Co-reporter:Anna G. Slater, Paul S. Reiss, Angeles Pulido, Marc A. Little, Daniel L. Holden, Linjiang Chen, Samantha Y. Chong, Ben M. Alston, Rob Clowes, Maciej Haranczyk, Michael E. Briggs, Tom Hasell, Graeme M. Day, and Andrew I. Cooper
ACS Central Science July 26, 2017 Volume 3(Issue 7) pp:734-734
Publication Date(Web):June 20, 2017
DOI:10.1021/acscentsci.7b00145
The physical properties of 3-D porous solids are defined by their molecular geometry. Hence, precise control of pore size, pore shape, and pore connectivity are needed to tailor them for specific applications. However, for porous molecular crystals, the modification of pore size by adding pore-blocking groups can also affect crystal packing in an unpredictable way. This precludes strategies adopted for isoreticular metal–organic frameworks, where addition of a small group, such as a methyl group, does not affect the basic framework topology. Here, we narrow the pore size of a cage molecule, CC3, in a systematic way by introducing methyl groups into the cage windows. Computational crystal structure prediction was used to anticipate the packing preferences of two homochiral methylated cages, CC14-R and CC15-R, and to assess the structure–energy landscape of a CC15-R/CC3-S cocrystal, designed such that both component cages could be directed to pack with a 3-D, interconnected pore structure. The experimental gas sorption properties of these three cage systems agree well with physical properties predicted by computational energy–structure–function maps.
Co-reporter:Josh E. Campbell;Jack Yang
Journal of Materials Chemistry C 2017 vol. 5(Issue 30) pp:7574-7584
Publication Date(Web):2017/08/03
DOI:10.1039/C7TC02553J
The computational assessment of materials through the prediction of molecular and crystal properties could accelerate the discovery of novel materials. Here, we present calculated energy–structure–function maps based on crystal structure prediction for a series of hypothetical organic molecular semiconductors, to demonstrate their utility in evaluating molecules prior to their synthesis. Charge transfer in organic semiconductors relies on the degree of π-conjugation and overlap of the π-systems of neighbouring molecules in the solid state. We explore the effects of varying levels of nitrogen substitution on the crystal packing and charge transport properties of aza-substituted pentacenes, in which C–H⋯N hydrogen bonding is predicted to favour co-planar molecular packing in preference to the edge-to-face herringbone packing seen for pentacene. The charge mobilities of predicted structures in the energy range of expected polymorphism were calculated, highlighting the important balance between intra- and intermolecular properties when designing novel organic semiconductors. The use of predicted landscapes to rank molecules according to their likely properties is discussed.
Co-reporter:Jonathan A. Foster;Krishna K. Damodaran;Antoine Maurin;Hugh P. G. Thompson;Gary J. Cameron;Jenifer Cuesta Bernal;Jonathan W. Steed
Chemical Science (2010-Present) 2017 vol. 8(Issue 1) pp:78-84
Publication Date(Web):2016/12/19
DOI:10.1039/C6SC04126D
We report the synthesis of a bis(urea) gelator designed to specifically mimic the chemical structure of the highly polymorphic drug substance ROY. Crystallization of ROY from toluene gels of this gelator results in the formation of the metastable red form instead of the thermodynamic yellow polymorph. In contrast, all other gels and solution control experiments give the yellow form. Conformational and crystal structure prediction methods have been used to propose the structure of the gel and show that the templation of the red form by the targeted gel results from conformational matching of the gelator to the ROY substrate coupled with overgrowth of ROY onto the local periodic structure of the gel fibres.
Co-reporter:David H. Case, Josh E. Campbell, Peter J. Bygrave, and Graeme M. Day
Journal of Chemical Theory and Computation 2016 Volume 12(Issue 2) pp:910-924
Publication Date(Web):December 30, 2015
DOI:10.1021/acs.jctc.5b01112
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 early and frequently during a quasi-random search of phase space. It is usually the complete sampling of higher energy structures that requires extended sampling. We show how the procedure can first be refined, through targetting the volume of the generated crystal structures, and then extended across a range of space groups to make a full CSP search and locate experimentally observed and lists of hypothetical polymorphs. As the described method has also been created to lie at the base of more involved approaches to CSP, which are being developed within the Global Lattice Energy Explorer (Glee) software, a few of these extensions are briefly discussed.
Co-reporter:Francesca Piana, David H. Case, Susana M. Ramalhete, Giuseppe Pileio, Marco Facciotti, Graeme M. Day, Yaroslav Z. Khimyak, Jesús Angulo, Richard C. D. Brown and Philip A. Gale
Soft Matter 2016 vol. 12(Issue 17) pp:4034-4043
Publication Date(Web):29 Mar 2016
DOI:10.1039/C6SM00607H
Eighteen N-aryl-N′-alkyl urea gelators were synthesised in order to understand the effect of head substituents on gelation performance. Minimum gelation concentration values obtained from gel formation studies were used to rank the compounds and revealed the remarkable performance of 4-methoxyphenyl urea gelator 15 in comparison to 4-nitrophenyl analogue 14, which could not be simply ascribed to substituent effects on the hydrogen bonding capabilities of the urea protons. Crystal structure prediction calculations indicated alternative low energy hydrogen bonding arrangements between the nitro group and urea protons in gelator 14, which were supported experimentally by NMR spectroscopy. As a consequence, it was possible to relate the observed differences to interference of the head substituents with the urea tape motif, disrupting the order of supramolecular packing. The combination of unbiased structure prediction calculations with NMR is proposed as a powerful approach to investigate the supramolecular arrangement in gel fibres and help understand the relationships between molecular structure and gel formation.
