W.D.S. Motherwell

Applications of the Cambridge Structural Database in organic chemistry and crystal chemistry

The Cambridge Structural Database (CSD) and its associated software systems have formed the basis for more than 800 research applications in structural chemistry, crystallography and the life sciences. Relevant references, dating from the mid-1970s, and brief synopses of these papers are collected in a database, DBUse, which is freely available via the CCDC website. This database has been used to review research applications of the CSD in organic chemistry, including supramolecular applications, and in organic crystal chemistry. The review concentrates on applications that have been published since 1990 and covers a wide range of topics, including structure correlation, conformational analysis, hydrogen bonding and other intermolecular interactions, studies of crystal packing, extended structural motifs, crystal engineering and polymorphism, and crystal structure prediction. Applications of CSD information in studies of crystal structure precision, the determination of crystal structures from powder diffraction data, together with applications in chemical informatics, are also discussed.

A test of crystal structure prediction of small organic molecules.

A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as correct. One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.

A third blind test of crystal structure prediction

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.

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. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors

The crystal structures of five hemiadducts of paracetamol with 1,4-dioxane, N-methylmorpholine, morpholine, N,N-dimethylpiperazine and piperazine and a related 1:1 adduct of paracetamol with 4,4-bipyridine are described. All structures are characterized by the formation of chains of paracetamol molecules, which are linked via either OHtriplebondO=C interactions [C(9) chains in graph-set notation] or NHtriplebondO=C interactions [C(4) chains], depending on the presence or absence of substituent groups on the guest molecule. In all cases except for the morpholine and bipyridine adducts these chains are connected by hydrogen-bond interactions with the guest molecules, which reside on crystallographic inversion centres. In the bipyridine adduct this linkage also involves a pi-stacking interaction; in the morpholine adduct it is formed between the OH groups of two opposed paracetamol molecules. Most adducts (that with 4,4-bipyridine is an exception) decompose on heating to give monoclinic paracetamol. This is the first systematic study of a series of co-crystals containing paracetamol.

Visualization and characterization of non-covalent networks in molecular crystals: automated assignment of graph-set descriptors for asymmetric molecules

A method of visualizing intermolecular networks (for example, hydrogen-bonded networks) in the crystalline state has been developed, based on the concept of link atoms, i.e. those atoms deemed to be in contact with each unique molecule or ion in the crystal chemical unit (CCU). Extension of a structure using each of these primary links can be achieved, enabling the generation and investigation of extended networks. Algorithms have been developed for the automatic assignment of graph-set notation for patterns up to second level, i.e. those involving one or two crystallographically independent non-covalent bonds, in the absence of internal crystallographic symmetry in the unique molecules of the CCU. The self, ring, chain and discrete motifs may be displayed by highlighting the atoms and bonds comprising the pattern. These methodologies have been implemented in the Cambridge Structural Database program PLUTO.

A strategy for predicting the crystal structures of flexible molecules: the polymorphism of phenobarbital

A computational exploration of the low energy crystal structures of the pharmaceutical molecule phenobarbital is presented as a test of an approach for the crystal structure prediction of flexible molecules. Traditional transferable force field methods of modelling flexible molecules are unreliable for the level of accuracy required in crystal structure prediction and we outline a strategy for improving the evaluation of relative energies of large sets of crystal structures. The approach involves treating the molecule as a set of linked rigid units, whose conformational energy is expressed as a function of the relative orientations of the rigid groups. The conformational energy is calculated by electronic structure methods and the intermolecular interactions using an atomic multipole description of electrostatics. A key consideration in our approach is the scalability to more typical pharmaceutical molecules of higher molecular weight with many more atoms and degrees of flexibility. Based on our calculations, crystal structures are proposed for the as-yet uncharacterised forms IV and V, as well as further polymorphs of phenobarbital.

The assignment and validation of metal oxidation states in the Cambridge Structural Database

A methodology has been developed for the semi-automatic assignment and checking of formal oxidation states for metal atoms in the majority of metallo-organic complexes stored in the Cambridge Structural Database (CSD). The method uses both chemical connectivity and bond-length data, via ligand donor group templates and bond-valence sums, respectively. In order to use bond-length data, the CSD program QUEST has been modified to allow the coordination sphere of metal atoms to be recalculated using user-defined criteria at search time. The new methodology has been used successfully to validate the +1, +2 and +3 oxidation states in 743 four-coordinate copper complexes in the CSD for which atomic coordinates are available in ca 99% of structures using one or other method, and both succeed for >86% of structures.

CSDSymmetry: the definitive database of point- group and space-group symmetry relationships in small-molecule crystal structures

An algorithm that perceives molecular symmetry has been applied to ca. 200,000 entries from the Cambridge Structural Database (CSD). For each molecule, the perceived point group, together with crystallographic properties such as space group, occupied Wyckoff positions and number of residues in the asymmetric unit, have been placed in a relational database, CSDSymmetry, using Microsoft Access software. Database queries can be constructed easily to find occurrences of any combination of molecular or crystallographic attributes, and thereby to answer questions on relative distributions. Some typical example queries are given. The inclusion of CSD reference codes enables direct visualization of search results using the Cambridge Crystallographic Data Centres three-dimensional structure visualizer, Mercury.

Structures of the monofluoro- and monochlorophenols at low temperature and high pressure

2-Fluorophenol, 3-fluorophenol and 3-chlorophenol were recrystallized from frozen solids at 260, 263 and 283 K. All compounds were also crystallized by the application of high pressure (0.36, 0.12 and 0.10 GPa). While 3-fluorophenol and 3-chlorophenol yielded the same phases under both conditions, different polymorphs were obtained for 2-fluorophenol. 4-Chlorophenol was crystallized both from the melt and from benzene to yield two different ambient-pressure polymorphs; crystallization from the melt at 0.02 GPa yielded the same phase as from benzene at ambient pressure. 3-Fluorophenol is unusual in forming a hydrogen-bonded chain along a 2(1) screw axis. Such behaviour is usually only observed for small alcohols, but here it appears to be stabilized by intermolecular C-H...F hydrogen-bond formation. 3-Chlorophenol is a more typical large alcohol and emulates a fourfold screw axis with two independent molecules positioned about a 2(1) axis, although there are significant distortions from this ideal geometry. The two phases of 4-chlorophenol consist of chains or rings connected by C-Cl...H interactions. The low-temperature and high-pressure polymorphs of 2-fluorophenol consist of chains of molecules connected through OH...OH hydrogen bonds; while inter-chain C-H...F interactions are significant at high pressure, there are none in the low-temperature form.