Cambridge Structural Database System Research Articles

The integration of solid-form informatics into solid-form selection.

To demonstrate how the use of structural informatics during drug development assists with the assessment of the risk of polymorphism and the selection of a commercial solid form. The application of structural chemistry knowledge derived from the hundreds of thousands of crystal structures contained in the Cambridge Structural Database to drug candidates is described. Examples given show the comparison of intermolecular geometries to database-derived statistics, the use of Full Interaction Maps to assess polymorph stability and the calculation of hydrogen bond propensities to provide assurance of a stable solid form. The software tools used are included in the Cambridge Structural Database System and the Solid Form Module of Mercury. The early identification of an unusual supramolecular motif in the development phase of maraviroc led to further experimental work to find the most stable polymorph. Analyses of two polymorphs of a pain candidate drug demonstrated how consideration of molecular conformation and intermolecular interactions were used for the assessment of relative stability. Informatics analysis confirmed that the solid form of crizotinib, a monomorphic system, had a low risk of polymorphism. The application of informatics-based assessment of new chemical entities complements experimental studies and provides a deeper understanding of the qualities of the structure. The information provided by structural analyses is incorporated into the assessment of risk. Informatics techniques are quick to apply and are straightforward to use, allowing an assessment of progressing drug candidates.

Utilizing organic and organometallic structural data in powder diffraction

The Cambridge Structural Database (CSD) is a database of small molecule organic and organometallic crystal structures elucidated using X-Ray and neutron crystallography. The CSD is distributed alongside a system of software (the Cambridge Structural Database System) to academic and industrial users. The system contains a number of applications (in particular DASH, ConQuest, and Mogul) that can be used to aid crystallographers in the solution and refinement of crystal structures from powder diffraction data, and in the interpretation of crystal structure models (in particular, Mercury). This publication uses a racemic form of ornidazole (Z′ = 3) to illustrate the efficacy of DASH in the crystal structure solution from powder diffraction data. Furthermore, numerous features in Mogul and Mercury that aid crystal structure solution and interpretation of crystallographic data are revised. Finally, a review of a new method for using database-derived geometric information directly in structural solution is presented.

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.

One in half a million: a solid form informatics study of a pharmaceutical crystal structure

We introduce a knowledge-based approach to the evaluation, analysis and prediction of the properties of a crystal form; described inclusively as Solid Form Informatics. This approach is exemplified using the recently published crystal structure of the drug lamotrigine in the context of the Cambridge Structural Database (CSD). Analysis at the molecular, intermolecular and supramolecular level is carried out using the range of software available in the CSD System alongside new research applications. This work provides a template for the thorough analysis of any crystal structure and paves the way toward a fully automated structural analysis for the drug formulation scientist, with the aim to better provide answers to the fundamental questions raised during the drug development process. To conclude, the knowledge gained about the structure is applied to predict the potential for a co-crystal formulation of the drug and to automatically select optimal co-crystal formers. The crystal structure of lamotrigine was the half-millionth structure to enter the CSD. We demonstrate how the 499,999 structures that preceded it are central to the analyses presented.

Teaching Three-Dimensional Structural Chemistry Using Crystal Structure Databases. 3. The Cambridge Structural Database System: Information Content and Access Software in Educational Applications

Parts 1 and 2 of this series described the educational value of experimental three-dimensional (3D) chemical structures determined by X-ray crystallography and retrieved from the crystallographic databases. In part 1, we described the information content of the Cambridge Structural Database (CSD) and discussed a representative teaching subset of ca. 500 CSD structures that have been selected for their educational relevance. In part 2, we exemplified the value of the CSD teaching subset by describing four worked examples of their use in a teaching context. Although the CSD teaching subset and its associated learning modules provide a major resource for chemical educators, there are many cases where the full CSD System, now covering more than 500,000 crystal structures, is essential to make an educational point. This is particularly true when introducing students to variance in real experimental observations, for example, where many hundreds of observations are required to generate statistically meaningful trends from the structural data or simply to introducing students to the search and manipulation of data that are commonly available in large chemical and biochemical databases. Here, we describe the complete CSD System and its associated software and highlight the extended range of discovery-based learning opportunities this affords.

