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Force Fields and Point Charges for Crystal Structure Modeling
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology.ORCID iD: 0000-0002-6647-3308
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology.
2009 (English)In: Industrial & Engineering Chemistry Research, ISSN 0888-5885, E-ISSN 1520-5045, Vol. 48, no 6, 2899-2912 p.Article in journal (Refereed) Published
Abstract [en]

Molecular simulation is increasingly used by chemical engineers and industrial chemists in process and product development. In particular, the possibility to predict the structure and stability of potential polymorphs of a substance is of tremendous interest to the pharmaceutical and specialty chemicals industry. Molecular mechanics modeling relies on the use of parametrized force fields and methods of assigning point charges to the atoms in the molecules. In commercial molecular simulation software, a wide variety of such combinations are available, and there is a need for critical assessment of the capabilities of the different alternatives. In the present work, the performance of several molecular mechanics force fields combined with different methods for the assignment of atomic point charges have been examined with regard to their ability to calculate absolute crystal lattice energies and their capacity to identify the experimental structure as a minimum on the potential energy hypersurface. Seven small, aromatic monomolecular crystalline compounds are used in the evaluation. It is found that the majority of the examined methods cannot be used to reliably predict absolute lattice energies. The most promising results were obtained with the Pcff force field using integral charges, and the Dreiding force field using Gasteiger charges, both of which performed with an accuracy of the same order of magnitude as the variations in experimental lattice energies. Overall, it has been observed that the best results are achieved if the same force field method is used to relax the crystal structure and calculate the energy, and to optimize and calculate the energy of the gas phase molecule used for the correction for changes in molecular geometry. The Pcff and Compass force fields with integral charges have been found to predict relaxed structures closest to the experimental ones. In addition, five different methods for determining point charges fitted to the electrostatic potential (ESP charges), available in the same software, have been evaluated. For each method, the molecular geometries of 10 small, organic molecules were optimized, and ESP charges calculated and analyzed for linear correlation with a set of reference charges of an accepted standard method, HF/6-31G*. Dmol-3 gives charges that correlate well with the reference charge. The charges from Vamp are not linearly scalable to the HF/6-31G*-level, which is attributed partly to the geometry optimization but mainly to the calculation of the ESP and the subsequent charge fit.

Place, publisher, year, edition, pages
2009. Vol. 48, no 6, 2899-2912 p.
Keyword [en]
Chemical engineers, Compass force fields, Critical assessments, Crystalline compounds, Dreiding force fields, Electrostatic potentials, Force field methods, Force fields, Gas-phase molecules, Geometry optimizations, Hf/6-31g, In process, Industrial chemists, Integral charges, Lattice energies, Linear correlations, Molecular geometries, Molecular simulations, Order of magnitudes, Organic molecules, Point charges, Potential energy hyper surfaces, Specialty chemicals, Standard methods, Structure modeling
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-10496DOI: 10.1021/ie800502mISI: 000264221600020Scopus ID: 2-s2.0-65349108076OAI: oai:DiVA.org:kth-10496DiVA: diva2:218128
Note

QC 20101029

Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Crystal Polymorphism of Substituted Monocyclic Aromatics
Open this publication in new window or tab >>Crystal Polymorphism of Substituted Monocyclic Aromatics
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: KTH, 2009. xiv, 73 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:26
Keyword
Crystallization, polymorphism, thermodynamics, kinetics, solubility, nucleation, crystal structure prediction, lattice energy, enthalpy, entropy, molecular mechanics, quantum mechanics, electrostatic potential, force field
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-10501 (URN)978-91-7415-342-2 (ISBN)
Presentation
2009-06-11, K1, KTH, Teknikringen 56, Stockholm, 11:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-26 Created: 2009-05-19 Last updated: 2010-10-29Bibliographically approved
2. Structural, Kinetic and Thermodynamic Aspects of the Crystal Polymorphism of Substituted Monocyclic Aromatic Compounds
Open this publication in new window or tab >>Structural, Kinetic and Thermodynamic Aspects of the Crystal Polymorphism of Substituted Monocyclic Aromatic Compounds
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This work concerns the interrelationship between thermodynamic, kinetic and structural aspects of crystal polymorphism. It is both experimental and theoretical, and limited with respect to compounds to substituted monocyclic aromatics.

