Funktionalisierte Poly(2-oxazoline) als neue Materialien stellen sowohl unter strukturellen Gesichtspunkten als auch im Hinblick auf potentielle Anwendungen eine interessante Polymerklasse dar. Die Ausbildung von hierarchischen Strukturen mit Poly(2-oxazolinen) über intermolekulare Wasserstoffbrückenbindungen ist hierbei ein bisher nicht beachteter Aspekt. Über einen bioinspirierten Ansatz sollten gezielt funktionelle Gruppen, die für einen hierarchischen Aufbau, z.B. in Proteinen, verantwortlich sind, in vereinfachter Weise auf die synthetische Substanzklasse der Poly(2-oxazoline) übertragen werden. Die vorliegende Arbeit beschäftigt sich mit der modularen Synthese neuer, funktionalisierter Poly(2-oxazolin) Homo- und Copolymere. Ausgehend von der Synthese von 2-(3-Butenyl)-2-oxazolin wurden definierte Präpolymere in einer kationischen Isomerisierungspolymerisation unter kontrolliert/„lebenden“ Bedingungen hergestellt. In einer anschließenden „Thio-Click“ (Thiol-En-Reaktion) Modifizierungsreaktion wurden die gewünschten funktionellen Gruppen quantitativ eingeführt. Hydroxylierte Poly(2-oxazoline) wurden hinsichtlich ihres Aggregationsverhaltens in Wasser untersucht. Bereits die jeweiligen Homopolymere bildeten aufgrund von intermolekularen Wasserstoffbrückenbindungen supramolekulare tubuläre Nanofasern aus. Durch Einsatz verschiedener analytischer Methoden konnte die innere Struktur der Nanoröhren beschrieben und ein entsprechendes Modell aufgestellt werden. Die dargestellten funktionellen Poly(2-oxazoline) wurden hinsichtlich ihrer Anwendung als potentielle, synthetische „antifreeze additives“ untersucht. Alle Polymere besitzen eine ausgeprägte Tendenz zur Nukleierung von Wasser und führen daher zu signifikanten Änderungen der Eismorphologie. Des weiteren wurde ein carboxyliertes Derivat zur biomimetischen Mineralisation von Kalziumcarbonat eingesetzt und nach phänomenologischen Gesichtspunkten untersucht. / Functionalized poly(2-oxazoline)s are a promising class of materials concerning their self-assembly behavior as well as for future applications. Hierarchical structure formation based on hydrogen bonding interactions has not been investigated yet. Applying a bioinspired approach, functional groups promoting hierarchical structure formation are introduced to poly(2-oxazoline)s. This work is focused on the modular synthesis of new functionalized poly(2-oxazoline) homo and copolymers. Starting from the synthesis of the new monomer 2-(3-butenyl)-2-oxazolin, well-defined precursor materials were prepared via cationic isomerization polymerization. Next, the polymers were quantitatively modified with the aimed functional groups using a “thio-click” (thiol-ene) reaction. The aggregation behaviour of hydroxylated poly(2-oxazolines) in water was investigated. Homo- as well as block copolymers can form supramolecular hollow nanofibers via intermolecular hydrogen bonding. Using a variety of different analytical methods, the structure of the nanotubes was determined and a formation model was proposed. Furthermore, the functionalized poly(2-oxazoline)s were investigated as synthetic mimics of natural anti-freeze additives. It was found, that these polymers show the tendency to nucleate water, thus influencing the morphology of ice. Finally, a carboxylated derivative was applied as an additive for the mineralization of calcium carbonate.

