The lines-of-force landscape of interactions between molecules in crystals; cohesive versus tolerant and `collateral damage' contact

A quantitative analysis of relative stabilities in organic crystal structures is possible by means of reliable calculations of interaction energies between pairs of molecules. Such calculations have been performed by the PIXEL method for 1108 non-ionic and 98 ionic organic crystals, yielding total energies and separate Coulombic polarization and dispersive contributions. A classification of molecule–molecule interactions emerges based on pair energy and its first derivative, the interaction force, which is estimated here explicitly along an approximate stretching path. When molecular separation is not at the minimum-energy value, as frequently happens, forces may be attractive or repulsive. This information provides a fine structural fingerprint and may be relevant to the mechanical properties of materials. The calculations show that the first coordination shell includes destabilizing contacts in ∼ 9% of crystal structures for compounds with highly polar chemical groups (e.g. CN, NO2, SO2). Calculations also show many pair contacts with weakly stabilizing (neutral) energies; such fine modulation is presumably what makes crystal structure prediction so difficult. Ionic organic salts or zwitterions, including small peptides, show a Madelung-mode pairing of opposite ions where the total lattice energy is stabilized from sums of strongly repulsive and strongly attractive interactions. No obvious relationships between atom–atom distances and interaction energies emerge, so analyses of crystal packing in terms of geometrical parameters alone should be conducted with due care.

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Towards computer-guided tuning of the crystal packing of porous organic cages

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314093322 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C667-C667

Author(s):

Angeles Pulido ◽

Ming Liu ◽

Paul Reiss ◽

Anna Slater ◽

Sam Chong ◽

...

Keyword(s):

Crystal Structure ◽

Crystal Engineering ◽

Molecular Sieves ◽

Structure Prediction ◽

Crystal Packing ◽

Aromatic Aldehydes ◽

Lattice Energy ◽

Building Blocks ◽

Molecular Assembly ◽

Computational Techniques

Among microporous materials, there has been an increasing recent interest in porous organic cage (POC) crystals, which can display permanent intrinsic (molecular) and extrinsic (crystal network) porosity. These materials can be used as molecular sieves for gas separation and potential applications as enzyme mimics have been suggested since they exhibit structural response toward guest molecules[1]. Small structural modifications of the initial building blocks of the porous organic molecules can lead to quite different molecular assembly[1]. Moreover, the crystal packing of POCs is based on weak molecular interactions and is less predictable that other porous materials such as MOFs or zeolites.[2] In this contribution, we show that computational techniques -molecular conformational searches and crystal structure prediction- can be successfully used to understand POC crystal packing preferences. Computational results will be presented for a series of closely related tetrahedral imine- and amine-linked porous molecules, formed by [4+6] condensation of aromatic aldehydes and cyclohexyl linked diamines. While the basic cage is known to have one strongly preferred crystal structure, the presence of small alkyl groups on the POC modifies its crystal packing preferences, leading to extensive polymorphism. Calculations were able to successfully identify these trends as well as to predict the structures obtained experimentally, demonstrating the potential for computational pre-screening in the design of POCs within targeted crystal structures. Moreover, the need of accurate molecular (ab initio calculations) and crystal (based on atom-atom potential lattice energy minimization) modelling for computer-guided crystal engineering will be discussed.

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Insight from energy surfaces: structure prediction by lattice energy exploration

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314099719 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C28-C28

Author(s):

Graeme Day

Keyword(s):

