The major aim of research reported on this thesis uses X-ray crystallography to investigate the structural features of a series of pentafluorosulfuranyl (SF₅) containing aromatic compounds, chalcogen amides, 2,4-diaryl-1,3-selenazoles and 2,4-diaryl-1,3-chalcogen azoles bearing SF₅ group and organo phosphorus-chalcogen macrocycles incorporationg double OP(S)SC[sub]n or OP(Se)SeC[sub]n scaffolds. The basic theory of crystallography is introduced in Chapter 1, followed by a general discussion on pentafluorosulfuranyl (SF₅) containing heteroatom compounds and sulfur/selenium heterocycles in Chapter 2. Ten pentafluorosulfuranyl (SF₅)-containing aromatic compounds have been studied crystallographically in Chapter 3. All S-F bond lengths in these compounds are very similar [1.571(3) to 1.618(3) Å and 178.5(3) to 180.0° for the C-S-F(ax) bond] and the angles of two adjacent F(eq) is approximate to 90°. The intramolecular C[sub](aryl)-H···F(eq) and intermolecular C[sub](aryl)-H···O/N/F/Cl interactions, and π-stacking interactions are observed in the packing frameworks. X-ray crystal structure analysis reveals that in the structures of 2,4-diaryl-1,3-selenazoles in Chapter 4, the five-membered N-C-Se-C-C rings have either planar or near-planar conformations, and exhibit a series of the intramolecular and intermolecular C-H∙∙∙O/N/Se/Br/Cl) interactions and π-stacking interactions. The crystal structures of 2,4-diaryl-1,3-chalcogen azoles with both a pentafluorosulfuranyl (SF₅) group and a five-membered N-C-Se-C-C ring have been investigated in Chapter 5. A diverse picture of molecular configuration and intramolecular/intermolecular C-H∙∙∙N/Se/S and π-stacking interactions information are disclosed in selenamide, thiamides, 1,3-selenazoles and 1,3-thiazoles. Nine organo phosphorus-chalcogen macrocycles with nine- to fifteen-membered ring incorporating double OP(S)SC[sub]n or OP(Se)SeC[sub]n scaffolds have been discussed crystallographically in Chapter 6. The similar intramolecular and intermolecular C-H∙∙∙O, C-H∙∙∙S or C-H∙∙∙Se interactions are observed to lead to the similar packing networks.

Understanding how atoms interact is a fundamental aspect of chemistry, biology and materials science. There have been great advances in the knowledge of covalent and ionic bonding over the past twenty years but one of the major challenges for chemistry is to develop full understanding of weak interatomic/intermolecular forces. This thesis describes fundamental studies that develop the basic understanding of weak interactions between heavier polarisable elements. The chosen methodology is to constrain heavy atoms using a rigid naphthalene backbone. When substituents larger than hydrogen, are positioned at close proximity at the peri-positions of a naphthalene molecule they experience steric strain; the extent of which is dictated by intramolecular interactions. These interactions can be repulsive due to steric hindrance or attractive due to weak or strong bonding. In efforts to understand the factors which influence distortion in sterically crowded naphthalenes and study possible weak intramolecular interactions between peri-atoms, investigations focussed on previously unknown mixed 1,8-disubstituted naphthalene systems. Mixed phosphorus-chalcogenide species were initially studied; three mixed phosphine compounds of the type Nap[ER][PPh2] were prepared along with their chalcogenides and a series of metal complexes. The study of interactions between heavy atoms was progressed by investigations into a series of mixed chalcogenide compounds of the type Nap[EPh][E’Ph] (E = S, Se, Te). Subsequent reaction of the chalcogenide systems with the di-halogens, dibromine and diiodine, afforded a mixture of charge transfer and insertion adducts displaying an array of different geometries around the chalcogen atom. From molecular structural studies, a collection of intramolecular peri-interactions were found, extending from no interaction due to repulsive effects, weak attractive 3c-4e type interactions and one example containing a strong covalent peri-bond. Further weak intramolecular interactions observed include CH-π and E•••E’ type interactions plus π-π stacking between adjacent phenyl rings. It was discovered that the bulk of the peri-atoms is influential on the distance between them, but this is not the only factor determining the naphthalene geometry. Inter- and intramolecular interactions can also have an impact and furthermore the number, size and electronic properties of substituents attached to the peri-atoms can determine molecular distortion.