Two polymorphs of the compound m-aminobenzoic acid have been experimentally isolated and characterized by ATR-FTIR spectroscopy, X-ray powder diffraction and optical microscopy. In addition, two polymorphs of the compound m-hydroxybenzoic acid have been isolated and characterized by ATR-FTIR spectroscopy, high-temperature XRPD, confocal Raman, hot-stage and scanning electron microscopy. For all polymorphs, melting properties and specific heat capacity have been determined calorimetrically, and the solubility in several pure solvents measured at different temperatures with a gravimetric method. The solid-state activity (ideal solubility), and the free energy, enthalpy and entropy of fusion have been determined as functions of temperature for all solid phases through a thermodynamic analysis of multiple experimental data. It is shown that m-aminobenzoic acid is an enantiotropic system, with a stability transition point determined to be located at approximately 156°C, and that the difference in free energy at room temperature between the polymorphs is considerable. It is further shown that m-hydroxybenzoic acid is a monotropic system, with minor differences in free energy, enthalpy and entropy.

1393 primary nucleation experiments have been carried out for both compounds in different series of repeatability experiments, differing with respect to solvent, cooling rate, saturation temperature and solution preparation and pre-treatment. It is found that in the vast majority of experiments, either the stable or the metastable polymorph is obtained in the pure form, and only for a few evaluated experimental conditions does one polymorph crystallize in all experiments. The fact that the polymorphic outcome of a crystallization is the result of the interplay between relative thermodynamic stability and nucleation kinetics, and that it is vital to perform multiple experiments under identical conditions when studying nucleation of polymorphic compounds, is strongly emphasized by the results of this work.

The main experimental variable which in this work has been found to affect which polymorph will preferentially crystallize is the solvent. For m-aminobenzoic acid, it is shown how a significantly metastable polymorph can be obtained by choosing a solvent in which nucleation of the stable form is sufficiently obstructed. For m-hydroxybenzoic acid, nucleation of the stable polymorph is promoted in solvents where the solubility is high. It is shown how this partly can be rationalized by analysing solubility data with respect to temperature dependence.

By crystallizing solutions differing only with respect to pre-treatment and which polymorph was dissolved, it is found that the immediate thermal and structural history of a solution can have a significant effect on nucleation, affecting the predisposition for overall nucleation as well as which polymorph will preferentially crystallize.

A set of polymorphic crystal structures has been compiled from the Cambridge Structural Database. It is found that statistically, about 50% crystallize in the crystallographic space group P21/c. Furthermore, it is found that crystal structures of polymorphs tend to differ significantly with respect to either hydrogen bond network or molecular conformation.

Molecular mechanics based Monte Carlo simulated annealing has been used to sample different potential crystal structures corresponding to minima in potential energy with respect to structural degrees of freedom, restricted to one space group, for each of the polymorphic compounds. It is found that all simulations result in very large numbers of predicted structures. About 15% of the predicted structures have excess relative lattice energies of <=10% compared to the most stable predicted structure; a limit verified to reflect maximum lattice energy differences between experimentally observed polymorphs of similar compounds. The number of predicted structures is found to correlate to molecular weight and to the number of rotatable covalent bonds. A close study of two compounds has shown that predicted structures tend to belong to different groups defined by unique hydrogen bond networks, located in well-defined regions in energy/packing space according to the close-packing principle. It is hypothesized that kinetic effects in combination with this structural segregation might affect the number of potential structures that can be realized experimentally.

The experimentally determined crystal structures of several compounds have been geometry-optimized (relaxed) to the nearest potential energy minimum using ten different combinations of common potential energy functions (force fields) and techniques for assigning nucleus-centred point charges used in the electrostatic description of the energy. Changes in structural coordinates upon relaxation have been quantified, crystal lattice energies calculated and compared with experimentally determined enthalpies of sublimation, and the energy difference before and after relaxation computed and analysed. It is found that certain combinations of force fields and charge assignment techniques work reasonably well for modelling crystal structures of small aromatics, provided that proper attention is paid to electrostatic description and to how the force field was parameterized.

A comparison of energy differences for randomly packed as well as experimentally determined crystal structures before and after relaxation suggests that the potential energy function for the solid state of a small organic molecule is highly undulating with many deep, narrow and steep minima.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. xvi, 75, v p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:35
Keyword
Polymorphism, crystallization, thermodynamics, kinetics, nucleation, crystallography, solubility, phase equilibria, polymorphic transformation, solution history, metastable zone, classical theory of nucleation, two-step theory of nucleation, cluster, crystal structure prediction, lattice energy, molecular mechanics, force field, electrostatic potential, potential energy hypersurface, m-aminobenzoic acid, m-hydroxybenzoic acid
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-33836 (URN)978-91-7415-993-6 (ISBN)
Public defence
2011-06-10, K1, Teknikringen 56, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20110527Available from: 2011-05-27 Created: 2011-05-19 Last updated: 2011-05-27Bibliographically approved

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