Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017. / Crystal engineering principles were used to cocrystallize sulfa drugs, sulfapyridine (SFP) and sulfadiazine (SFD) with aromatic acids and an amine via solution crystallization. Sulfapyridine formed cocrystals with 3-nitrobenzoic acid (SFP∙3NBA), 5-bromosalicylic acid (SFP∙5BSA), 4-dimethylaminopyridine (SFP∙4DMAP) and salts with 4-nitrobenzoic acid [SFP+][4NBA-], 3,5-dinitrosalicylic acid [SFP+][DNSA-] and 3,5-dibromosalicylic acid [SFP+][DBSA-], while sulfadiazine formed a salt with 3,5-dinitrosalicylic acid [SFD+][DNSA-]. The newly formed complexes were analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), fourier transform infrared spectroscopy (FTIR), single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD) and nuclear magnetic resonance spectroscopy (1H and 13C NMR). The hydrogen bonding and crystal packing of the new solid forms were analyzed with the aid of Mercury and CrystalExplorer. The SFP and SFD compounds exhibit tautomerism. In this work it was investigated how the introduction of coformers with varying acidity provides the possibility to form a variety of synthons, and therefore disrupt the common preferred interactions within the sulfonamides. Using selected acids as coformers, the effect on crystal packing of the coformer’s substituent position was examined by using the isomers 3NBA and 4NBA. 5BSA and DBSA were employed to analyse the effect of the number of substituents on hydrogen bond formation and crystal packing. In addition, it was investigated how small structural changes in the pharmaceutical compound influences the crystal packing by cocrystallising structurally similar SFP and SFD with the same coformer. Evaluation of the change in coformer acidity was studied by using a pyridine coformer, 4DMAP, and its crystal packing was analyzed and compared to structures formed with carboxylic acid coformers. Finally, we examined how inter-conversion of tautomers promotes crystal formation by conforming to the geometric demands of the different coformers. / National Research Foundation(NRF)

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Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The impact of the molecular electrostatic potential values (MEPs) in halogen and hydrogen bond interactions were explored using two acceptors with multiple acceptor sites with twelve hydrogen-bond donors, five halogen bond donors and four mixed halogen and hydrogen bond donors. The results suggested if the difference between the two acceptor sites is above 38 kJ/mol both hydrogen and halogen bond donors prefer the acceptor site with the highest MEP value and this selectivity was lost if the difference is below 26 kJ/mol. To examine the potential of halogen-bond donors in organocatalysis, a halogen-bond donor molecule was synthesized and the catalytic activity was measured using a benchmark Ritter type solvolysis reaction. Results suggested the catalytic activity of the halogen-bond donor molecule with > 90 % conversion of the product with the use of a stoichiometric amount of the catalyst for 96 hrs. Successful use of the control molecules confirm that the catalytic activity is an outcome of having halogen-bond donors in the molecule. The benefit of using a structural mimic in landscaping the structural outcomes of poorly soluble molecules was explored using an anticancer drug erlotinib. A structural mimic was synthesized by maintaining all binding sites that are important to design a structural landscape and the structural outcomes were analyzed using five FDA approved dicarboxylic acids. The results suggested that the structural outcomes of the mimic can be related to the actual drug erlotinib. Solubility and thermal behavior analysis of the co-crystals also suggested that with the systematic changes of the co-crystallization agent, it is possible to make predictable changes to the physical properties. To observe the effect of co-crystallization technology in reducing the chemical reactivity and sensitivity of an energetic compound dinitrobenzotriazole, a series of co-crystallization experiments was carried out using fourteen nitrogen and oxygen based acceptors. Four co-crystals were obtained and the acceptors were identified as supramolecular protecting groups which led to successful diminish of chemical instability and decreased impact sensitivity. Hygroscopicity and chemical reactivity of tetranitrobisimidazole, a potential RDX replacement, was successfully decreased by protecting the acidic N-H protons in the molecule by introducing suitable co-formers. Introduction of the N-oxide based acceptors into the system enhanced the stability while retaining most of the desirable energetic properties.

No description available.