Atoms construct the molecules and molecules construct the material substances (with the exceptions as well, e.g.., metals, where atoms directly construct the material substances). Intermolecular interactions play an important role in most of the branches of sciences, ranging from material sciences to biological sciences. Van der Waals interactions are weak intermolecular interactions while hydrogen bonding varies in strength from weak to strong (1 to 40 kcal/mol). The present work focuses on applying some theoretical methods (ab initio and Atoms in Molecules theory) on these interactions to differentiate them with physically meaningful parameters such as hydrogen bond radii and atoms in molecules theory parameters. 1)Defining and calculating H-bond radii have been done using atoms in molecules theory approach which can explain ruling out the presence or absence of an H-bond in an intermolecular interaction. 2) A blue-shift of 200 cm-1 for a weakly bound complex is unprecedented. Our studies on weakly bound complexes showed the blue-shift of 200 cm-1 for H3C•••CIF and shift has been found to be purely from the mixing of normal modes and not because of an interaction. 3)Methane, a symmetric top molecule can act both as H-bond acceptor and donor. The present work shows that methane is rather a better H-bond acceptor than a donor and all the calculated parameters are in favor of this description. 4) Microwave spectrometer is an ultimate tool (at least at present) for structural characterization of the weakly bound complexes accurately. The rotational spectrum of the weakly bound isotopomer weakly bound complexes accurately. The rotational spectrum of the weakly bound isotopomer 13CC5H6•••Ar, which is a symmetric top and gives only “B” rotational constant. Moreover, the A rotational constant of the complex is the same as the rotational constant for 13CC5H6, which has no dipole moment. C2H2 molecule is an astrophysically important molecule as it is present in asymptotic giant branch and T-type stars (Teff<3000K). Due to its various infrared active vibrational modes, C2H2 is one of the most important sources in cool stars. The production of C2H2 infrared spectroscopic data at high temperature is therefore essential to trace back physical characteristics of these objects and to model the radiative transfer in their envelope. The databases such as “HITRAN”, do not have enough data available for stimulating high temperature spectra. Keeping all these objectives in mind, high temperature emission spectrum of acetylene has been recorded around 3µm region of acetylene.

Os métodos computacionais da química quântica foram empregados para estudar as estruturas moleculares e as energias de interação de cátions e ânions que são componentes de alguns líquidos iônicos funcionalizados, derivados do imidazólio. O estudo teve como objetivo comparar e relacionar os efeitos da presença de funcionalização nos substituintes das posições 1 e 3 do cátion imidazólio, nas propriedades desses líquidos iônicos. Essa funcionalização pode ocorrer pela presença de insaturações, grupos aromáticos, éteres, álcoois, tióis, aminas, nitrilas entre outros grupos nas cadeias dos substituintes. Nesta tese são reportados os estudos dos complexos formados por ânions tetrafluorborato e cátions imidazólio substituídos por grupos metila, etila, propila, butila, isobutila, vinila, propargila, alila, crotila e metalila, observando assim o efeito da presença de substituintes contendo cadeias insaturadas em comparação com os de cadeias saturadas nas estruturas, distribuições de carga, energias de interação e propriedades físico-químicas desses sistemas. Nesses sistemas foram observados intensos efeitos de polarização e transferência de carga ânion-cátion. Foram encontradas diversas relações entre volumes iônicos, energias de interação dos íons e as propriedades de transporte dos respectivos líquidos iônicos. / The methods of computational quantum chemistry have been used to study the molecular structures and the interaction energies of cations and anions which are components of some functionalized ionic liquids derived from imidazolium. The objective of this study is comparing and relating the effects of the presence of functionalization of the side chains of the imidazolium with the properties of these ionic liquids. This functionalization can occur by the presence of unsaturated side chains, aromatic groups, ether, alcohols, thiols, amines, nitriles among other groups in the side chains. In this thesis are reported the studies of the complexes formed of tetrafluorborate anions and imidazolium cations with side chains methyl, ethyl, propyl, butyl, isobutyl, vinyl, propargyl, allyl, crotyl and methallyl, thus observing the effects of the presence of unsaturated side chains compared to saturated ones on the structures, charge distributions, interaction energies and physicochemical properties of these systems. It was observed in these systems strong effects of polarization and anion-cation charge transfer. It was found several relations between ionic volumes, interation energies of the ions and the transport properties of the respective ionic liquids.

