Browsing by Author "Dippenaar, Alwyn Bernard"

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    Hydrate formation in pharmaceutically relevant salts
    (Stellenbosch : Stellenbosch University, 2014-12) Dippenaar, Alwyn Bernard; Esterhuysen, Catharine; Haynes, Delia A.; Stellenbosch University.Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: A theoretical and experimental study was performed in order to identify factors that influence the propensity of compounds containing anionic functional groups that are commonly found on pharmaceutical drug compounds to form hydrates. A Cambridge Structural Database (CSD) survey was initially undertaken to determine the propensity of different pharmaceutically acceptable anions to form hydrates. The results showed that hydrate formation will take place more regularly when the polarity of the functional group increases. Furthermore, if the charge distribution is very concentrated over the polar groups, hydrate formation will occur more readily. This observation was further investigated by performing a series of potential energy surface (PES) scans for the hydrogen bond (H-bond) in the structure of N-(aminoiminomethyl)-N-methylglycine monohydrate (creatine monohydrate) with various Density Functional Theory (DFT) and Wave Functional Theory (WFT) methods. WFT is often also referred to as ab initio, which refers to the construction of the wave function from first principles when this theory is applied. The scans revealed that several strong and directional H-bonds with different geometrical parameters between the carboxylate group and the water molecule are possible, which suggests that the H-bond plays an important role in driving the formation of pharmaceutical hydrates. A total of 44 hydrate structures were identified that have pharmaceutically acceptable functional groups. Optimisations in the gas phase and in an implicit solvent polarisable continuum solvent model with a variety of solvents showed that there is a significant dependence of the H-bond interaction energy on the anionic group as well as the steric density of surrounding substituents. It was found that the M06-2X method utilising the 6-311++G(d,p) basis set outperformed the other methods that were tested when compared to optimisations performed with the benchmark MP2/aug-cc-pVTZ level of theory. Furthermore, the strength of the H-bond was measured in the 44 experimentally determined structures by using a total of five generalized gradient approximation (GGA) methods, of which two methods contained the DFT-D3 correction. The results of these DFT methods were subsequently compared to results obtained at the benchmark MP2/aug-cc-pVTZ level of theory. The M06-2X method was identified as the most economical method to calculate H-bond energies. It was also found that the H-bond interaction energy shows a substantial dependence on the electrostatic environment. This was observed by a significant decrease in H-bond strength as the relative permittivity of the solvent increases. The effect of steric density on the H-bond interaction energy was investigated by performing hydrogen bond propensity calculations. These values were then compared to the interaction energies of each structure and the results showed that the presence of large bulky substituents can lead to an increase in bond energy by forcing the anionic functional group closer to the water molecule. Contrastingly, the bulky group can also push the anionic group away from the water molecule and result in a decrease in bond energy. Approximate values for the amount of stabilisation offered to the H-bonding system by the surrounding crystalline environment were calculated by optimising the H-bond geometrical parameters of selected compounds with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. The H-bond interaction energies were then calculated at the M06-2X/6-311++G(d,p) level of theory and compared to the H-bond interaction energies in geometries that have been fully optimised. After these energies were compared and the crystal packing of each structure was investigated, it was found that the packing of some structures within the crystalline environment limits the number of H-bonds that can be formed between the water and the compound of interest. Full optimisation calculations result in structures with cooperative stabilisation, such that more than one H-bond is found between the two fragments. The effect of substituents on H-bond interaction energy was investigated by the addition of six electron-donating and electron-withdrawing groups on four aromatic compounds with different anionic functional groups, namely carboxylate, nitrogen dioxide, sulfonate and phosphonate. It should also be mentioned that the nitrogen dioxide is not an anionic functional group, but it was included as it is a neutral radical that often forms hydrogen bonds. A total of 80 structures were optimised with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. This was followed by counterpoise corrected single point calculations at the M06-2X/6-311++G(d,p) level of theory. The results showed that the H-bond interaction energy bears no relationship to the inductive strength or the inductive ability of the substituents, but rather the ability of these substituents to rotate the anionic functional group and allow cooperative stabilisation of the H-bond. Furthermore, AIM analysis was performed for the substituted H-bonded aromatic structure. The results showed that electron-donating groups that are placed at the para position yield stronger H-bonds, which is once again accompanied by cooperative stabilisation. Electron-withdrawing groups with sufficient inductive effects can result in a weaker H-bond when placed at the meta position. The effect of water activity (aw) on the hydrate crystal formation was investigated experimentally by performing a series of crystallisations in various solvent mixtures. These mixtures consisted of water mixed with acetone, ethanol and ethyl acetate. A total of three organic acids were used in crystal formation, namely pyridine-4-carboxylic acid (isonicotinic acid), N-amino-iminomethyl-N-methylglycine (creatine) and benzene-1,3,5-tricarboxylic acid. It was found that water activity affects the formation of the hydrate as well as the anhydrous product. Additionally, nucleation and super saturation plays a large role in crystal formation and can serve as an effective technique when the formation of crystals of an appropriate shape and size is required for further analysis.