Crystal Structure ◽

Structure Prediction ◽

Crystal Packing ◽

Lattice Energy ◽

Organic Crystals ◽

Crystal Structure Prediction ◽

Stability Order ◽

The Stability ◽

Solid Form ◽

Energy Surfaces

A long-standing challenge for the application of computational chemistry in the field of crystallography is the prediction of crystal packing, given no more than the chemical bonding of the molecules being crystallised. Recent years have seen significant progress towards reliable crystal structure prediction methods, even for traditionally challenging systems involving flexible molecules and multi-component solids [1]. These methods are based on global searches of the lattice energy surface: a search is performed to locate all possible packing arrangements, and these structures are ranked by their calculated energy [2]. One aim of this lecture is to provide an overview of advances in methods for crystal structure prediction, focussing on molecular organic crystals, and highlighting strategies that are being explored to extend the reach of these methods to more complex systems. A second aim is to discuss the range applications of crystal structure prediction calculations, which have traditionally included solid form screening, particularly of pharmaceutically active molecules, and structure determination. As energy models become more reliable at correctly ranking the stability order of putative structures, and the timescale required for structure searching decreases, crystal structure prediction has the potential for the discovery of novel molecular materials with targeted properties. Prospects for computer-guided discovery of materials will be discussed.

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Reducing Crystal Structure Overprediction of Ibuprofen with Large Scale Molecular Dynamics Simulations

10.26434/chemrxiv.14556072 ◽

2021 ◽

Author(s):

Nicholas Francia ◽

Louise Price ◽

Matteo Salvalaglio

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Crystal Structures ◽

Finite Temperature ◽

Structure Prediction ◽

Large Scale ◽

Lattice Energy ◽

Racemic Mixture ◽

Dynamics Simulations

<p>The control of the crystal form is a central issue in the pharmaceutical industry. The identification of putative polymorphs through Crystal Structure Prediction (CSP) methods is based on lattice energy calculations, which are known to significantly over-predict the number of plausible crystal structures. A valuable tool to reduce overprediction is to employ physics-based, dynamic simulations to coalesce lattice energy minima separated by small barriers into a smaller number of more stable geometries once thermal effects are introduced. Molecular dynamics simulations and enhanced sampling methods can be employed in this context to simulate crystal structures at finite temperature and pressure. </p><p>Here we demonstrate the applicability of approaches based on molecular dynamics to systematically process realistic CSP datasets containing several hundreds of crystal structures. The system investigated is ibuprofen, a conformationally flexible active pharmaceutical ingredient that crystallises both in enantiopure forms and as a racemic mixture. By introducing a hierarchical approach in the analysis of finite-temperature supercell configurations, we can post-process a dataset of 555 crystal structures, identifying 65% of the initial structures as labile, while maintaining all the experimentally known crystal structures in the final, reduced set. Moreover, the extensive nature of the initial dataset allows one to gain quantitative insight into the persistence and the propensity to transform of crystal structures containing common hydrogen-bonded intermolecular interaction motifs.</p>

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Hydrogen-bonding network in the organic salts of 4-nitrobenzoic acid

Open Chemistry ◽

10.2478/s11532-006-0023-3 ◽

2006 ◽

Vol 4 (3) ◽

pp. 458-475 ◽

Cited By ~ 1

Author(s):

Yurii Chumakov ◽

Yurii Simonov ◽

Mata Grozav ◽

Manuela Crisan ◽

Gabriele Bocelli ◽

...

Keyword(s):

Hydrogen Bonding ◽

Hydrogen Bonds ◽

Crystal Structures ◽

Crystal Packing ◽

Building Blocks ◽

Supramolecular Architecture ◽

Two Dimensional ◽

Organic Salts ◽

Nitrobenzoic Acid ◽

Ionic Forms

AbstractThe crystal structures of six novel salts of 4-nitrobenzoic acid — namely, 2-hydroxyethylammonium 4-nitrobenzoate (I), 2-hydroxypropylammonium 4-nitrobenzoate (II), 1-(hydroxymethyl)propylammonium 4-nitrobenzoate (III), 3-hydroxypropylammonium 4-nitrobenzoate (IV), bis-(2-hydroxyethylammonium) 4-nitrobenzoate (V), morpholinium 4-nitrobenzoate (VI) — containing the same anion but different cations have been studied. The ionic forms of I-VI serve as building blocks of the supramolecular architecture, and in crystals they are held together via ionic N-H···O and O-H···O hydrogen bonds. In the crystal packing the building blocks of I-III are self-assembled via N-H...O, O-H···O and C-H...O hydrogen bonds to form the chains which are further consolidated into two-dimensional layers by the same type of interactions. In IV-VI the chain-like structures have been generated by building blocks.