Os métodos computacionais da química quântica foram empregados para estudar as estruturas moleculares e as energias de interação de cátions e ânions que são componentes de alguns líquidos iônicos funcionalizados, derivados do imidazólio. O estudo teve como objetivo comparar e relacionar os efeitos da presença de funcionalização nos substituintes das posições 1 e 3 do cátion imidazólio, nas propriedades desses líquidos iônicos. Essa funcionalização pode ocorrer pela presença de insaturações, grupos aromáticos, éteres, álcoois, tióis, aminas, nitrilas entre outros grupos nas cadeias dos substituintes. Nesta tese são reportados os estudos dos complexos formados por ânions tetrafluorborato e cátions imidazólio substituídos por grupos metila, etila, propila, butila, isobutila, vinila, propargila, alila, crotila e metalila, observando assim o efeito da presença de substituintes contendo cadeias insaturadas em comparação com os de cadeias saturadas nas estruturas, distribuições de carga, energias de interação e propriedades físico-químicas desses sistemas. Nesses sistemas foram observados intensos efeitos de polarização e transferência de carga ânion-cátion. Foram encontradas diversas relações entre volumes iônicos, energias de interação dos íons e as propriedades de transporte dos respectivos líquidos iônicos. / The methods of computational quantum chemistry have been used to study the molecular structures and the interaction energies of cations and anions which are components of some functionalized ionic liquids derived from imidazolium. The objective of this study is comparing and relating the effects of the presence of functionalization of the side chains of the imidazolium with the properties of these ionic liquids. This functionalization can occur by the presence of unsaturated side chains, aromatic groups, ether, alcohols, thiols, amines, nitriles among other groups in the side chains. In this thesis are reported the studies of the complexes formed of tetrafluorborate anions and imidazolium cations with side chains methyl, ethyl, propyl, butyl, isobutyl, vinyl, propargyl, allyl, crotyl and methallyl, thus observing the effects of the presence of unsaturated side chains compared to saturated ones on the structures, charge distributions, interaction energies and physicochemical properties of these systems. It was observed in these systems strong effects of polarization and anion-cation charge transfer. It was found several relations between ionic volumes, interation energies of the ions and the transport properties of the respective ionic liquids.

Os métodos computacionais da química quântica foram empregados para estudar as estruturas moleculares e as energias de interação de cátions e ânions que são componentes de alguns líquidos iônicos funcionalizados, derivados do imidazólio. O estudo teve como objetivo comparar e relacionar os efeitos da presença de funcionalização nos substituintes das posições 1 e 3 do cátion imidazólio, nas propriedades desses líquidos iônicos. Essa funcionalização pode ocorrer pela presença de insaturações, grupos aromáticos, éteres, álcoois, tióis, aminas, nitrilas entre outros grupos nas cadeias dos substituintes. Nesta tese são reportados os estudos dos complexos formados por ânions tetrafluorborato e cátions imidazólio substituídos por grupos metila, etila, propila, butila, isobutila, vinila, propargila, alila, crotila e metalila, observando assim o efeito da presença de substituintes contendo cadeias insaturadas em comparação com os de cadeias saturadas nas estruturas, distribuições de carga, energias de interação e propriedades físico-químicas desses sistemas. Nesses sistemas foram observados intensos efeitos de polarização e transferência de carga ânion-cátion. Foram encontradas diversas relações entre volumes iônicos, energias de interação dos íons e as propriedades de transporte dos respectivos líquidos iônicos. / The methods of computational quantum chemistry have been used to study the molecular structures and the interaction energies of cations and anions which are components of some functionalized ionic liquids derived from imidazolium. The objective of this study is comparing and relating the effects of the presence of functionalization of the side chains of the imidazolium with the properties of these ionic liquids. This functionalization can occur by the presence of unsaturated side chains, aromatic groups, ether, alcohols, thiols, amines, nitriles among other groups in the side chains. In this thesis are reported the studies of the complexes formed of tetrafluorborate anions and imidazolium cations with side chains methyl, ethyl, propyl, butyl, isobutyl, vinyl, propargyl, allyl, crotyl and methallyl, thus observing the effects of the presence of unsaturated side chains compared to saturated ones on the structures, charge distributions, interaction energies and physicochemical properties of these systems. It was observed in these systems strong effects of polarization and anion-cation charge transfer. It was found several relations between ionic volumes, interation energies of the ions and the transport properties of the respective ionic liquids.