Organic frameworks with rigid backbones, such as acenaphthene, are highly suitable for the study of interatomic interactions. The short “natural” peri-distance (2.44 Å) and the rigidity of the aromatic system causes considerable steric strain between peri-substituted heteroatoms. As a consequence, substitution at both peri-positions leads to in- and out-of-plane distortions, which often result in buckling of the ring system. In order to relax this geometric strain, weak bonding interactions can also exist between the peri-substituents. This thesis focuses on the synthesis, structural characterisation and investigation of a range of sterically crowded peri-substituted acenaphthene compounds. This involves the study of the acenaphthene geometry, through X-ray crystallography when different peri-substituents occupy the close 5,6-positions; our main focus is to study weak non-bonded interactions that can occur across the peri-gap, for example weakly attractive three-centre four-electron (3c-4e) type interactions which are known to prevail in such compounds under the appropriate conditions. Repulsion within these systems, resulting from the steric crowding of the peri-space is also investigated, employing changes in bond lengths, bay-region angle splay, displacement of atoms from the mean plane and central acenaphthene torsion angles to help quantify the degree of acenaphthene distortion, which are all conveniently probed by the peri-distance. To this end we have synthesised a range of novel sterically crowded mixed bromo-tin acenaphthene derivatives (Chapter 3), chalcogen-tin acenaphthene molecules (Chapter 4), phosphorus–tin derivatives (Chapter 5) and a series of homologous tin-tin acenaphthenes (Chapter 6). All the compounds studied in this thesis were characterised by multinuclear NMR spectroscopy and X-ray crystallography in an effort to gain a greater understanding of the deformation that occurs when disparate functionalities are located in close proximity and explore the potential for weak non-covalent intramolecular interactions to occur.

Noncovalent interactions are vital for functioning of biological systems. For instance, they facilitate DNA base pairing or protein folding. Recently, in addition to classical noncovalent interactions such as hydrogen bond, nonclassical noncovalent interactions have been discovered. An example of these interactions is halogen bond belonging to the class of σ-hole interactions, the knowledge of which is already being useful for medical compound design. The aim of this work is to find out if the chalcogen bond, also a σ-hole interaction, plays a role in the binding of existing viral inhibitors, too. Following that, we are also interested whether or to what extent can these existing chalcogen bonds be optimized for a greater affinity of the inhibitor binding. Several protein-ligand crystal structures exhibiting geometrical properties favoring a chalcogen bond have been found in the PDB database. We examined the interaction energies and the interaction energy geometrical dependencies of model systems derived from these crystal structures by means of quantum chemical calculations. Further we have optimized their strength by a series of substitutions. We thus propose that chalcogen bond can become a player in rational design of inhibitors of viral enzymes and their protein target. Keywords: Noncovalent...

