Using electron density to predict synthon formation in a 4-hydroxybenzoic acid : 4,4′-bipyridine cocrystal

Jonathan J. Du, Stephen A. Stanton, Peter A. Williams, Jennifer A. Ong, Paul W. Groundwater, Jacob Overgaard, James A. Platts, David E. Hibbs

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

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 cocrystal 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 crystallization 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 stabilize 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 kJ mol–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 endeavors and concluded that although in this case the single molecule crystal was more thermodynamically stable, the asymmetry of the cocrystal 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 cocrystals to improve pharmaceuticals. These findings highlight the utility of high-resolution single-crystal X-ray crystallography in rationalizing observed physical properties.
Original languageEnglish
Pages (from-to)1786-1798
Number of pages13
JournalCrystal Growth and Design
Volume18
Issue number3
DOIs
Publication statusPublished - 2018

Keywords

  • bipyridinium compounds
  • crystallography
  • crystals
  • drugs
  • electrons
  • hydroxybenzoic acids
  • structure

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