Mercury 4.0: from visualization to analysis, design and prediction.

The program Mercury, developed at the Cambridge Crystallographic Data Centre, was originally designed primarily as a crystal structure visualization tool. Over the years the fields and scientific communities of chemical crystallography and crystal engineering have developed to require more advanced structural analysis software. Mercury has evolved alongside these scientific communities and is now a powerful analysis, design and prediction platform which goes a lot further than simple structure visualization.

Hydrogen bonding at C=Se acceptors in selenoureas, selenoamides and selones.

In recent years there has been considerable interest in chalcogen and hydrogen bonding involving Se atoms, but a general understanding of their nature and behaviour has yet to emerge. In the present work, the hydrogen-bonding ability and nature of Se atoms in selenourea derivatives, selenoamides and selones has been explored using analysis of the Cambridge Structural Database and ab initio calculations. In the CSD there are 70 C=Se structures forming hydrogen bonds, all of them selenourea derivatives or selenoamides. Analysis of intramolecular geometries and ab initio partial charges show that this bonding stems from resonance-induced C(δ+)=Se(δ-) dipoles, much like hydrogen bonding to C=S acceptors. C=Se acceptors are in many respects similar to C=S acceptors, with similar vdW-normalized hydrogen-bond lengths and calculated interaction strengths. The similarity between the C=S and C=Se acceptors for hydrogen bonding should inform and guide the use of C=Se in crystal engineering.

Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals.

In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJ mol(-1) for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos 2ξ term to represent the electronic barrier with an intramolecular atom-atom exp-6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules.

Hydrogen-bond coordination in organic crystal structures: statistics, predictions and applications.

Statistical models to predict the number of hydrogen bonds that might be formed by any donor or acceptor atom in a crystal structure have been derived using organic structures in the Cambridge Structural Database. This hydrogen-bond coordination behaviour has been uniquely defined for more than 70 unique atom types, and has led to the development of a methodology to construct hypothetical hydrogen-bond arrangements. Comparing the constructed hydrogen-bond arrangements with known crystal structures shows promise in the assessment of structural stability, and some initial examples of industrially relevant polymorphs, co-crystals and hydrates are described.

Role of chloroform and dichloromethane solvent molecules in crystal packing: an interaction propensity study.

Using the Cambridge Structural Database (CSD), it is shown that the acidic C-H donors of chloroform and dichloromethane, respectively, form hydrogen bonds with N, O, S, halides or carbon-bound halogens in 82% and 77% of structures in which such interactions can occur. This hydrogen-bond potency is retained to a significant degree even in the presence of the more conventional O-H and N-H donors. The hydrogen-bond propensities exhibited by the C-H protons in CHCl3 and CH2Cl2 are similar to those of the acetylenic C-C≡C-H proton. However, involvement of the Cl atoms of CHCl3 and CH2Cl2 in non-bonded interactions is rather limited: the propensities for formation of (O or N)-H...Cl bonds are only 6% in both cases, while the propensities for the formation of halogen-halogen bonds is generally < 15%, with only Cl...Br interactions having slightly higher values. While C(phenyl)-H...Cl interactions are commonly observed, they are of low propensity and have distances at the upper end of the van der Waals limit. We conclude that the acidic C-H protons in chloroform and dichloromethane solvent molecules play a clear role in the involvement of these molecules in molecular aggregation in crystal structures, and this is exemplified by hydrogen-bond predictions made using the statistical propensity tool which is now part of the CSD system.

The versatile role of the ethynyl group in crystal packing: an interaction propensity study.

It is well documented that the ethynyl group can act as a hydrogen-bond donor via its acidic C-H, and as a hydrogen-bond acceptor via the triple-bond π-density. Using the Cambridge Structural Database (CSD), it is shown that C-C≡C-H forms hydrogen bonds to N, O, S or halogens in 74% of structures in which these bonds can form. Additionally, the ethynyl group forms C-H···π interactions with itself or with phenyl groups in 23% of structures and accepts hydrogen bonds from O-H, N-H or C(aromatic)-H in 47% of structures where such bonds are possible. Overall, C-C≡C-H acts as a donor or acceptor in 87% of structures in which it occurs. These propensities for hydrogen-bond formation have been determined using quite tight geometrical constraints, and many more ethynyl groups form interactions with only slight relaxations of these constraints. We conclude that the ethynyl group makes crucial contributions to molecular aggregation in crystal structures, and this is exemplified by hydrogen-bond predictions for specific structures made using the statistical propensity tool now available in CSD system software.

Quantifying homo- and heteromolecular hydrogen bonds as a guide for adduct formation.