Made available in DSpace on 2014-07-29T15:30:35Z (GMT). No. of bitstreams: 1 dissertacao maria regilda araujo fernandes.pdf: 889828 bytes, checksum: eeac21e7e2102f6042640b9c030c3870 (MD5) Previous issue date: 2009-02-27 / The pathogenic fungus Paracoccidioides brasiliensis is the etiologic agent of Paracoccidioidomycosis (PCM). The main route of contamination is the inhalation of fungal propagules that convert to yeast in the host tissues. The urease is among the factors of virulence described for dimorphic fungus. It hydrolyzes the urea producing molecules of ammonia and carbamate. Pbure has 3,012 bp, corresponding to a predicted protein of 837 amino acids, predicted molecular mass of 90 kDa and pI 6.0. PbURE has signature to nickel-dependent enzyme for its activity. The phylogenetic relationship between PbURE and urease from other fungi was evaluated. The cDNA that encodes PbURE was inserted into the expression vector pET-32a and recombinant protein of 103 kDa was expressed. Polyclonal antibody were produced against PbUREr and used on Western blot, Far-Western blot and ELISA. The results showed that PbUREr interferes on interaction between P. brasiliensis and pulmonary epithelial cells A549. PbUREr was able to bind to proteins fibronectin and type IV collagen, components of the extracellular matrix (ECM). The interaction between PbURE and calnexin protein was identified by the technique of two-hybrid. / O fungo patogênico humano Paracoccidioides brasiliensis é o agente etiológico da Paracoccidioidomicose (PCM). A principal via de contaminação é a inalação de micélios ou conídios do fungo que se convertem em leveduras no hospedeiro. Dentre os fatores de virulência descritos para fungos dimórficos está a urease, a qual hidrolisa uréia produzindo amônia e carbamato. Pbure possui 3.012 pb, correspondendo a uma proteína predita de 837 aminoácidos, massa molecular predita de 90 kDa e pI 6.0. PbURE possui assinatura de uma enzima dependente de níquel para sua atividade. A relação filogenética entre PbURE e ureases de outros fungos foi avaliada. O cDNA que codifica PbURE foi inserido no vetor de expressão pET-32a e a proteína recombinante de 103 kDa foi expressa. Anticorpo policlonal foi produzido contra PbUREr e utilizados nos ensaios de Western blot, Far-Western blot e ELISA. Os resultados mostram que PbUREr interfere na interação entre P. brasiliensis e células epiteliais pulmonares A549. PbUREr foi capaz de se ligar às proteínas fibronectina e colágeno tipo IV, componentes da matriz extracelular (MEC). A interação entre PbURE e a proteína calnexina foi identificada através da técnica de duplo-híbrido.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-04-24T13:45:43Z No. of bitstreams: 2 Dissertação - Andrea Leite Camargo Santana - 2017.pdf: 3114758 bytes, checksum: 4fa4c3e9a2e7062f2940b053f1250619 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-04-24T13:46:06Z (GMT) No. of bitstreams: 2 Dissertação - Andrea Leite Camargo Santana - 2017.pdf: 3114758 bytes, checksum: 4fa4c3e9a2e7062f2940b053f1250619 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-04-24T13:46:06Z (GMT). No. of bitstreams: 2 Dissertação - Andrea Leite Camargo Santana - 2017.pdf: 3114758 bytes, checksum: 4fa4c3e9a2e7062f2940b053f1250619 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-03-29 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Paracoccidioides fungi are the causative agents of paracoccidioidomycosis, an endemic disease in Latin America with great socioeconomic importance. Inhalation of spores, the infectious particles of the fungus, is a common way to get the infection. Its treatment is slow and generates long-term side effects making it necessary to study new metabolic pathways that can be potential targets for antifungal development. In this context, stands out the chiquimate pathway in Paracoccidioides spp., related to the production of chorismate and production of aromatic amino acids, and the chorismate synthase involved in the last stage of this pathway. The chorismate synthase from Pb18 was cloned into pGEX-4T3 vector, expressed in pLysS cells and purified on a glutathione-sepharose column. Antibodies were produced from the immunization of mice with the recombinant protein obtained and used in Western blot assay to confirm protein expression. For characterization of the enzyme, its modeling was carried out. Pull-down-GST assay was performed to identify interactions between the chorismate synthase and soluble proteins present in total protein extract of Pb18. The interactions found included proteins of different functional categories related to protein synthesis, related with metabolism of common intermediates