Teaching Three-Dimensional Structural Chemistry Using Crystal Structure Databases. 4. Examples of Discovery-Based Learning Using the Complete Cambridge Structural Database

Parts 1 and 2 of this series described the educational value of experimental three-dimensional (3D) chemical structures determined by X-ray crystallography and retrieved from the crystallographic databases. In part 1, we described the information content of the Cambridge Structural Database (CSD) and discussed a representative teaching subset of ca. 500 CSD structures that have been selected for their educational relevance. In part 2, we exemplified the value of the CSD teaching subset by describing four worked examples of their use in a teaching context. Although the CSD teaching subset and its associated learning modules provide a major resource for chemical educators, there are many cases where the full CSD System is essential to make an educational point. In part 3, we describe the complete CSD System and its associated software and highlight the extended range of discovery-based learning opportunities this affords. Here, we illustrate a number of teaching examples that take advantage of the massive structural information content of the complete CSD System to broaden and enhance the chemical education experience, including, for example, studies of mean molecular dimensions, stereochemistry and conformations, metal coordination sphere geometries, hydrogen bonding and other supramolecular phenomena, and reaction pathways.

Applications of the Cambridge Structural Database in chemical education.

The Cambridge Structural Database (CSD) is a vast and ever growing compendium of accurate three-dimensional structures that has massive chemical diversity across organic and metal-organic compounds. For these reasons, the CSD is finding significant uses in chemical education, and these applications are reviewed. As part of the teaching initiative of the Cambridge Crystallographic Data Centre (CCDC), a teaching subset of more than 500 CSD structures has been created that illustrate key chemical concepts, and a number of teaching modules have been devised that make use of this subset in a teaching environment. All of this material is freely available from the CCDC website, and the subset can be freely viewed and interrogated using WebCSD, an internet application for searching and displaying CSD information content. In some cases, however, the complete CSD System is required for specific educational applications, and some examples of these more extensive teaching modules are also discussed. The educational value of visualizing real three-dimensional structures, and of handling real experimental results, is stressed throughout.

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.

Conformational polymorphism and aromaticity in crystalline dibenzotetraaza[14]annulene derivatives

The structures of two single crystal modifications, orange and yellow, of 7,16-dibenzoyl-6,8,15,17-tetramethyl-5,14-dihydrodibenzo [b,i][1,4,8,11]tetraazacyclotetradecine were determined in room and low temperatures. The aromaticity of the 14-membered macrocyclic ring system was studied with the use of HOMA index and compared to the values calculated for the structures found in the Cambridge Structural Database System. The nature of the polymorphism of the investigated molecules was elucidated. The molecules of the orange and yellow modifications differ in the mutual orientation of the benzoyl groups. The molecular conformation in the yellow crystals is stabilized by two intramolecular hydrogen bonds, C–H⋯OC, which do not occur in the orange modification. Weak, but numerous, intermolecular bonds of this type occur in both modifications, but in the orange polymorph a π–π interaction is also observed, while in the yellow modification a C–H⋯N intermolecular bond is formed.

Conformational analysis of 2,3-substituted propenoates

Three X-ray structure analyses and theoretical conformational analyses combining molecular mechanics (SYBYL), semiempirical (AM1) and ab initio (HF/6-31G∗) calculations of nine 2,3-substituted propenoates are presented. The results of the quantochemical and crystallographic calculations and a survey of structural related molecules using the Cambridge Structural Database System are in concordance and show that steric hindering among substituents and possible inter and intramolecular hydrogen bonding are major factors that influence the geometrical configuration of substituents. The physical and chemical sense of these factors and the reasonable agreement between the semiempirical and ab initio results as well as between theoretical and experimental results have confirmed that the method which was applied for the theoretical conformational analysis is good and useful for related organic molecules.

