Using Electron Density to Predict Synthon Formation in a 4-Hydroxybenzoic Acid: 4,4′-Bipyridine Cocrystal

• DOI: 10.1021/acs.cgd.7b01676
• Publication Date: 2018-01-11T18:47:03Z
• Authors: Jonathan J. Du; Stephen A. Stanton; Peter A. Williams; Jennifer A. Ong; Paul W. Groundwater; Jacob Overgaard; James A. Platts; David E. Hibbs
• Keywords: bipyridinium compounds; XXXXXX - Unknown; crystals; electrons; structure; crystallography; 540; 01 natural sciences; hydroxybenzoic acids; drugs; 0104 chemical sciences

Experimental charge density distribution studies complemented by quantum mechanical theoretical calculations of 4-hydroxybenzoic acid (4HBA) (1), 4,4'-bipyridine (44BP) (2) and one polymorphic form of the co-crystal containing 4HBA and 44BP molecules in a 2:1 ratio (3), have been carried out via high resolution single-crystal X-ray diffraction. Synthon formation was found to be the main driving force for crystallisation in both (1) and (3) with a carboxylic acid homosynthon present in (1) and a heterosynthon in (3) comprised of a carboxylic acid from 4HBA and a pyridine nitrogen and aromatic hydrogen from 44BP. Topological analysis revealed the bonding in the homosynthon to be stronger than the heterosynthon (305.88 versus. 193.95 kJ mol-1) with a greater number of weak interactions in (3) helping to stabilise the structure. The distance from the hydrogen and hydrogen bond acceptor to the bond critical point (bcp) was also found to be a significant factor in determining bond strength, potentially having a greater effect than lone pair directionality. Two different methods of lattice energy calculations were carried out and both methods found (1) to be more stable than (3) by ~40 and 10 kJmol-1 for the LATEN and PIXEL methods respectively. Energy framework diagrams reveal (1) to be dominated by coulombic forces while both coulombic and dispersion forces are prominent in (3) contributing equally to the lattice energy. This study examined the utility of homosynthons and heterosynthons in future crystal engineering endeavours and concluded that although in this case the single molecule crystal was more thermodynamically stable, the asymmetry of the co-crystal system allowed it to form a wider range of interactions resulting in only a small reduction in stability. This highlights the potential of using heterosynthons to develop co-crystals to improve pharmaceuticals. These findings highlight the utility of high resolution single crystal X-ray crystallography in rationalising observed physical properties.