such as folate and quinolinate or related with the availability of ATP, phosphoenolpyruvate and erythrose-4-phosphate required in the chiquimate pathway. Unexpected interactions with proteins of the cell cycle and also with regulating proteins of the cell division process were observed. / Fungos do gênero Paracoccidioides são os agentes causadores da paracoccidioidomicose, uma doença endêmica na América Latina de grande importância socioeconômica. A inalação de esporos, partículas infecciosas do fungo, é uma forma comum de adquirir a infecção. O seu tratamento é lento e gera efeitos colaterais tornando necessário o estudo de novas vias metabólicas que sejam potenciais alvos para o desenvolvimento de antifúngicos. Nesse contexto, destaca-se a via do chiquimato em Paracoccidioides spp., relacionada à obtenção de corismato e produção de aminoácidos aromáticos, sendo corismato sintase a enzima envolvida na última etapa dessa via. A corismato sintase proveniente de Pb18 foi clonada em vetor pGEX-4T3, expressa em células pLysS e purificada em coluna de glutationa-sefarose. Anticorpos foram produzidos a partir da imunização de camundongos com a proteína recombinante obtida e utilizados em ensaio de Western blot a fim de confirmar a expressão proteica. A modelagem da corismato sintase foi realizada e os aminoácidos envolvidos no sítio ativo foram identificados. Ensaios de pull-down-GST foram realizados a fim de identificar os complexos de interações entre a corismato sintase e proteínas solúveis presentes em extrato proteico total de Pb18. As interações encontradas incluíram proteínas de diferentes categorias funcionais relacionadas à síntese proteica, ao metabolismo de intermediários comuns como folato e quinolinato ou ainda com a disponibilidade de ATP, fosfoenolpiruvato e eritrose-4-fosfato necessários na via do chiquimato. Interações inesperadas com proteínas do ciclo celular e também com proteínas reguladoras do processo de divisão celular foram observadas.

Le kétoprofène est un anti-inflammatoire non stéroïdien connu par ses propriétés analgésiques et antipyrétiques. Cependant, il présente une très faible solubilité dans l'eau, ce qui limite sa biodisponibilité. Afin de résoudre ce problème, le principe actif est administré sous forme de sels solubles dans l’eau avec le sodium, la lysine, l’arginine, la N-méthylglucamine et le trométamol. L’objectif de cette thèse était d’apporter pour la première fois la caractérisation structurale des sels de kétoprofène racémique et du S-kétoprofène avec la L-lysine et le trométamol, et de chercher à obtenir la structure cristalline de nouveaux co-cristaux ou sels de kétoprofène, pour analyser la relation structure-propriétés de ces formes solides. Nous avons réussi à faire la croissance cristalline des sels de kétoprofène racémique et de S-kétoprofène avec le trométamol et la L-lysine, ainsi qu’avec l’amine 2-amino-2-méthylpropanol. L’analyse des structures de ces sels a montré qu’ils sont tous formés par des couches anioniques de kétoprofènates entre les quelles s’insèrent les cations grâces aux liaisons hydrogène fortes de type N-H…O et O-H…O. Les cations forment des couches dans les sels avec le trométamol et la L-lysine. Cependant, ils ne sont connectés que par des interactions de Van der Waals dans les sels de 2-amino-2-méthylpropanol. La cohésion des couches anioniques est assurée par des interactions faibles de type C-H…O, C-H…π ou C-H…N. L’étude de l’épaisseur des couches anionique, ainsi que la surface et le volume occupé par un anion kétoprofènate dans une couche montre des variations significatives dans les différents sels. Ces variations peuvent être expliquées par des différences des conformations des anions kétoprofènates. L’étude des paramètres géométriques des anions kétoprofènates dans les sels et ceux des molécules de kétoprofène dans les principes actifs montre que les variations les plus importantes touchent les angles de torsions engageant le groupement carboxylate/acide carboxylique qui interagit avec les molécules/anions voisines par des liaisons hydrogène intermoléculaires courtes et fortement directionnelles. Les interactions dans lesquelles les cycles aromatiques sont engagés sont plutôt faibles, par conséquent les angles de torsions mettant en jeu ces cycles varient peu dans les différentes structures cristallines. Différentes techniques ont été également utilisées pour caractériser les sels : diffraction des rayons X sur poudre, calorimétrie différentielle à balayage (DSC), spectroscopie infrarouge (IR), analyse thermogravimétrique (ATG) et résonance magnétique nucléaire à l’état solide (RMN). Les résultats obtenus ont été corrélés aux structures