Molecular Mechanics: The Cross-conjugated Carbonyl Group in Heterocyclic Compounds. 1. Parameterisation (MM2) of the &gt;C=O Bond

A new type of carbon atom has been included in the MM2 force field when it is part of a carbonyl group cross-conjugated in a heterocyclic molecule. This carbon atom is fully included in the π system calculation. New stretching parameters for the C=O bond have been estimated by a statistical process from X-ray molecular structures recorded in the Cambridge Structural Database System. The proposed parameters have been found appropriate for compounds in which the atoms adjacent to the carbonyl are a carbon and a heteroatom i.e. mainly for the α-pyrone ring and the conjugated "lactams". They are inappropriate for carbonates and oxazo-ones but should be valid for quinones provided that they are not involved in a charge transfer complex. The mean unsigned deviation for 111 bond lengths (89 cyclic molecules) is 0.01A but the maximum deviation can reach ± 0.03A. Part of the observed dispersion could be the result of the variation of the effective dielectric constant D from one crystal to another.

Statistical Analysis of Noncovalent Interactions of Anion Groups in Crystal Structures. III. Metal Complexes of Thiocyanate and their Hydrogen-Donor Accepting Function

The bidentate function of the thiocyanate anion was studied using the Cambridge Structural Database System. Complexing properties (metal–thiocyanate interactions) with respect to metal cations were analysed. Two main classes were distinguished: (a) alkali and alkaline earth metals, and (b) metals of Zn and Cu groups and transition metals (group VIII). Good correlations were found between the nature of the metal (radius, oxidation state and charge) and its position relative to the thiocyanate unit. Hydrogen-bond acceptor properties of discrete and complexed SCN units were compared. The extraordinarily active hydrogen-bonding behaviour allows this anion to act as a powerful bridge between different molecular fragments. In metal complexes the cation provokes a redistribution of anionic charge in SCN and the distribution of electron density, in turn, controls the hydrogen-bonding properties of the terminal acceptor atom. Binding properties of thiocyanate in biological systems were illustrated using the Brookhaven Protein Data Bank. A comparison of anion binding in small-molecule structures and in macromolecular structures shows good agreement.

EFFECT OF CHALCOGEN SUBSTITUENTS (X=Se, S, O) ON MOLECULAR PROPERTIES OF 5-p-CHLOROBENZYLIDENE-3-METHYL-2-X-HYDANTOIN: X-RAY, PM-3 AND DATABASE STUDY

The X-ray structure analysis of a single crystal of 5-p-chlorobenzylidene-3-metyl-2-Se-hydantoin was carried out. It revealed that the molecule is a 2 isomer with approximately planar conformation, the angle between the hydantoin and p-chlorophenyl planes being 4.2(1)°. The molecules form dimers linked by weak hydrogen bonds N-H···, Se and C-H··· Se about an inversion center. Semiempirical quantum mechanics calculations (PM-3) were performed for the three molecules of 5-p-chlorobenzylidene-3-methyl-2-X-hydantoin, where X=Se, S, O. Their results suggest that the planar conformation of these molecules is less energetically favourable than that with the planar molecular fragments significantly tilted to each other. Thus, the planar conformation which was found for many benzylidene derivatives in the crystalline state using Cambridge Structural Database System may be stabilized by intermolecular interactions. The net atomic charges and the bond lengths in the hydantoin ring are strongly affected by the X substituents. The electronegativity of X and the charge distribution in the hydantoin ring seem to be the most important factors in determining the anticonvulsant activity in the three compounds.

An Attractive Interaction between the π-Cloud of C6F6and Electron-Donor Atoms

A theoretical study of the possible interaction of the π-cloud of hexafluorobenzene (C6F6) with several small electron-donor molecules (FH, HLi, :CH2, NCH, and CNH) has been carried out. The calculations have been performed using HF, MP2, and hybrid HF/DFT methods (B3LYP) with the 6-31G** and 6-311++G** basis sets. The topology of the electron density of the complexes has been characterized using the AIM methodology. The characteristics of the electron density and molecular electrostatic potential maps of benzene and hexafluorobenzene have been compared. Finally, the results obtained from a search in the Cambridge Structural Database system of this kind of interaction are shown.