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Crystal structure and packing energy calculations of (+)-6-aminopenicillanic acid

Acta Crystallographica Section C Crystal Structure Communications ◽

10.1107/s0108270113025924 ◽

2013 ◽

Vol 69 (11) ◽

pp. 1238-1242 ◽

Cited By ~ 2

Author(s):

Sofiane Saouane ◽

Gernot Buth ◽

Francesca P. A. Fabbiani

Keyword(s):

Crystal Structure ◽

Crystal Packing ◽

Three Dimensional ◽

Lattice Energy ◽

Interaction Energies ◽

Energy Calculations ◽

X Ray ◽

Carboxylate Groups ◽

Dimensional Network ◽

Complementary Analysis

The X-ray single-crystal structure of (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, commonly known as (+)-6-aminopenicillanic acid (C8H12N2O3S) and a precursor of a variety of semi-synthetic penicillins, has been determined from synchrotron data at 150 K. The structure represents an ordered zwitterion and the crystals are nonmerohedrally twinned. The crystal structure is composed of a three-dimensional network built by three charge-assisted hydrogen bonds between the ammonium and carboxylate groups. The complementary analysis of the crystal packing by thePIXELmethod brings to light the nature and ranking of the energetically most stabilizing intermolecular interaction energies. In accordance with the zwitterionic nature of the structure,PIXELlattice energy calculations confirm the predominance of the Coulombic term (−379.1 kJ mol−1) ahead of the polarization (−141.4 kJ mol−1), dispersion (−133.7 kJ mol−1) and repulsion (266.3 kJ mol−1) contributions.

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Predicting Porous Molecular Crystals and Clathrates

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314083740 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C1625-C1625

Author(s):

Jonas Nyman ◽

Graeme Day

Keyword(s):

Crystal Structure ◽

Crystal Structures ◽

Structure Prediction ◽

Molecular Crystals ◽

Volume Ratio ◽

Lattice Energy ◽

Computer Algorithms ◽

Crystal Structure Prediction ◽

Powerful Method ◽

Simple Molecules

The last decade has seen dramatic improvements in the theories and computer algorithms underlying computational Crystal Structure Predictions [1]. It is now possible to reliably obtain the most likely crystal structures of at least simple molecules starting from nothing more than a drawing of the molecule. We can now go even further and look for rare and exotic kinds of crystals such as porous molecular crystals, clathrates and inclusion compounds among our predictions and calculate their physical properties [2], paving the way for the "science of hypothetical materials". In our poster, we present results on the prediction of fluorophenol xenon clathrates. We have performed crystal structure predictions by global lattice energy searches on o- and m-fluorophenol. The predicted structures have then been analyzed for porosity and their likelihood of being clathrates. From the several thousands of predicted structures, we select a few likely candidates according to an empirical rule based on the guest to host volume ratio [3]. Results from solid state xenon-129 NMR indicate that we have successfully determined the crystal structures of both o- and m-fluorophenol xenon clathrates and we suggest that Crystal Structure Prediction in combination with xenon-129 NMR is a powerful method for determining the structures of clathrates in general.

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Specific energy contributions associated with competing hydrogen bond motifs

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314094571 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C542-C542

Author(s):

Thomas Gelbrich ◽

Ulrich Griesser

Keyword(s):