cristallines. Les mesures de solubilité du sel de kétoprofène racémique-trométamol et des deux polymorphes des sels de S-kétoprofène avec le trométamol confirment que ces derniers ont des solubilités très améliorées par rapport aux principes actifs purs / Ketoprofen is a non-steroidal anti-inflammatory drug known by its analgesic and antipyretic properties. However, it has a very low water solubility, which limits its bioavailability. To solve this problem, the active pharmaceutical ingredient is administered as a water soluble salt with sodium, lysine, arginine, N-methylglucamine or trometamol. The scope of this thesis is to study, for the first time, the crystal structures of salts of both racemic and S-ketoprofen with L-lysine and trometamol, and to obtain the crystal structure of new ketoprofen co-crystals or salts, in order to analyze the relationship between the structure and the properties of these solid forms. We succeeded to control the crystal growth of the salts of racemic and S-ketoprofen with trometamol and L-lysine, and with 2-amino-2-methyl propanol. The analysis of these salt structures has shown that they are formed by anionic layers of ketoprofenates which are inserted between the cations thanks to strong N-H...O and O-H...O hydrogen bonds. The cations form layers in trometamol and L-lysine salts. However, they are only connected by van der Waals interactions in the salts of 2-amino-2-methylpropanol. The cohesion of the anionic layers is ensured by weak C-H...O, C-H...π or C-H...N interactions. The study of the thickness of anionic layers, as well as that of the surface and the volume occupied by a ketoprofenate anion in each anionic layer, shows significant differences in the salts. These variations may be explained by differences in the conformations of ketoprofenates anions. The study of geometrical parameters of ketoprofenate anions in the salts and those of the ketoprofen molecules in the pure active ingredients shows that the most important changes affect the twisting angles engaging the carboxylate/carboxylic acid that interacts with neighboring molecules/anions by short and highly directional intermolecular hydrogen bonds. The interactions in which the aromatic rings are incurred are rather weak, therefore the twisting angles involving these cycles slightly vary in the different crystal structures. Various techniques have also been used to characterize the salt, such as powder X-ray diffraction, differential scanning calorimetry (DSC), infrared (IR) spectroscopy, thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMR). The results were correlated with the crystal structures. The solubility measurements of the racemic ketoprofen-trometamol salt and the two polymorphs of S-ketoprofen-trometamol salts confirm that they have greatly improved solubility compared to the pure active ingredients

Three distinct aspects, disorder, polymorphism and co-crystal formation have been addressed in molecular crystals in terms of intra- and intermolecular interactions involving halogens, weak hydrogen bonds and van der Waals interactions. A basic introductory chapter highlights the importance of these three aspects followed by a foreword to the contents. Chapter 1 employs in situ cryo-crystallization techniques to study the crystal and molecular structures of compounds which are liquids at room temperature. Section 1.1 deals with the crystal structure analyses of low melting chloro- and bromo-substituted anilines which reveal both the importance of hydrogen bonds and weak interactions involving different halogens. The halogen⋅⋅⋅halogen interactions are compared with fluorine and iodine substituted compounds to bring out the relevance of both size and polarizability characteristics. Section 1.2 describes the crystal structures of benzyl derivative compounds utilizing the concept of in situ cryo-crystallization. This analysis brings out the correlation between acidity of benzyl derivative compounds with its preference of either a (sp2)C-H⋅⋅⋅π or (sp3)C-H⋅⋅⋅π interactions in the crystal packing. Chapter 2 consists of two sections dealing with the preference of halogen⋅⋅⋅halogen interactions in supramolecular chemistry. Section 2.1 discusses a statistically large number of crystal structures in halogen substituted benzanilide compounds. It reveals the importance of hetero halogen F⋅⋅⋅X (Cl, Br), homo halogen X⋅⋅⋅X (F, Cl, Br, I), C-X⋅⋅⋅π and C-H⋅⋅⋅F interactions in terms of their directionality and preferences to complement a primary N-H⋅⋅⋅O hydrogen bond in directing the three-dimensional supramolecular assembly. Section 2.2 deals with solvent induced polymorphism which highlights the role of weak interactions