Advanced materials (Deerfield Beach, Fla.), Jan 4, 2017
Some of the most successful approaches to structural design in materials chemistry have exploited... more Some of the most successful approaches to structural design in materials chemistry have exploited strong directional bonds, whose geometric reliability lends predictability to solid-state assembly. For example, metal-organic frameworks are an important design platform in materials chemistry. By contrast, the structure of molecular crystals is defined by a balance of weaker intermolecular forces, and small changes to the molecular building blocks can lead to large changes in crystal packing. Hence, empirical rules are inherently less reliable for engineering the structures of molecular solids. Energy-structure-function (ESF) maps are a new approach for the discovery of functional organic crystals. These maps fuse crystal-structure prediction with the computation of physical properties to allow researchers to choose the most promising molecule for a given application, prior to its synthesis. ESF maps were used recently to discover a highly porous molecular crystal that has a high meth...
Acta Crystallographica Section B-structural Science, Jan 1, 2009
We report on the organization and outcome of the fourth blind test of crystal structure predictio... more We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, ... more Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
Control of the solid-state arrangement of molecules within a crystal is a central challenge for o... more Control of the solid-state arrangement of molecules within a crystal is a central challenge for organic materials chemistry. In the context of solid pharmaceuticals, addressing this challenge results in significant investment (of research time and finance) in methods for the discovery and the prediction of solid-state properties of new solid forms, such as polymorphs or salts. There are, however, limitations on the ability of salts and polymorphs to produce functional pharmaceutical materials. Salt formation is limited to molecules containing ...
International journal of pharmaceutics, Jan 14, 2011
The range of target structures in the fifth international blind test of crystal structure predict... more The range of target structures in the fifth international blind test of crystal structure prediction was extended to include a highly flexible molecule, (benzyl-(4-(4-methyl-5-(p-tolylsulfonyl)-1,3-thiazol-2-yl)phenyl)carbamate, as a challenge representative of modern pharmaceuticals. Two of the groups participating in the blind test independently predicted the correct structure. The methods they used are described and contrasted, and the implications of the capability to tackle molecules of this complexity are discussed.
Journal of chemical theory and computation, Jan 13, 2016
Generating sets of trial structures that sample the configurational space of crystal packing poss... more Generating sets of trial structures that sample the configurational space of crystal packing possibilities is an essential step in the process of ab initio crystal structure prediction (CSP). One effective methodology for performing such a search relies on low-discrepancy, quasi-random sampling, and our implementation of such a search for molecular crystals is described in this paper. Herein we restrict ourselves to rigid organic molecules and, by considering their geometric properties, build trial crystal packings as starting points for local lattice energy minimization. We also describe a method to match instances of the same structure, which we use to measure the convergence of our packing search toward completeness. The use of these tools is demonstrated for a set of molecules with diverse molecular characteristics and as representative of areas of application where CSP has been applied. An important finding is that the lowest energy crystal structures are typically located earl...
In this chapter we provide a description of the computational tools used for the calculation of t... more In this chapter we provide a description of the computational tools used for the calculation of the terahertz absorption spectrum of a crystalline material, with a particular focus on molecular crystals. We explain using examples why it is not correct to use the normal modes of vibration of an isolated molecule to understand the vibrational spectrum of a material in the terahertz range, but that the features in this spectral region are largely related to intermolecular interactions. It is, therefore, necessary to use methods that consider the ...
A computational search to predict the crystal structure of parabanic acid produced the known P21/... more A computational search to predict the crystal structure of parabanic acid produced the known P21/c crystal structure as the global minimum in the lattice energy. However, there are many hypothetical structures only 2–6 kJ molJ1 less stable than the known form, which are within the energy range of possible polymorphism and have reasonable mechanical properties and relative growth rates. The harmonic intermolecular frequencies and the attachment energy estimate of relative growth rates suggest that the known polymorph is ...
Scheme 1. Structures of melamine (M, left) and uric acid (U, right). Bridgehead atoms C a and C b... more Scheme 1. Structures of melamine (M, left) and uric acid (U, right). Bridgehead atoms C a and C b of uric acid are labeled.
A computational study of 1061 experimentally determined crystal structures of 508 polymorphic org... more A computational study of 1061 experimentally determined crystal structures of 508 polymorphic organic molecules has been performed with state-of-the-art lattice energy minimisation methods, using a hybrid method that combines density functional theory intramolecular energies with an anisotropic atom–atom intermolecular model. Rigid molecule lattice dynamical calculations have also been performed to estimate the vibrational contributions to lattice free energies. Distributions of the differences in lattice energy, free energy, zero point energy, entropy and heat capacity between polymorphs are presented. Polymorphic lattice energy differences are typically very small: over half of polymorph pairs are separated by less than 2 kJ mol−1 and lattice energy differences exceed 7.2 kJ mol−1 in only 5% of cases. Unsurprisingly, vibrational contributions to polymorph free energy differences at ambient conditions are dominated by entropy differences. The distribution of vibrational energy differences is narrower than lattice energy differences, rarely exceeding 2 kJ mol−1. However, these relatively small vibrational free energy contributions are large enough to cause a re-ranking of polymorph stability below, or at, room temperature in 9% of the polymorph pairs.
