Browsing by Author "Akerele, Oluwatoyin Omolara"

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    Computational and experimental investigation of factors affecting the quality of multi-component crystals
    (Stellenbosch : Stellenbosch University, 2022-03) Akerele, Oluwatoyin Omolara; Esterhuysen, Catharine; Haynes, Delia; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: A series of six substituted benzoic acid and fifteen substituted pyridine compounds have been crystallised together to form multi-component co-crystals or salts. The crystal structures obtained from single-crystal X-ray diffraction show that the hydrogen bond between the carboxylic acid group and pyridine nitrogen is strong, resulting in a robust synthon that is present in all the co-crystals and salts formed. The nature of the synthon, including hydrogen bond strengths and geometries and the co-planar of the acid and base in the multi-component crystals was investigated using both experimental and computational approaches. The hydrogen-bond energy between the acid and base is related to the Npyr-Ocarb distance as we found low distances correspond to strong interactions and vice versa in both co-crystals and salts. It was found that in the presence of NH2 substituents ortho to the pyridine an 𝑅22(8) hydrogen-bonded ring forms that leads to co-planarity of the two molecules. This is likely to promote the formation of a slip plane, which in turn may improve the tabletability of such salts or co-crystals. These results were confirmed by a Cambridge Structural Database search that showed that the properties identified are also generally relevant for the 879 related multi-component crystal structures previously reported. These crystal structures were then used as a basis for the identification of intrinsic factors that affect the crystal quality. The hydrogen-bond energies between the acid-base unit in salts is stronger than those in co-crystals, suggesting that salts are more stable than co-crystals. Similar observations were obtained for the lattice energies, the free energies of interactions, polarisation energies, and the strengths of hydrogen bond donor and acceptor. This means the presence of ionic components makes these interactions stronger and thereby stabilises the multi-component crystal. However, in salts this does not automatically translate into a good-quality crystal as we observed good- and poor-quality crystals for both salts and co-crystals. This means ionicity does not determine the formation of quality crystals. Further investigation revealed that the factors influencing crystal quality depend on the chemical species involved; there is no common factor that cut across all the compounds. The interactions associated with the packing of the crystal structures, and not necessarily the hydrogen bond between the acid-base pair were most commonly found to be responsible for the formation of good-quality salt crystals. The quality of co-crystals is influenced by both the strength of the hydrogen bond within the acid-base unit and the interactions with molecules surrounding the unit. The absence of a substituent at the para position in the acid component was found to hinder the formation of good-quality co-crystals. Comparison of two similar compounds that produce crystals of different quality reveals that the strong lattice energy, electrostatic energy, a small difference in the strength of hydrogen bond donor and hydrogen bond acceptor of acid and base, the presence of strong interactions around the benzoic-acid…pyridine synthons, are the factors that influence the formation of good-quality crystals. These interactions that play a role are typically strong hydrogen bonds, π- π stacking, and C-H…O bonds; the greater the number of interactions with high energy in a complex, the better the quality of crystals that will be formed. Finally, the organic bases used in this study were found to impact crystal formation, for instance, 2-amino-4-methyl pyridine and 2-amino-5-nitropyridine are good co-formers that generally facilitate strong interactions and give rise to good-quality crystals, while co-formers such as 4-cyanopyridine and 2-amino-6-methylpyridine typically form weak interactions, resulting in poor-quality crystals.