Novas espécies moleculares HSeI e HISe presentes na superfície de energia potencial (SEP) singleto 1[H, Se, I], como também a molécula diatômica monoiodeto de selênio (SeI), foram investigadas teoricamente em alto nível de teoria, CCSD(T)/CBS e SACASSCF/ MRCI, respectivamente, pela primeira vez na literatura. Todos estados eletrônicos dupletos e quartetos (Λ+S) que se correlacionam com os três primeiros canais de dissociação da molécula SeI, assim como os estados Ω associados, fornecem resultados conáveis para ajudar a entender a falta de dados experimentais de transições eletrônicas e no planejamento experimental para a determinação de parâmetros espectroscópicos. Ainda sobre este sistema, as probabilidades de transições foram calculadas para as transições X2 - X1, A1 - X1, A2 - X1, e A2 - X2, originadas pela transição proibida por spin 14Σ- X 2II, e os correspondentes tempos de vida radiativa obtidos. Os aspectos energéticos, estruturais e espectroscópicos associados aos estados estacion ários na SEP 1[H, Se, I] também foram caracterizados, assim como determinados os calores de formação dos isômeros. Os cálculos foram realizados com uma série de conjuntos de funções de base atômicas consistentes na correlação (aug-cc-pVnZ-PP, n = D, T, Q e 5) e os resultados extrapolados no limite de base completa (CBS). Contribuições de efeitos de correlação caroço-valência na função de onda e de anarmonicidade nas frequências vibracionais também foram explorados, fornecendo uma fonte de dados bastante confiáveis para estas espécies químicas ainda desconhecidas. O isômero HSeI é mais estável em relação ao HISe em 42; 04 kcal mol-1. Estes dois isômeros estão separados por uma barreira (ΔG#) de 52; 35 kcal mol-1. Correções devido aos efeitos de acoplamento spin- órbita e de relativísticos escalares também foram considerados na obtenção das energias de atomizações. Para o SeI, estimamos valores de calores de formação (ΔfH) de 36; 87 e 35; 16 kcal mol-1 a 0 K e a 298; 15 K; para o HSeI, obtivemos 18; 25 e 16; 72 kcal mol-1, respectivamente. De modo geral, esperamos que a conabilidade dos resultados presentes neste trabalho possa servir como um excelente guia para espectroscopistas na busca e caracterização dessas espécies químicas ainda desconhecidas experimentalmente. / New molecular species HSeI and HISe lying on the 1[H, Se, I] potencial energy surface (PES) as well as the diatomic molecule selenium monoiodide (SeI) were investigated theoretically for the rst time at a high level of theory, CCSD(T)/CBS and SACASSCF/MRCI, respectively. The overall picture of all doublet and quartet (Λ+S) states correlating with the three lowest dissociation channels of the SeI and the associated states provide reliable results to help understand the lack of experimental data on its transitions and to plan the investigation and determination of spectroscopic parameters. Transition probabilities were computed for the transitions X2 - X1, A1 - X1, A2 - X1, and A2 - X2, originated from the spin-forbidden 14Σ- - X 2II system, and the orresponding radiative lifetimes evaluated. The energetic, structural and spectroscopic aspects associated with the stationary points and transition state in the PES 1[H, Se, I] were also characterized, as well as the heat of formation of the isomers. Computations were carried out with the series correlation consistent basis sets (aug-cc-pVnZ-PP) and the results extrapolated to the complete basis set limit. Accounting for core-valence correlation into the wavefunction, and of anharmonic eects on the vibrational frequencies were also explored, making the results of the structural, energetic, and vibrational properties a very reliable source of data for these yet unknown species. The isomer HSeI turned out to be more stable by 42:04 kcal mol-1 than HSeI. These two isomers are separated by a barrier (ΔG#) of 52:35 kcal mol-1. Corrections arising from spin-orbit and scalar relativistic eects were also considered in the evaluation of atomization energies. For SeI, we estimate ΔfH values of 36:87 and 35:16 kcal mol-1 at 0 K and 298:15 K; for HSeI, we had 18:25 and 16:72 kcal mol-1, respectively. In general, we hope that the reliability of the results present in this work can serve as an excellent guide for spectroscopists in the search and characterization of these chemical species still unknown experimentally.