Co-reporter:Jonas Nyman, Orla Sheehan Pundyke and Graeme M. Day
Physical Chemistry Chemical Physics 2016 vol. 18(Issue 23) pp:15828-15837
Publication Date(Web):17 May 2016
DOI:10.1039/C6CP02261H
We present an assessment of the performance of several force fields for modelling intermolecular interactions in organic molecular crystals using the X23 benchmark set. The performance of the force fields is compared to several popular dispersion corrected density functional methods. In addition, we present our implementation of lattice vibrational free energy calculations in the quasi-harmonic approximation, using several methods to account for phonon dispersion. This allows us to also benchmark the force fields' reproduction of finite temperature crystal structures. The results demonstrate that anisotropic atom–atom multipole-based force fields can be as accurate as several popular DFT-D methods, but have errors 2–3 times larger than the current best DFT-D methods. The largest error in the examined force fields is a systematic underestimation of the (absolute) lattice energy.
Co-reporter:Edward O. Pyzer-Knapp;Hugh P. G. Thompson
Acta Crystallographica Section B 2016 Volume 72(Issue 4) pp:477-487
Publication Date(Web):
DOI:10.1107/S2052520616007708
We present a re-parameterization of a popular intermolecular force field for describing intermolecular interactions in the organic solid state. Specifically we optimize the performance of the exp-6 force field when used in conjunction with atomic multipole electrostatics. We also parameterize force fields that are optimized for use with multipoles derived from polarized molecular electron densities, to account for induction effects in molecular crystals. Parameterization is performed against a set of 186 experimentally determined, low-temperature crystal structures and 53 measured sublimation enthalpies of hydrogen-bonding organic molecules. The resulting force fields are tested on a validation set of 129 crystal structures and show improved reproduction of the structures and lattice energies of a range of organic molecular crystals compared with the original force field with atomic partial charge electrostatics. Unit-cell dimensions of the validation set are typically reproduced to within 3% with the re-parameterized force fields. Lattice energies, which were all included during parameterization, are systematically underestimated when compared with measured sublimation enthalpies, with mean absolute errors of between 7.4 and 9.0%.
Co-reporter:Jonas Nyman and Graeme M. Day
CrystEngComm 2015 vol. 17(Issue 28) pp:5154-5165
Publication Date(Web):23 Mar 2015
DOI:10.1039/C5CE00045A
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.
Co-reporter:Hugh P. G. Thompson and Graeme M. Day
Chemical Science 2014 vol. 5(Issue 8) pp:3173-3182
Publication Date(Web):13 May 2014
DOI:10.1039/C4SC01132E
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−1 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.
Co-reporter:Edward O. Pyzer-Knapp, Hugh P. G. Thompson, Florian Schiffmann, Kim E. Jelfs, Samantha Y. Chong, Marc A. Little, Andrew I. Cooper and Graeme M. Day
Chemical Science 2014 vol. 5(Issue 6) pp:2235-2245
Publication Date(Web):11 Mar 2014
DOI:10.1039/C4SC00095A
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.
Co-reporter:Maria Baias ; Jean-Nicolas Dumez ; Per H. Svensson ; Staffan Schantz ; Graeme M. Day ;Lyndon Emsley
Journal of the American Chemical Society 2013 Volume 135(Issue 46) pp:17501-17507
Publication Date(Web):October 29, 2013
DOI:10.1021/ja4088874
The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.
Co-reporter:Maria Baias, Cory M. Widdifield, Jean-Nicolas Dumez, Hugh P. G. Thompson, Timothy G. Cooper, Elodie Salager, Sirena Bassil, Robin S. Stein, Anne Lesage, Graeme M. Day and Lyndon Emsley
Physical Chemistry Chemical Physics 2013 vol. 15(Issue 21) pp:8069-8080
Publication Date(Web):19 Feb 2013
DOI:10.1039/C3CP41095A
A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection.
Co-reporter:Dr. Mark D. Eddleston;Dr. Katarzyna E. Hejczyk;Dr. Erica G. Bithell;Dr. Graeme M. Day; William Jones
Chemistry - A European Journal 2013 Volume 19( Issue 24) pp:7883-7888
Publication Date(Web):
DOI:10.1002/chem.201204369
Abstract
A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of theophylline, at a concentration below the limits of detection of analytical methods routinely used for pharmaceutical characterisation. Detection and characterisation of crystallites of this new form were achieved with transmission electron microscopy, exploiting the combination of high magnification imaging and electron diffraction measurements. A plausible crystal structure was identified by indexing experimental electron-diffraction patterns from a single crystallite of the new polymorph against a reference set of putative crystal structures of theophylline generated by global lattice energy minimisation calculations.