In principle, the development of computational methods for structure and property prediction offe... more In principle, the development of computational methods for structure and property prediction offers the potential for the in silico design of functional materials. Here, we evaluate the crystal energy landscapes of a series of porous organic cages, for which small changes in chemical structure lead to completely different crystal packing arrangements and, hence, porosity. The differences in crystal packing are not intuitively obvious from the molecular structure, and hence qualitative approaches to crystal engineering have limited scope for designing new materials. We find that the crystal structures and the resulting porosity of these molecular crystals can generally be predicted in silico, such that computational screening of similar compounds should be possible. The computational predictability of organic cage crystal packing is demonstrated by the subsequent discovery, during screening of crystallisation conditions, of the lowest energy predicted structure for one of the cages.
The ability to anticipate the shape adopted by flexible molecules in the solid state is crucial f... more The ability to anticipate the shape adopted by flexible molecules in the solid state is crucial for engineering and predicting crystal packing and, hence, properties. In this study, the conformations adopted by flexible molecules in their crystal structures are assessed in terms of their relationship to the calculated global conformational landscape. The study quantifies the limits on molecular strain that can be induced by intermolecular interactions in single-component crystal structures of molecules with no intramolecular hydrogen bonding, demonstrating that some molecules are distorted by up to 20 kJ/mol by crystal packing forces. Furthermore, we find that crystallisation often selects high energy conformers, but only when the high energy conformer is more extended than the lower energy options, allowing for greater intermolecular stabilisation. Based on these observations, we propose that the crystallisability of conformers is assessed in terms of their energies and surface areas. We formulate this as a parameterised pseudo-energy related to molecular surface area, which leads to a dramatic improvement in our ability to predict the conformations adopted by molecules in their crystal structures.
The ability of computational methods to predict the structures and energetics that determine the ... more The ability of computational methods to predict the structures and energetics that determine the equilibrium of solid state mechanochemical reactions has been assessed. Two previously characterised base catalysed metathesis reactions between aromatic disulfides are studied using crystal structure prediction methods and lattice energy calculations that combine molecular electronic structure methods with anisotropic atom-atom potentials. We find that lattice energy searches locate three of the six crystal structures as global minima on their respective crystal energy landscapes. The remaining structures are less successfully predicted, due to problems modelling relative conformational energies due to limitations of the density functional theory method for calculating intramolecular energies. Prediction of the overall reaction energies proves challenging for current methods, but the results show promise as a base on which to build more accurate and reliable approaches.
Advanced materials (Deerfield Beach, Fla.), Jan 4, 2017
Some of the most successful approaches to structural design in materials chemistry have exploited... more Some of the most successful approaches to structural design in materials chemistry have exploited strong directional bonds, whose geometric reliability lends predictability to solid-state assembly. For example, metal-organic frameworks are an important design platform in materials chemistry. By contrast, the structure of molecular crystals is defined by a balance of weaker intermolecular forces, and small changes to the molecular building blocks can lead to large changes in crystal packing. Hence, empirical rules are inherently less reliable for engineering the structures of molecular solids. Energy-structure-function (ESF) maps are a new approach for the discovery of functional organic crystals. These maps fuse crystal-structure prediction with the computation of physical properties to allow researchers to choose the most promising molecule for a given application, prior to its synthesis. ESF maps were used recently to discover a highly porous molecular crystal that has a high meth...
Acta Crystallographica Section B-structural Science, Jan 1, 2009
We report on the organization and outcome of the fourth blind test of crystal structure predictio... more We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, ... more Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
Control of the solid-state arrangement of molecules within a crystal is a central challenge for o... more Control of the solid-state arrangement of molecules within a crystal is a central challenge for organic materials chemistry. In the context of solid pharmaceuticals, addressing this challenge results in significant investment (of research time and finance) in methods for the discovery and the prediction of solid-state properties of new solid forms, such as polymorphs or salts. There are, however, limitations on the ability of salts and polymorphs to produce functional pharmaceutical materials. Salt formation is limited to molecules containing ...
International journal of pharmaceutics, Jan 14, 2011
The range of target structures in the fifth international blind test of crystal structure predict... more The range of target structures in the fifth international blind test of crystal structure prediction was extended to include a highly flexible molecule, (benzyl-(4-(4-methyl-5-(p-tolylsulfonyl)-1,3-thiazol-2-yl)phenyl)carbamate, as a challenge representative of modern pharmaceuticals. Two of the groups participating in the blind test independently predicted the correct structure. The methods they used are described and contrasted, and the implications of the capability to tackle molecules of this complexity are discussed.
Journal of chemical theory and computation, Jan 13, 2016
Generating sets of trial structures that sample the configurational space of crystal packing poss... more Generating sets of trial structures that sample the configurational space of crystal packing possibilities is an essential step in the process of ab initio crystal structure prediction (CSP). One effective methodology for performing such a search relies on low-discrepancy, quasi-random sampling, and our implementation of such a search for molecular crystals is described in this paper. Herein we restrict ourselves to rigid organic molecules and, by considering their geometric properties, build trial crystal packings as starting points for local lattice energy minimization. We also describe a method to match instances of the same structure, which we use to measure the convergence of our packing search toward completeness. The use of these tools is demonstrated for a set of molecules with diverse molecular characteristics and as representative of areas of application where CSP has been applied. An important finding is that the lowest energy crystal structures are typically located earl...