Crystal Packing ◽

Lattice Energy ◽

Model System ◽

Dispersion Forces ◽

Interaction Energies ◽

Individual Contributions ◽

Small Set ◽

N Form ◽

The Difference ◽

Small Clusters

The semi-classical density sums (SCDS-Pixel) method [1] was used to study the intermolecular interaction energies in six polymorphs of phenobarbital, a model system for the barbiturate class of compounds.[2] Barbiturates display a rigid pyrimidinetrione ring whose two N–H and three C=O functions can be employed in H-bonding. The ensuing intermolecular N–H···O=C interactions result in a small set of standard H-bonded chain, layer and framework motifs.[3] Even though the average number of N–H···O=C bonds per molecule is always two, the standard barbiturate H-bond motifs differ in the number of intermolecular two-point and one-point N–H···O=C connections per molecule, i.e. (1; 0), (½; 1), (0; 2). For each polymorph (I, II, III, V, VI, X), cumulated Pixel energies, E(n), were calculated for the first n (n = 1, 2, 3, ...) interactions associated with the highest individual contributions to the lattice energy. The obtained sets of E(n) values were compared to one another to establish the differences associated with the formation of the alternate N–H···O=C motifs. Those polymorphs whose N–H···O bonded structures are dominated by two-point connections have superior E(n) values for small clusters of molecules (low n). However, this advantage diminishes gradually if larger clusters of molecules are considered and is completely compensated at n = 8. This indicates that crystal packing on the basis of one-point connection N–H···O=C motifs is viable only because the latter enable the formation of more advantageous weaker interactions which are dominated by dispersion forces. This case illustrates that an assessment of competing H-bond motifs cannot be restricted to just those molecules that are directly involved in H-bond interactions. Rather, the complete crystal packing has to be taken into account. [Figure: Evolution of the difference between E(n) (form V; one-point connections) and E(n)' (form III; two-point connections) with n].

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Quantitative Lattice Energy Analysis of Intermolecular Interactions in Crystal Structures of Some Benzimidazole Derivatives

Oriental Journal of Physical Sciences ◽

10.13005/ojps05.01-02.08 ◽

2020 ◽

Vol 5 (1-2) ◽

pp. 53-62

Author(s):

Gopal Sharma ◽

Rajni Kant

Keyword(s):

Crystal Structures ◽

Intermolecular Interactions ◽

Energy Analysis ◽

Crystal Packing ◽

Lattice Energy ◽

Molecular Packing ◽

Benzimidazole Derivatives ◽

Intermolecular Hydrogen Bonds ◽

Centrosymmetric Dimers

The benzimidazole moiety found in a large number of biologically important drugs has not been completely realized as yet in respect of its strength and directionality of its molecular interactions. To understand the role played by the intermolecular interactions in the benzimidazole derivatives, lattice energy of a series of five important molecules has been computed and results accrued thereof have been discussed. Analysis of molecular packing based on the intermolecular interaction energies suggests existence of different molecular pairs that play an important role in the stabilization of the crystal structures. Interaction energy analysis of such motifs reveals that intermolecular interactions of the type N-H…N and C-H…N happen to be the major contributors to the stabilization of molecular packing in the unit cell. N-H…π and C-H…π type edge-to-face stacking interactions also contribute significantly to the stabilization of crystal packing. The pairs of N-H…N intermolecular hydrogen bonds link the molecules into centrosymmetric dimers making a contribution of -14 to -18.52 kcal/mol towards stabilization, whereas C-H…N bonds link the molecules into dimers in the energy range of -2 to -5 kcal/mol. Additionally, the role of π…π interactions has also been investigated in molecular stabilization.

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A third blind test of crystal structure prediction

Acta Crystallographica Section B Structural Science ◽

10.1107/s0108768105016563 ◽

2005 ◽

Vol 61 (5) ◽

pp. 511-527 ◽

Cited By ~ 268

Author(s):

G. M. Day ◽

W. D. S. Motherwell ◽

H. L. Ammon ◽

S. X. M. Boerrigter ◽

R. G. Della Valle ◽

...

Keyword(s):

Crystal Structure ◽

Crystal Structures ◽

Structure Prediction ◽

Lattice Energy ◽

Crystal Structure Prediction ◽

Success Rates ◽

Blind Test ◽

Energy Models ◽

Successful Prediction ◽

Structure Report

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z′ = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests – there was only one successful prediction for any of the three `blind' molecules. For the `simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

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