A literature review on the geometry of hydrogen bonding showed that the geometry is often de-emphasized or even ignored, probably because of the inherent flexibility of many systems studied. Examination of molecular models suggested the geometrically constrained bicyclo [2, 2, 1] heptane system wherein hydrogen bond distances and angles might be more easily predicted. Dihydroboration-oxidation of norbornadiene was shown to yield exo, exo-2,5-norbornadiol, thus clarifying uncertainties in the literature. 2, 5-Norbornadiol was oxidized to the corresponding dione, heretofore inadequately characterized. Several derivatives of the dione were prepared, and spectral data were accumulated for the dione, its precursor, and its derivatives. The mono(ethylene ketal) of 2,5-norbornadione was prepared as a key intermediate in projected synthesis schemes. Preliminary work was initiated in converting it to compounds of interest. Although norbornadione was prepared by dihydroboration followed directly with oxidation, the yields were low under all conditions tried. Consequently, a two-step sequence was used.

No description available.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第23386号 / 薬科博第143号 / 新制||薬科||16(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 川端 猛夫, 教授 高須 清誠, 教授 大野 浩章 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

"Molecular engineering of some 2,4,6-(substituted biarylamino)-1,3,5-triazines and crystal data belonging to the products 2,4,6-(m,m’-ditolylamino)-1,3,5-triazine, 2,4,6-(p,p’-ditolylamino)-1,3,5-triazine and 2,4,6-(phenyl-p-tolylamino)-1,3,5-triazine were reported. Retrosynthetic analysis of trigonal octupolar networks led to the identification of tris-substituted diarylamino-triazines as molecular analogs of Piedfort units formed by cofacial dimers of 2,4,6-triaryloxy-1,3,5-triazine molecules. Synthesis of mono and diarylamiono triazines is achieved by coupling of the corresponding anilines with cyanuric chloride. Synthesis of diarylamines exhibiting different functional groups on two phenyl rings is attempted; the successful attempt in the case of phenyl-p-tolylamine is described. All the crystals obtained so far belong to centrosymmetric space group P21/c. Though none of the molecules retain trigonal symmetry in the crystal structures, pseudo-trigonal assembly of molecules is identified in some cases. The assembly of molecules within the crystals results in columnar structures formed by C-H..N and C-H..pi interactions."

Non-covalent interactions are of great importance in biology, chemistry, and material sciences. Although much information about different types of non-covalent interactions is available, incorporating them in a molecular design to generate a molecule that can undergo association to form a molecular assembly with bulk properties of interest is a challenge. To understand and harness intermolecular interactions, we have designed an indane 2,5-diketopiperazine (DKP) scaffold. Crystal engineering studies with this scaffold show that the molecules assemble into one dimensional tapes via reciprocal amide hydrogen bonds, tapes assemble into two dimensional sheets via arene-arene interactions, and sheets assemble into three dimensional solids via van der Waals contacts. A series of tetraalkoxy-substituted DKPs previously investigated exhibited liquid crystalline behavior. A new class of DKPs with one alkoxy substituent, rather than two, on each benzene ring has been synthesized. Thermochemical studies of the new DKPs by differential scanning calorimetry and polarized optical microscopy show that they are not liquid crystalline as expected. However, in the process of making the DKPs, conformationally constrained tyrosine analogues, (R)- and (S)-5-hydroxy-2-aminoindan- 2-carboxylic acids, were prepared by chromatographic separation of diastereomeric dipeptide derivatives formed from N-Boc-L-phenylalanine. Absolute configurations were assigned by X-ray crystallographic analysis. The series of tetraalkoxy-substituted DKPs showed a remarkable trend in freezing point. The freezing point for the series decreases with an increase in alkyl chain length. To understand the relationship between the crystal packing interactions and the freezing point trend, a study of the association of DKPs in solution by NMR was initiated. An Nmethylated 2,5-diketopiperazine was previously synthesized and studied by NMR using chloroform as solvent to obtain equilibrium constants for self association. Attempted multi-step syntheses of a more lipophilic N-3,7-dimethyloctyl 2,5-diketopiperazine, which was expected to have solubility in non-interfering solvents such as carbon disulfide, benzene, and carbon tetrachloride, failed. In response, a direct and concise method for accessing N-alkyl DKPs was developed, and an N-decyl 2,5-diketopiperazine was synthesized. X-ray crystallographic analysis of the N-decyl 2,5-diketopiperazine reveals formation of dimers via hydrogen bonding in the solid state.

No description available.