Novas espécies moleculares HSeI e HISe presentes na superfície de energia potencial (SEP) singleto 1[H, Se, I], como também a molécula diatômica monoiodeto de selênio (SeI), foram investigadas teoricamente em alto nível de teoria, CCSD(T)/CBS e SACASSCF/ MRCI, respectivamente, pela primeira vez na literatura. Todos estados eletrônicos dupletos e quartetos (Λ+S) que se correlacionam com os três primeiros canais de dissociação da molécula SeI, assim como os estados Ω associados, fornecem resultados conáveis para ajudar a entender a falta de dados experimentais de transições eletrônicas e no planejamento experimental para a determinação de parâmetros espectroscópicos. Ainda sobre este sistema, as probabilidades de transições foram calculadas para as transições X2 - X1, A1 - X1, A2 - X1, e A2 - X2, originadas pela transição proibida por spin 14Σ- X 2II, e os correspondentes tempos de vida radiativa obtidos. Os aspectos energéticos, estruturais e espectroscópicos associados aos estados estacion ários na SEP 1[H, Se, I] também foram caracterizados, assim como determinados os calores de formação dos isômeros. Os cálculos foram realizados com uma série de conjuntos de funções de base atômicas consistentes na correlação (aug-cc-pVnZ-PP, n = D, T, Q e 5) e os resultados extrapolados no limite de base completa (CBS). Contribuições de efeitos de correlação caroço-valência na função de onda e de anarmonicidade nas frequências vibracionais também foram explorados, fornecendo uma fonte de dados bastante confiáveis para estas espécies químicas ainda desconhecidas. O isômero HSeI é mais estável em relação ao HISe em 42; 04 kcal mol-1. Estes dois isômeros estão separados por uma barreira (ΔG#) de 52; 35 kcal mol-1. Correções devido aos efeitos de acoplamento spin- órbita e de relativísticos escalares também foram considerados na obtenção das energias de atomizações. Para o SeI, estimamos valores de calores de formação (ΔfH) de 36; 87 e 35; 16 kcal mol-1 a 0 K e a 298; 15 K; para o HSeI, obtivemos 18; 25 e 16; 72 kcal mol-1, respectivamente. De modo geral, esperamos que a conabilidade dos resultados presentes neste trabalho possa servir como um excelente guia para espectroscopistas na busca e caracterização dessas espécies químicas ainda desconhecidas experimentalmente. / New molecular species HSeI and HISe lying on the 1[H, Se, I] potencial energy surface (PES) as well as the diatomic molecule selenium monoiodide (SeI) were investigated theoretically for the rst time at a high level of theory, CCSD(T)/CBS and SACASSCF/MRCI, respectively. The overall picture of all doublet and quartet (Λ+S) states correlating with the three lowest dissociation channels of the SeI and the associated states provide reliable results to help understand the lack of experimental data on its transitions and to plan the investigation and determination of spectroscopic parameters. Transition probabilities were computed for the transitions X2 - X1, A1 - X1, A2 - X1, and A2 - X2, originated from the spin-forbidden 14Σ- - X 2II system, and the orresponding radiative lifetimes evaluated. The energetic, structural and spectroscopic aspects associated with the stationary points and transition state in the PES 1[H, Se, I] were also characterized, as well as the heat of formation of the isomers. Computations were carried out with the series correlation consistent basis sets (aug-cc-pVnZ-PP) and the results extrapolated to the complete basis set limit. Accounting for core-valence correlation into the wavefunction, and of anharmonic eects on the vibrational frequencies were also explored, making the results of the structural, energetic, and vibrational properties a very reliable source of data for these yet unknown species. The isomer HSeI turned out to be more stable by 42:04 kcal mol-1 than HSeI. These two isomers are separated by a barrier (ΔG#) of 52:35 kcal mol-1. Corrections arising from spin-orbit and scalar relativistic eects were also considered in the evaluation of atomization energies. For SeI, we estimate ΔfH values of 36:87 and 35:16 kcal mol-1 at 0 K and 298:15 K; for HSeI, we had 18:25 and 16:72 kcal mol-1, respectively. In general, we hope that the reliability of the results present in this work can serve as an excellent guide for spectroscopists in the search and characterization of these chemical species still unknown experimentally.