In this chapter we provide a description of the computational tools used for the calculation of t... more In this chapter we provide a description of the computational tools used for the calculation of the terahertz absorption spectrum of a crystalline material, with a particular focus on molecular crystals. We explain using examples why it is not correct to use the normal modes of vibration of an isolated molecule to understand the vibrational spectrum of a material in the terahertz range, but that the features in this spectral region are largely related to intermolecular interactions. It is, therefore, necessary to use methods that consider the ...
A computational search to predict the crystal structure of parabanic acid produced the known P21/... more A computational search to predict the crystal structure of parabanic acid produced the known P21/c crystal structure as the global minimum in the lattice energy. However, there are many hypothetical structures only 2–6 kJ molJ1 less stable than the known form, which are within the energy range of possible polymorphism and have reasonable mechanical properties and relative growth rates. The harmonic intermolecular frequencies and the attachment energy estimate of relative growth rates suggest that the known polymorph is ...
Scheme 1. Structures of melamine (M, left) and uric acid (U, right). Bridgehead atoms C a and C b... more Scheme 1. Structures of melamine (M, left) and uric acid (U, right). Bridgehead atoms C a and C b of uric acid are labeled.
A computational study of 1061 experimentally determined crystal structures of 508 polymorphic org... more A computational study of 1061 experimentally determined crystal structures of 508 polymorphic organic molecules has been performed with state-of-the-art lattice energy minimisation methods, using a hybrid method that combines density functional theory intramolecular energies with an anisotropic atom–atom intermolecular model. Rigid molecule lattice dynamical calculations have also been performed to estimate the vibrational contributions to lattice free energies. Distributions of the differences in lattice energy, free energy, zero point energy, entropy and heat capacity between polymorphs are presented. Polymorphic lattice energy differences are typically very small: over half of polymorph pairs are separated by less than 2 kJ mol−1 and lattice energy differences exceed 7.2 kJ mol−1 in only 5% of cases. Unsurprisingly, vibrational contributions to polymorph free energy differences at ambient conditions are dominated by entropy differences. The distribution of vibrational energy differences is narrower than lattice energy differences, rarely exceeding 2 kJ mol−1. However, these relatively small vibrational free energy contributions are large enough to cause a re-ranking of polymorph stability below, or at, room temperature in 9% of the polymorph pairs.
In principle, the development of computational methods for structure and property prediction offe... more In principle, the development of computational methods for structure and property prediction offers the potential for the in silico design of functional materials. Here, we evaluate the crystal energy landscapes of a series of porous organic cages, for which small changes in chemical structure lead to completely different crystal packing arrangements and, hence, porosity. The differences in crystal packing are not intuitively obvious from the molecular structure, and hence qualitative approaches to crystal engineering have limited scope for designing new materials. We find that the crystal structures and the resulting porosity of these molecular crystals can generally be predicted in silico, such that computational screening of similar compounds should be possible. The computational predictability of organic cage crystal packing is demonstrated by the subsequent discovery, during screening of crystallisation conditions, of the lowest energy predicted structure for one of the cages.
The ability to anticipate the shape adopted by flexible molecules in the solid state is crucial f... more The ability to anticipate the shape adopted by flexible molecules in the solid state is crucial for engineering and predicting crystal packing and, hence, properties. In this study, the conformations adopted by flexible molecules in their crystal structures are assessed in terms of their relationship to the calculated global conformational landscape. The study quantifies the limits on molecular strain that can be induced by intermolecular interactions in single-component crystal structures of molecules with no intramolecular hydrogen bonding, demonstrating that some molecules are distorted by up to 20 kJ/mol by crystal packing forces. Furthermore, we find that crystallisation often selects high energy conformers, but only when the high energy conformer is more extended than the lower energy options, allowing for greater intermolecular stabilisation. Based on these observations, we propose that the crystallisability of conformers is assessed in terms of their energies and surface areas. We formulate this as a parameterised pseudo-energy related to molecular surface area, which leads to a dramatic improvement in our ability to predict the conformations adopted by molecules in their crystal structures.
The ability of computational methods to predict the structures and energetics that determine the ... more The ability of computational methods to predict the structures and energetics that determine the equilibrium of solid state mechanochemical reactions has been assessed. Two previously characterised base catalysed metathesis reactions between aromatic disulfides are studied using crystal structure prediction methods and lattice energy calculations that combine molecular electronic structure methods with anisotropic atom-atom potentials. We find that lattice energy searches locate three of the six crystal structures as global minima on their respective crystal energy landscapes. The remaining structures are less successfully predicted, due to problems modelling relative conformational energies due to limitations of the density functional theory method for calculating intramolecular energies. Prediction of the overall reaction energies proves challenging for current methods, but the results show promise as a base on which to build more accurate and reliable approaches.
Uploads
Papers by Graeme Day