Co-reporter:Dr. Mark D. Eddleston;Dr. Katarzyna E. Hejczyk;Dr. Erica G. Bithell;Dr. Graeme M. Day; William Jones
Chemistry - A European Journal 2013 Volume 19( Issue 24) pp:7874-7882
Publication Date(Web):
DOI:10.1002/chem.201204368
Abstract
Electron diffraction offers advantages over X-ray based methods for crystal structure determination because it can be applied to sub-micron sized crystallites, and picogram quantities of material. For molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. Automated electron diffraction tomography provides one possible solution. We demonstrate here, however, an alternative approach in which a set of putative crystal structures of the compound of interest is generated by crystal structure prediction methods and electron diffraction is used to determine which of these putative structures is experimentally observed. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the application of the methodology to the pharmaceutical compounds paracetamol, scyllo-inositol and theophylline.
Co-reporter:Hugh P. G. Thompson and Graeme M. Day
Chemical Science (2010-Present) 2014 - vol. 5(Issue 8) pp:NaN3182-3182
Publication Date(Web):2014/05/13
DOI:10.1039/C4SC01132E
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−1 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.
Co-reporter:Jonas Nyman, Orla Sheehan Pundyke and Graeme M. Day
Physical Chemistry Chemical Physics 2016 - vol. 18(Issue 23) pp:NaN15837-15837
Publication Date(Web):2016/05/17
DOI:10.1039/C6CP02261H
We present an assessment of the performance of several force fields for modelling intermolecular interactions in organic molecular crystals using the X23 benchmark set. The performance of the force fields is compared to several popular dispersion corrected density functional methods. In addition, we present our implementation of lattice vibrational free energy calculations in the quasi-harmonic approximation, using several methods to account for phonon dispersion. This allows us to also benchmark the force fields' reproduction of finite temperature crystal structures. The results demonstrate that anisotropic atom–atom multipole-based force fields can be as accurate as several popular DFT-D methods, but have errors 2–3 times larger than the current best DFT-D methods. The largest error in the examined force fields is a systematic underestimation of the (absolute) lattice energy.
Co-reporter:Maria Baias, Cory M. Widdifield, Jean-Nicolas Dumez, Hugh P. G. Thompson, Timothy G. Cooper, Elodie Salager, Sirena Bassil, Robin S. Stein, Anne Lesage, Graeme M. Day and Lyndon Emsley
Physical Chemistry Chemical Physics 2013 - vol. 15(Issue 21) pp:NaN8080-8080
Publication Date(Web):2013/02/19
DOI:10.1039/C3CP41095A
A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection.
Co-reporter:Edward O. Pyzer-Knapp, Hugh P. G. Thompson, Florian Schiffmann, Kim E. Jelfs, Samantha Y. Chong, Marc A. Little, Andrew I. Cooper and Graeme M. Day
Chemical Science (2010-Present) 2014 - vol. 5(Issue 6) pp:NaN2245-2245
Publication Date(Web):2014/03/11
DOI:10.1039/C4SC00095A
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.
Co-reporter:Jonas Nyman and Graeme M. Day
Physical Chemistry Chemical Physics 2016 - vol. 18(Issue 45) pp:NaN31143-31143
Publication Date(Web):2016/10/31
DOI:10.1039/C6CP05447A
We present a large-scale study of the temperature-dependence of structures, free energy differences and properties of polymorphic molecular organic crystals. Lattice-vibrational Gibbs free energy differences between 475 pairs of polymorphs of organic molecular crystals have been calculated at 0 K and at their respective melting points, using a highly accurate anisotropic multipole-based force field and including thermal expansion through the use of a (negative) thermal pressure. Re-ranking of the relative thermodynamic stability of the polymorphs in each pair indicates the possibility of an enantiotropic phase transition between the crystal structures, which occurs in 21% of the studied systems. While vibrational contributions to free energies can have a significant effect on thermodynamic stability, the impact of thermal expansion on polymorph free energy differences is generally very small. We also calculate thermal expansion coefficients for the 864 crystal structures and investigate the temperature-dependence of mechanical properties, and pairwise differences in these properties between polymorphs.
Co-reporter:Jonathan A. Foster, Krishna K. Damodaran, Antoine Maurin, Graeme M. Day, Hugh P. G. Thompson, Gary J. Cameron, Jenifer Cuesta Bernal and Jonathan W. Steed
Chemical Science (2010-Present) 2017 - vol. 8(Issue 1) pp:NaN84-84
Publication Date(Web):2016/10/07
DOI:10.1039/C6SC04126D
We report the synthesis of a bis(urea) gelator designed to specifically mimic the chemical structure of the highly polymorphic drug substance ROY. Crystallization of ROY from toluene gels of this gelator results in the formation of the metastable red form instead of the thermodynamic yellow polymorph. In contrast, all other gels and solution control experiments give the yellow form. Conformational and crystal structure prediction methods have been used to propose the structure of the gel and show that the templation of the red form by the targeted gel results from conformational matching of the gelator to the ROY substrate coupled with overgrowth of ROY onto the local periodic structure of the gel fibres.
