Dynamic simulation of orientational disorder in organic crystals: methyl groups, trifluoromethyl groups and whole molecules.

Large amplitude librations of atomic groups or of entire molecules in their crystals are simulated using optimized intermolecular potentials and crystal structures deposited in the Cambridge Structural Database. The analysis proceeds by a simple static model in which reorientations take place in a fixed environment, or by Monte Carlo (MC) simulation of equilibria dotted by rotational defects, or eventually by full Molecular Dynamics (MD). The simplest approach provides a valuable qualitative preview, but MC and MD are becoming easily accessible to the general solid-state chemist thanks to the facilities of the newly developed Milano Chemistry Molecular Simulation (MiCMoS) platform.

A quantitative measure of halogen bond activation in cocrystallization.

A theoretical investigation of bond lengths and bond energies for several kinds of halogen bonding interactions is carried out using the PIXEL method. The effect of different kinds of activating agents, fluoro-, nitro-, ethynyl substitution and combinations thereof, is assessed quantitatively, and is found to be fully consistent with the results of literature screenings of the corresponding strengths, as judged by the ease of formation of cocrystals. In the best combination of activators the halogen bond is comparable or superior to a strong O-HO hydrogen bond in what concerns stabilization energies and stretching force constants.

Are racemic crystals favored over homochiral crystals by higher stability or by kinetics? Insights from comparative studies of crystalline stereoisomers.

The crystal and molecular structures of 134 pairs of diastereoisomers and of 279 racemic-homochiral pairs were retrieved from the Cambridge Structural Database. Lattice and intramolecular energies are calculated. Density differences between crystals of stereoisomers of all kind are mostly within 5%, as observed also for crystal polymorphs.

Intermolecular interaction energies in molecular crystals: comparison and agreement of localized Møller-Plesset 2, dispersion-corrected density functional, and classical empirical two-body calculations.

A comparative analysis of the intermolecular energy for a data set including 60 molecular crystals with a large variety of functional groups has been carried out using three different computational approaches: (i) a method based on a physically meaningful empirical partition of the interaction energy (PIXEL), (ii) density functional methods with a posteriori empirical correction for the dispersion interactions (DFT-D), and (iii) a full periodic ab initio quantum mechanical method based on Møller-Plesset perturbation theory for the electron correlation using localized crystal orbitals (LMP2). Due to the large computational cost, LMP2 calculations have been restricted to a subset of seven molecular crystal comprising benzene, formic acid, formamide, succinic anhydride, urea, oxalic acid, and nitroguanidine, and the results compared with PIXEL and DFT-D data as well as with the experimental data show excellent agreement among all adopted methods. This shows that both DFT-D and PIXEL approaches are robust predictive tools for studying molecular crystals.

Computational studies of crystal structure and bonding.

The analysis, prediction, and control of crystal structures are frontier topics in present-day research in view of their importance for materials science, pharmaceutical sciences, and many other chemical processes. Computational crystallography is nowadays a branch of the chemical and physicals sciences dealing with the study of inner structure, intermolecular bonding, and cohesive energies in crystals. This chapter, mainly focused on organic compounds, first reviews the current methods for X-ray diffraction data treatment, and the new tools available both for quantitative statistical analysis of geometries of intermolecular contacts using crystallographic databases and for the comparison of crystal structures to detect similarities or differences.

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.

A structural and spectroscopic investigation of the hydrochlorination of 4,4'-methylenedianiline.

The hydrochlorination of 4,4'-methylenedianiline, NH(2)C(6)H(4)CH(2)C(6)H(4)NH(2) (MDA), in chlorobenzene to produce 4,4'-methylenedianiline dihydrochloride, [H(3)NC(6)H(4)CH(2)C(6)H(4)NH(3)]Cl(2) (MDA x 2 HCl) is an important reaction for the production of isocyanates, which are used to manufacture polyurethanes. This reaction is examined here. MDA is moderately soluble in chlorobenzene, whereas MDA x 2 HCl is effectively insoluble.

How molecules stick together in organic crystals: weak intermolecular interactions.

This tutorial review introduces the fundamentals of intermolecular interactions in terms of the underlying physics and goes on to illustrate the most popular methods for the computer simulation of intermolecular interactions, from atom-atom potentials to ab initio methods, including intermediate, hybrid methods, with an appreciation of their relative merits and costs. Typical results are critically presented, culminating in the most difficult exercise of all, the computer prediction of crystal structures. Perspectives on our present and future ability to understand and exploit intermolecular interactions are given.

A structural and spectroscopic investigation of the hydrochlorination of 4-benzylaniline: the interaction of anhydrous hydrogen chloride with chlorobenzene.

The hydrochlorination of 4-benzylaniline in chlorobenzene to produce 4-benzylaniline hydrochloride has been examined. This has required spectroscopic and computational analysis of the solvation of gaseous HCl in the process solvent. The characterisation of the reagent and product of the hydrochlorination reaction by various techniques, including FTIR and (1)H NMR spectroscopy and X-ray diffraction, is described.

Coulombic and dispersive factors in the molecular recognition of peptides: PIXEL calculations on two NNQQ (Asn-Asn-Gln-Gln) crystal polymorphs.

