledge of partition coefficient values is of high importance in chemical and pharmaceutical separation process design or as a measure of the increasingly important environmental fate. Here again, the agreement between experimental data and simulation predictions is excellent, with an absolute average deviation of 0.28 log P units. However, this deviation can be decreased down to 0.14 log P units, just by optimizing partial atomic charges of acetone in the water phase. Consequently, molecular simulation is proven to be a tool with strong physical basis able to predict log P with competitive accuracy when compared to the popular statistical methods with weak physical basis.

Predicting hydration Gibbs energies of alkyl-aromatics using molecular simulation: a comparison of current force fields and the development of a new parameter set for accurate solvation data

The Gibbs energy of hydration is an important quantity to understand the molecular behavior in aqueous systems at constant temperature and pressure. In this work we review the performance of some popular force fields, namely TraPPE, OPLS-AA and Gromos, in reproducing the experimental Gibbs energies of hydration of several alkyl-aromatic compounds--benzene, mono-, di- and tri-substituted alkylbenzenes--using molecular simulation techniques. In the second part of the paper, we report a new model that is able to improve such hydration energy predictions, based on Lennard Jones parameters from the recent TraPPE-EH force field and atomic partial charges obtained from natural population analysis of density functional theory calculations. We apply a scaling factor determined by fitting the experimental hydration energy of only two solutes, and then present a simple rule to generate atomic partial charges for different substituted alkyl-aromatics. This rule has the added advantages of eliminating the unnecessary assumption of fixed charge on every substituted carbon atom and providing a simple guideline for extrapolating the charge assignment to any multi-substituted alkyl-aromatic molecule. The point charges derived here yield excellent predictions of experimental Gibbs energies of hydration, with an overall absolute average deviation of less than 0.6 kJ mol(-1). This new parameter set can also give good predictive performance for other thermodynamic properties and liquid structural information.