in two case studies. The preference and directionality of C-H⋅⋅⋅F and Cl⋅⋅⋅Cl interactions lead to dimorphic modifications in case of 3-chloro-N-(2-fluorophenyl)benzamide whereas in case of 2-iodo-N-(4-bromophenyl)benzamide the interactions are through C-H⋅⋅⋅π and I⋅⋅⋅I contacts. Further, the analysis is supported using morphological evidence, DSC (Differential scanning calorimetry) and Powder X-ray diffraction data. Chapter 3 has three sections, concentrating on disorder and its consequence in crystal structures. Section 3.1 discusses the apparent shortening of the C(sp3)–C(sp3) bond analysed via a variable temperature X-ray diffraction study in racemic 1,1′-binaphthalene-2,2′-diyl diethyl bis(carbonate). Variable temperature single crystal X-ray diffraction studies show that the shortening is entirely due to positional disorder and not due to thermal effects. A supercell formation at T≤150 K depicts the formation of a Z'= 2 structure. Section 3.2 deals with crystal structure analysis of Ethyl-4-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate which clarifies the discrepancy in the higher value of the residual electron density in the literature in terms of positional disorder of fluorine at ortho sites. The existence of fluorine atom at the para position on the phenyl ring of another isomeric molecule leads to disorder induced conformational polymorphism through the involvement of the ethyl group. The static disorder of ethyl group which is associated with only one molecule (Z′=2) could be resolved at 120 K. This supports the results of the previous section (3.1). Section 3.3 reports crystal structure analysis of disordered fluorine in benzanilide compounds. The preference of interactions involving fluorine in either ortho sites or meta sites could be one of the reasons for the positional disorder of both possible sites. With one of the structure showing high Z′ value due to differences in the occupancy of disordered fluorine atom. CSD (Cambridge Structural Database) analysis indicates that the percentage of disorder in halogenated crystal structures having halogen atom at either ortho site or meta site decreases from fluorine to iodine. Further, the analysis points out that the disorder in fluorine containing compounds is mostly localized at the fluorine position whereas for other halogenated disordered structures, the disorder appears at other parts of the molecule. Chapter 4 discusses co-crystal formation and analysis of intermolecular interactions. It consists of two sections. Section 4.1 discusses co-crystal formation of nicotinamide with benzoic acid and seven other derivatives by changing the functional group at different positions of benzoic acid. Hydroxyl (-OH) group at 4/3-postion of benzoic acid prefers phenol⋅⋅⋅pyridine synthon when at 2-position it prefers acid⋅⋅⋅pyridine synthon. The preference of amide anticatemer over dimer synthon is supported by additional C-H⋅⋅⋅O hydrogen bonds. In case of 3,5-dinitro-2-hydroxy benzoic acid, the disorder in hydroxyl (-OH) group at ortho site leads to salt formation. Section 4.2 describes co-crystal study of adenine and thymine (AT) as free nucleobases. This result reveals the formation of AT (2:1) complex with both Hoogsteen and “quasi-Watson-Crick” hydrogen bonds. The hydrogen bonded bases using the Hoogsteen and the “quasi-Watson-Crick” interactions generate a hexagonal supramolecular motif. Four water molecules are located inside the hexagonal void of this complex. A high temperature study on the same crystal shows that at 313K, one of the water molecules escapes from the lattice resulting in the small change in unit cell parameters. However, the space group remains the same and the hexagonal void remains unaltered. With further increase in temperature, the crystal deteriorates irreversibly which clearly brings out the importance of water molecule in the molecular recognition of adenine-thymine complex. Chapter 5 discusses crystal structure analysis of trans-atovaquone (antimalarial drug), its new polymorph form including one stereoisomer (cis) and five other derivatives with different functional groups. Based on the conformational features of these compounds and the characteristics of the nature of hydrogen bonding and other weak intra and intermolecular interactions, docking studies with cytochrome bc1 complex provide valuable insight into the atomistic details of protein-inhibitor interactions. The docking results reveal that atovaquone and its derivatives, owing to their nature of hydrogen bond and the propensity towards the formation of weaker hydrogen bonds involving the chlorine atom as well appear as good candidates for drug evaluation.

