Elna Pidcock

Nitrogen-centered Lewis bases are well established as nucleophiles in synthetic chemistry, as ligands in coordination chemistry and as pervasive components of hydrogen bonding in chemistry and structural biology. Their role as acceptors of halogen, chalcogen, pnictogen and tetrel bonds, collectively σ-hole interactions, is also well established experimentally, but only selectively investigated through exploration of geometric and energetic trends. Here we report a comprehensive study, in which we identify the prevalence of this class of interactions and analyze experimental geometric trends from crystallographic data. These analyses are supported by high-accuracy coupled-cluster quantum chemical calculations of interaction energies and use of symmetry-adapted perturbation theory (SAPT) to examine the underlying energetic contributions. Our focus is on comparison, across the four families of σ-hole interactions, of the behavior for Nsp3 vs Nsp2 vs Nsp hybridization at the nitrogen atom bearing the lone pair. Halogen and chalcogen bonds are more abundant than pnictogen and tetrel bonds, whereas interaction prevalence tends to be greatest for the heavier congeners in each σ-hole donor group (i.e., I, Te, Sb/Bi, Sn/Pb). The relative prevalence of tetrel bonds compared to halogen bonds increases from Nsp3 to Nsp2 to Nsp acceptors, highlighting the importance of steric demands. The heavier congeners among the σ-hole donors generally form interactions with shorter normalized interaction distances, although this is mitigated by sterics, most prominently for tetrel bonds and for Nsp3 Lewis bases. Preference for linearity with respect to the σ-hole angle and the angle at the nitrogen lone pair follow the trend Nsp3 > Nsp2 > Nsp also as a consequence of steric demands. More generally, SAPT analysis of interaction energies clearly indicates the prominent influence of sterics, through exchange repulsion, on angular preferences of all interactions. The broader implications of these comprehensive results in areas such as supramolecular, materials and medicinal chemistry are considered.

A new methodology to perform virtual coformer screening, utilising data gathered on hydrogen-bonding interactions present in the organic subset of the Cambridge Structural Database (CSD), is presented. From a target molecule, commonly interacting functional groups are identified from the CSD and appropriate coformers, containing those functional groups, are suggested. The method, available as a script in Mercury , provides a quick and data-driven approach to coformer selection.

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.

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.

The crystal structure of an indomethacin–nicotinamide (1 : 1) co-crystal produced by milling has been determined from laboratory powder X-ray diffraction (PXRD) data. The hydrogen bonding motifs observed in the structure represent one of the most probable of all the possible combinations of donors and acceptors in the constituent molecules.

We have previously reported on hydrogen bond propensity calculations for the potential formation of adducts between pyrimethamine and dicarboxylic acids. Here we extend the range of potential synthon interactions using a variety of potential coformers. Specifically calculations were performed to predict the possibility of the formation of molecular adducts, 1a–1h, between the anti-malarial drug pyrimethamine (1) and (a) carbamazepine, (b) theophylline, (c) aspirin, (d) α-ketoglutaric acid, (e) saccharin, (f) p-coumaric acid, (g) succinimide and (h) L-isoleucine. The bonds of highest propensity were predicted between 1 and coformers (b–h), indicating a high probability of formation of adducts between 1 and b–h. In contrast the bonds of highest propensity were between reactants and the solvent for the adduct 1a, indicating either a high probability of the reactants crystallizing as solvates or incorporation of solvent into the adduct lattice. Experimental results agreed with the propensity calculations with the formation of a solvated cocrystal (1a·CH₃OH). The successful application of hydrogen bond propensity calculations to the prediction of likely outcomes of these cocrystallization reactions suggests that this may be a useful tool in designing more targeted screening experiments.

The specific crystalline form of a compound has a significant impact on its solid state properties. A key requirement for chemists developing crystalline materials is therefore to understand and evaluate the crystal form under investigation. We show here how the visualisation of molecular interaction maps within the context of a crystal structure can be used to evaluate the stability of polymorphic structures, assess multiple types of non-covalent interactions and provide a platform for crystal morphology analysis. Examples of three industrially-relevant compounds – sulfathiazole, anastrozole and cipamfylline – illustrate this well. A qualitative agreement with experimental stability data is observed for the five sulfathiazole crystal forms. The anastrozole crystal structure is demonstrated to optimise interactions to the strongest acceptor sites even though there are no conventional hydrogen-bond donors in the structure. Finally, the fastest growing plane of the needle-like morphology of cipamfylline is shown to have more H-bond donor and acceptor interactions per surface area than the slower growing planes.