The crystal-packing and cohesive energies in the structures of two polymorphs of the title tetrapeptide have been analyzed using molecule-molecule energies calculated using the PIXEL method. Coulombic energies are non-empirical and are much more accurate than those calculated using point-charge methods. The results explain and rationalize the cohesion and mutual recognition of these peptide molecules, with a clear distinction between polar and dispersive contributions, shedding light on subtle differences between polymorphic arrangements.

Hydrogen bond strength and bond geometry in cyclic dimers of crystalline carboxylic acids.

In a study of 101 crystal structures of carboxylic acids we have observed a clear trend in the difference between the formally single and formally double C-O bond distances, as observed by X-ray diffraction, with a clear-cut distinction between aromatic acids, where the two distances are similar, and non-aromatic acids, where the two distances distinctly differ by 0.06-0.12 A.

Synthesis, X-ray diffraction and computational study of the crystal packing of polycyclic hydrocarbons featuring aromatic and perfluoroaromatic rings condensed in the same molecule: 1,2,3,4-tetrafluoronaphthalene, -anthracene and -phenanthrene.

We have synthesised some planar polycyclic compounds, in which unsubstituted aromatic rings are condensed with perfluorinated aromatic rings, and have carried out a combined X-ray diffraction and computational study to analyse their self-recognition behaviour in crystalline phases. We compare our results with the parent hydrocarbons and with other compounds that have a variable degree of fluorination. Whereas the molecular planes in crystals of hydrocarbons with mono- or difluorinated aromatic rings or of perfluorinated compounds arrange themselves in V-shaped configurations, our present results show that perfluorinated rings tend to stack over unsubstituted rings even when these two moieties coexist in a condensed system, producing crystalline materials with parallel molecular layers with the arene-perfluoroarene recognition pattern.

A solid-state chemist's view of the crystal polymorphism of organic compounds.

In a survey of some structural and energetic aspects of crystal polymorphism, definitions are proposed, and a method for generating an unequivocal fingerprint of the cohesive pattern of an organic crystal structure is presented. The method identifies the electronic nature of molecule-molecule interactions in crystals, and its application requires a minimal training in basic crystallography and molecular modeling. The analysis suggests that thermodynamic and physical properties of polymorphs of organic crystals are quite often very similar, and sometimes depend on morphology as well as on crystal structure.

Computer simulations and analysis of structural and energetic features of some crystalline energetic materials.

A database of 43 literature X-ray crystal structure determinations for compounds with known, or possible, energetic properties has been collected along with some sublimation enthalpies. A statistical study of these crystal structures, when compared to a sample of general organic crystals, reveals a population of anomalously short intermolecular oxygen-oxygen separations with an average crystal packing coefficient of 0.77 that differs significantly from 0.

X-ray diffraction and theoretical studies for the quantitative assessment of intermolecular arene-perfluoroarene stacking interactions.

The arene-perfluoroarene stacking interaction was studied by experimental and theoretical methods. A series of compounds with different possibilities for formation of this recognition motif in the solid state were synthesized, and their crystal structures determined by single-crystal X-ray diffraction. The crystal packing of these compounds, as well as the packing of related compounds retrieved from crystallographic databases, were analyzed with quantitative crystal potentials: total lattice energies and the cohesive energies of closest molecular pairs in the crystals were calculated.

Molecular recognition in organic crystals: directed intermolecular bonds or nonlocalized bonding?

Molecules are held together mainly by forces acting between individual atoms. Does the same apply to molecular clusters? Does intermolecular cohesion depend on weak bonds between individual atoms in different molecules or on less localized, more diffuse interactions between molecules? We discuss these questions from several viewpoints and in particular compare interpretations based on the extension of Bader's atoms in molecules (AIM) theory to cover closed-shell intermolecular interactions with interpretations based on the new pixel method for the calculation of coulombic, polarization, dispersion, and repulsion energies from the electron density of molecular clusters.

Molecular recognition and crystal energy landscapes: an X-ray and computational study of caffeine and other methylxanthines.

We introduce a new approach to crystal-packing analysis, based on the study of mutual recognition modes of entire molecules or of molecular moieties, rather than a search for selected atom-atom contacts, and on the study of crystal energy landscapes over many computer-generated polymorphs, rather than a quest for the one most stable crystal structure. The computational tools for this task are a polymorph generator and the PIXEL density sums method for the calculation of intermolecular energies. From this perspective, the molecular recognition, crystal packing, and solid-state phase behavior of caffeine and several methylxanthines (purine-2,6-diones) have been analyzed.

X-ray diffraction and packing analysis on vintage crystals: Wilhelm Koerner's nitrobenzene derivatives from the School of Agricultural Sciences in Milano.

The crystal structures of six nitrotoluene derivatives, synthesized by Wilhelm Koerner about a century ago and retrieved from a depository at the University of Milano, were determined. The correct assignment of molecular structures is verified. The geometry of the nitro groups and factors affecting the orientation of nitro groups with respect to the benzene ring are discussed, also using an auxiliary set of crystal structures retrieved from the Cambridge Structural Database.

Crystal structure prediction of small organic molecules: a second blind test.

The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy.

X-ray diffraction and molecular simulation study of the crystalline and liquid states of succinic anhydride.

The crystal structure of succinic anhydride was studied at five temperatures between 100 K and the melting point by single-crystal X-ray diffraction. The temperature dependence of molecular libration tensors was determined. Intermolecular interactions, in particular through unusually close molecule-molecule contacts, are discussed, with a detailed calculation of electrostatic energies.