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    Rationalising the solid-state properties of dithiadiazolyl radicals using a combined theoretical and experimental approach
    (Stellenbosch : Stellenbosch University, 2018-03) Dippenaar, Alwyn Bernard; Esterhuysen, Catharine; Haynes, Delia A.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: The work describes a series of theoretical and experimental studies carried out to better understand the solid-state properties of 1,2,3,5-dithiadiazolyl (DTDA) radicals. The attempted co-crystallisation of 4-(4'-cyano-2',3',5',6'-tetrafluorophenyl)-1,2,3,5-dithiadiazolyl (2) and 4-(2',6'-difluoro-phenyl)-1,2,3,5-dithiadiazolyl (7) yielded the α-phase of 2, which had previously been shown to only grow on a cold finger at -10 °C. The needle-shaped β-phase crystals of 2 were found to be the first DTDA radical that exhibits flexible properties. The experimental work focussed on the properties of four DTDA radicals. The synthesis of 4-(4'-bromo-2',3',5',6'-tetrafluorophenyl)-1,2,3,5-dithiadiazolyl (3) produced a mixture of the desired product and a novel co-crystal (3-cox). The crystal structure of 3-cox was found to contain dimeric pairs of 3 co-crystallised with starting material, 4-bromo-2,3,5,6-tetrafluoro-benzonitrile. The joint refinement of high-resolution X-ray diffraction (HXRD) and polarised neutron diffraction (PND) data was used to determine the spin density of 4-(2',3',5',6'-tetrafluoro-4'-nitrophenyl)-1,2,3,5-dithiadiazolyl (4). The spin density values were found to be in good agreement with previously determined experimental values, with the majority of the spin density on the sulfur and nitrogen atoms of the heterocyclic radical ring. In the computational part of this study, a series of calculations was performed to investigate why specific DTDA radicals prefer monomeric or dimeric modes of association in the solid state. Geometry optimisations and single point energy calculations showed that dimeric radicals yield attractive energies if the geometry optimisation and single point calculations are performed in the singlet or triplet state, whereas monomeric radicals only interact attractively in the triplet state, irrespective of how the geometry optimisation had been undertaken. Radical 3 was found to be the one exception as it exhibits attractive energies for both monomeric and dimeric modes of association. This agreed with the experimental results as the crystal structures of 3 and 3-cox exhibit monomeric and dimeric modes of association between molecules of 3, respectively. Geometry and interaction energy calculations on substituted radicals showed that the ortho and para groups could reduce the tendency of DTDAs to dimerise. Lastly, the results from the first and second sections were used as a basis for a series of calculations to predict the mode of association in radicals that have not yet been synthesised (‘unknown radicals’). Geometry optimisation and interaction energy calculations were performed on the unknown radicals arranged in eight monomeric or dimeric modes of association. The results were used to identify three of the compounds as likely to associate in the dimeric mode, while three were expected to form monomeric radicals. Crystals were obtained for 4-(3'-fluoro-4'-trifluoromethylphenyl)-1,2,3,5-dithiadiazyl (32) and 4-(4'-bromophenyl)-1,2,3,5-dithiadiazyl (33). The crystal structure of radical 32 shows that the molecules exhibit a trans-cofacial mode of association, which was computationally predicted as the most stable mode of association. Similarly, in the crystal structure of radical 33, the molecules exhibit a cisoid mode of association, which was computationally predicted as one of the most stable modes of association. Taken together, the results from the study show that a combination of theoretical and experimental methods provide a powerful tool for studying the properties of DTDAs.