How good is fluorine as a hydrogen bond acceptor?

This study is aimed at evaluating organic fluorine as a hydrogen bonding acceptor. A review of short F…H contacts from all of the organofluorine compounds deposited in the Cambridge Structural Database System (CSDS) was carried out and in parallel a theoretical estimate of the energy of such contacts with inter nuclear distance was executed. A total of 548 structures emerged which contained 1163 unique CF bonds and only 166 of these fluorine atoms posessed short CF…HX contacts of ≤ 2.35Å. Contacts between fluorine and hydrogen bound to carbon (CF…HC) represent the major category of short contacts however these were not judged to be hydrogen bonds as they are weak with energies similar to those of van der Waals complexes. Short contacts between F and the acidic hydrogens of HO or HN are rare in the CSDS with only 12 and 28 occurring respectively. There was only one contact below 2.0Å. Ab initio calculations have evaluated the relative stability and optimum distance of CF…HO bonds between water and fluoromethane and fluoroethene. It emerges that the C(sp 3)F fluorine in fluoromethane can enter into stronger hydrogen bonds than C(sp 2)F of fluoroethene. The X-ray data reinforces the conclusion that C(sp 3)F fluorine is a better hydrogen bond acceptor than C(sp 2)F fluorine. The C(sp 3)F…HO bond is less than half the strength (2.38 kcal mol −1) of a CO…HO and the C(sp 2)F…HO bond (1.48 kcal mol −1) is about half as weak again. Overall however short contacts in the Database which are consistent with an optimal F…H bond are extremely rare.

The development of versions 3 and 4 of the Cambridge Structural Database System

ed, together with any associated supplementary (deposited) data. The CSD itself acts as a computerized depository for large-volume numerical results for some 30 journals. A total of 584 primary sources are now referenced in the CSD, of which 74 are regularly scanned in-house to provide ca. 80% of current input. Remaining references are located via a scan of secondary sources, particularly Chemical Abstracts. Each entry in the CSD relates to a specific crystal structure determination of a specific chemical compound. Each entry is identified by a CSD reference code (REFCODE). This consists of eight characters: the first six are alphabetic and identify the chemical compound (initially assigned as a mnemonic of the compound name, now generated automatically for new compounds), the last two characters are digits which trace the publication history and define (a) whether the paper is a republication by the same authors (perhaps reporting an improved coordinate set) or (b) whether the paper is a redetermination by a different set of authors. The information recorded for each entry may conveniently be categorized according to its dimensionality, as described below and illustrated in Figure 1. 1 D information consists of bibliographic and chemical text strings, together with certain individual numeric items: comBATCH OR VERSION 4 GRAPHICS VERSION 4 GRAPHICS

Automated conformational analysis from crystallographic data. 3. Three-dimensional pattern recognition within the Cambridge Structural Database system: implementation and practical examples

A unified computational procedure is described for the identification of conformational subgroups for a chemical fragment from crystal structure data. Fragment conformations are defined by N, torsion angles for Nj occurrences of the fragment in the Cambridge Structural Database. Subdivision of this multivariate data set is performed by a choice of clustering algorithms (single-linkage, complete-linkage, JarvisPatrick). Both asymmetric and symmetric fragments are handled routinely. The algorithms yield optimum superposition of a given conformation in a single cluster and place discrete clusters into a single asymmetric unit of conformational space. The unified procedure generates graphical and numerical indicators of clustering efficiency: (i) principal-component plots of the optimally superimposed data set, (ii) a simple statistical summary for each cluster, (iii) measures of intracluster shape and size, (iv) details of intercluster separations. Major clusters are ranked in order of decreasing population and the 'most representative fragment' (MRF: the fragment of the data set which is closest to the cluster centroid) is identified in each case. Atomic coordinates for the MRF's may be output for use as conformational alternatives in model building. The complete procedure is successfully applied to the automated conformational analysis of two very different systems, the cyclic 1-azacycloheptane moiety and the acyclic Cx7 side chain typical of cholesterol and related steroids.