An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions (1a-1j) were carried out between the anti-malarial drug pyrimethamine (1) and the acids oxalic (a), malonic (b), acetylenedicarboxylic (c), adipic (d), pimelic (e), suberic (f), azelaic acids (g), as well as hexachlorobenzene (h), 1,4-diiodobenzene (i), and 1,4-diiodotetrafluorobenzene (j); seven (1a to 1g) of these successfully formed salts. Five of these seven salts were found to be either hydrated or solvated. Hydrogen bond propensity calculations predict that hydrogen bonds between 1 and acids a-g are more likely to form rather than the H bonds involved in self-association, providing a rationale for the observation of the seven new salts. In contrast, propensity of hydrogen bonds between 1 and h-j is much smaller as compared to other bonds predicted for self-association/solvate formation, in agreement with the observed unsuccessful reactions.

Successful prediction of a model pharmaceutical in the fifth blind test of crystal structure prediction.

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.

Universal prediction of intramolecular hydrogen bonds in organic crystals.

A complete exploration of intramolecular hydrogen bonds (IHBs) has been undertaken using a combination of statistical analyses of the Cambridge Structural Database and computation of ab initio interaction energies for prototypical hydrogen-bonded fragments. Notable correlations have been revealed between computed energies, hydrogen-bond geometries, donor and acceptor chemistry, and frequencies of occurrence. Significantly, we find that 95% of all observed IHBs correspond to the five-, six- or seven-membered rings. Our method to predict a propensity for hydrogen-bond occurrence in a crystal has been adapted for such IHBs, applying topological and chemical descriptors derived from our findings. In contrast to intermolecular hydrogen bonding, it is found that IHBs can be predicted across the complete chemical landscape from a single optimized probability model, which is presented. Predictivity of 85% has been obtained for generic organic structures, which can exceed 90% for discrete classes of IHB.

Persistent hydrogen bonding in polymorphic crystal structures.

The significance of hydrogen bonding and its variability in polymorphic crystal structures is explored using new automated structural analysis methods. The concept of a chemically equivalent hydrogen bond is defined, which may be identified in pairs of structures, revealing those types of bonds that may persist, or not, in moving from one polymorphic form to another. Their frequency and nature are investigated in 882 polymorphic structures from the Cambridge Structural Database. A new method to compare conformations of equivalent molecules is introduced and applied to derive distinct subsets of conformational and packing polymorphs. The roles of chemical functionality and hydrogen-bond geometry in persistent interactions are systematically explored. Detailed structural comparisons reveal a large majority of persistent hydrogen bonds that are energetically crucial to structural stability.

Hydrogen-bond motifs in the crystals of hydrophobic amino acids.

A computer program has been developed to survey a set of crystal structures for hydrogen-bond motifs. Possible ring and chain motifs are generated automatically from a user-defined list of interacting molecular fragments and intermolecular interactions. The new program was used to analyse the hydrogen-bond networks in the crystals of 52 zwitterionic alpha-amino acids. All the possible chain motifs (repeating 1-4 molecules) are frequent, while the frequency of ring motifs (2-6 molecules) ranges from 0 to 85% of the structures. The list of motifs displayed by each structure reveals structural similarities and it can be used to compare polymorphs. The motifs formed in cocrystals of alpha-amino acids and in crystals of beta- and gamma-amino acids are similar to those of alpha-amino acids.

Knowledge-based model of hydrogen-bonding propensity in organic crystals.

A new method is presented to predict which donors and acceptors form hydrogen bonds in a crystal structure, based on the statistical analysis of hydrogen bonds in the Cambridge Structural Database (CSD). The method is named the logit hydrogen-bonding propensity (LHP) model. The approach has a potential application in identifying both likely and unusual hydrogen bonding, which can help to rationalize stable and metastable crystalline forms, of relevance to drug development in the pharmaceutical industry. Whilst polymorph prediction techniques are widely used, the LHP model is knowledge-based and is not restricted by the computational issues of polymorph prediction, and as such may form a valuable precursor to polymorph screening. Model construction applies logistic regression, using training data obtained with a new survey method based on the CSD system. The survey categorizes the hydrogen bonds and extracts model parameter values using descriptive structural and chemical properties from three-dimensional organic crystal structures. LHP predictions from a fitted model are made using two-dimensional observables alone. In the initial cases analysed, the model is highly accurate, achieving approximately 90% correct classification of both observed hydrogen bonds and non-interacting donor-acceptor pairs. Extensive statistical validation shows the LHP model to be robust across a range of small-molecule organic crystal structures.