The thesis entitled “Intermolecular Interactions in Molecular Crystals: Quantitative Estimates from Experimental and Theoretical Charge Densities” consists of four chapters and an Appendix. Chapter 1 highlights the principles of crystal engineering from charge density point of view. Chapter 2 (Section I - III) deals with the evaluation of weak intermolecular interactions and in particular related to the features of concomitant polymorphism. Chapter 3 describes the co-operative role of weak interactions in the presence of strong hydrogen bonds in small bioactive molecules in terms of topological properties. Chapter 4 unravels the inter-ion interactions in terms of charge density features in an ionic salt. The general conclusions of the works presented in this thesis are provided at the end of the chapters. Appendix A explores the varieties of hydrogen bonds in a simple molecule. Identification of intermolecular interactions based purely on distance-angle criteria is inadequate and in the context of ‘quantitative crystal engineering’, recognition of critical points in terms of charge density distribution becomes extremely relevant to justify the occurrence of any interaction in the intermolecular space. The results from single crystal X-ray diffraction data at 90K (compound in chapter 4 at 113K) have been compared with those from periodic theoretical calculations via DFT method at high-level basis set (B3LYP/6-31G**) in order to establish a common platform between theory and experiment. Chapter 1 gives a brief review on crystal engineering to analyze intermolecular interactions along with the description of both experimental and theoretical approaches used in the analysis of charge densities in molecular crystals. The eight of Koch and Popelier’s criteria, defined using the theory of “Atoms in Molecules”, to characterize hydrogen bonds have also been discussed in detail. Chapter 2 (I) presents the charge density analysis in coumarin, 1-thiocoumarin, and 3-acetylcoumarin. Coumarin has been extensively studied as it finds applications in several areas of synthetic chemistry, medicinal chemistry, and photochemistry. The packing of molecules in the crystal lattice is governed by weak C−HLO and C−HLπ interactions only. The variations in charge density properties and derived local energy densities have been investigated in these regions of intermolecular interactions. The lacuna of the identification of a lower limit for the hydrogen bond formation has been addressed in terms of all eight of Koch and Popelier’s criteria, to bring out the distinguishing features between a hydrogen bond (C−HLO) and a van der Waals interaction (C−HLπ) for the first time. Chapter 2 (II) highlights the nature of intermolecular interactions involving sulfur in 1-thiocoumarin, 2-thiocoumarin, and dithiocoumarin. These compounds pack in the crystal lattice mainly via weak C−HLS and SLS interactions. The analysis of experimental and theoretical charge densities clearly categorizes these interactions as pure van der Waals in nature. The distribution of charge densities in the vicinity of the S atom has been analyzed to get better insights into the nature of sulfur in different environments. Chapter 2 (III) provides a detailed investigation of the charge density distribution in concomitant polymorphs of 3-acetylcoumarin. The electron density maps in the two forms demonstrate the differences in the nature of the charge density distribution particularly in the features associated with C−HLO and C−HLπ interactions. The net charges derived based on the population analysis via multipole refinement and also the charges evaluated via integration over the atomic basins and the molecular dipole moments show significant differences. The lattice energies calculated from experimental charge density approach clearly suggest that form A is thermodynamically stable compared to form B. Mapping of electrostatic potential over the molecular surfaces also bring out the differences between the two forms. Chapter 3 describes the analysis of charge density distribution in three small bioactive molecules, 2-thiouracil, cytosine monohydrate, and salicylic acid. These molecules pack in the crystal lattice via strong hydrogen bonds, such as N−HLO, N−HLS, and O−HLO. In spite of the presence of such strong hydrogen bonds, the weak interactions like C−HLO and C−HLS also contribute in tandem to the packing features. The distribution of charge densities in intermolecular space provides a quantitative comparison on the strength of both strong and weak interactions. The variations in electronegativity associated with the S, O, and N atoms are clearly seen in the electrostatic potential maps over the molecular surfaces. Chapter 4 deals with study of intermolecular interactions in N,N,N´N´-tetramethylethlenediammonium dithiocyanate, analyzed based on experimental charge densities from X-ray diffraction data at 113 K and compared with theoretical charge densities. The packing in the crystal lattice is governed mainly by a strong N+−H…N− hydrogen bond along with several weak interactions such as C−HLS, C−HLN, and C−HLπ. The charge density distribution in the region of inter-ionic interaction is also highlighted and the electrostatic potential map clearly provides the insights in to its interacting feature. Appendix A describes the experimental and theoretical charge density studies in 1-formyl-3-thiosemicarbazide and the assessment of five varieties of hydrogen bonds.