Τα τελευταία έτη η σύνθεση και ο χαρακτηρισμός μονοδιάστατων νανοδομών αποκτά αυξανόμενο ερευνητικό ενδιαφέρον καθώς συνδυάζουν φαινόμενα από την νάνο κλίμακα με την δυνατότητα χειρισμού τους λόγω του μεγάλου μήκους τους. Εκτός από τα καθιερωμένα υλικά με αυτήν την μορφολογία όπως είναι οι νανοσωλήνες άνθρακα, οι νανοράβδοι οξειδίου του ψευδαργύρου και τα νανοκαλώδια πυριτίου μία κατηγορία υλικών που αναπτύσσει τέτοιες νανοδομές είναι τα χαλκογενή Σελήνιο και Τελλούριο γεγονός που εξηγείται από την υψηλής ανισοτροπίας κρυσταλλική τους δομή. Στόχος αυτής της εργασίας είναι η παραγωγή, μέσω φωτοαποδόμησης, νανοσωλήνων Τελλουρίου οι οποίοι μέσω φωτοοξείδωσης μετατρέπονται σε νανοκαλώδια Οξειδίου του Τελλουρίου. Η διερεύνηση της κινητικής του φαινομένου ανάλογα με το χρησιμοποιούμενο μήκος κύματος και την ένταση της ακτινοβολίας καθώς και ο χαρακτηρισμός των παραγόμενων νανοδομών γίνεται με φασματοσκοπία Raman. Τα συμπεράσματα στα οποία καταλήγουμε ενισχύονται από μία σειρά άλλων πειραματικών μεθόδων όπως περίθλαση ακτίνων Χ (XRD) και ηλεκτρονική μικροσκοπία σάρωσης και διέλευσης (SEM, TEM). / One dimensional (1D) nanostructures of semiconducting oxides and elemental chalcogens culminate over the last decade in nanotechnology owing to their unique properties exploitable in several applications sectors. Whereas several synthetic strategies have been established for rational design of 1D materials using solution chemistry and high temperature evaporation methods, much less attention has been given to the laser-assisted growth of hybrid nanostructures. Here, we present a laser-assisted method for the controlled fabrication of Te nanotubes. A series of light-driven phase transition is employed to controllably transform Te nanotubes to core-Te/sheath-TeO2 and/or even neat TeO2 nanowires. This solid-state laser-processing of semiconducting materials apart from offering new opportunities for the fast and spatially controlled fabrication of anisotropic nanostructures, provides a means of simultaneous growing and integrating these nanostructures into an optoelectronic or photonic device.

Orientador: Prof. Dr. Maurício Domingues Coutinho Neto / Coorientador: Prof. Dr. Rodrigo Luiz Oliveira Rodrigues Cunha / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Ciência e Tecnologia/Química, Santo André, 2018. / Recentemente completaram-se dois séculos da descoberta do selênio, um elemento controverso que pode ser considerado tóxico e ao mesmo tempo essencial. Apesar de suas propriedades antagônicas, compostos de selênio possuem um grande apelo biológico desde o relato de sua incorporação em enzimas, através da selenocisteína. Neste contexto, os compostos de selênio e telúrio tem se destacado devido às suas propriedades anti-inflamatória, antioxidante, antiviral e antimicrobiana. E portanto, como potenciais quimioterápicos contra doenças cardiovasculares, infecciosas, neurológicas e parasitárias. Esses compostos também tem se mostrado promissores na inibição de cisteína-catepsinas. Essas enzimas são ubíquas e participam de diversas funções no organismo humano. Porém, a atividade desregulada de cisteína proteases está relacionada com o desenvolvimento de diversas patologias, que as fazem importantes alvos terapêuticos no planejamento de novos fármacos. Ensaios experimentais com calcogenuranas mostraram bons resultados na inibição de cisteína proteases. Embora o mecanismo de reação desses compostos ainda não tenha sido completamente esclarecido, a literatura propõe que a inibição ocorre através da reação de troca de ligante entre o grupo tiol e o átomo de calcogênio em sua forma hipervalente. Nesta abordagem, cálculos de mecânica quântica foram utilizados para a investigação do mecanismo de reação através da análise da energia livre de Gibbs envolvida em trocas de ligantes, utilizando a teoria do funcional de densidade (DFT), com o funcional B3LYP e base 6311-G+(d), considerando efeitos de dispersão e correção de ponto zero. Cálculos híbridos com metodologia quântica acoplada à dinâmica molecular (Quantum Mechanics / Molecular mechanics - QM/MM) foram desenvolvidos para avaliar a energia envolvida na inibição de papaína por selenurana utilizando o software AMBER em interface com o software Orca. Para a dinâmica molecular utilizou-se o campo de força geral do Amber (General Amber Force Field - GAFF) e o modelo de solvatação explícita TIP3P, enquanto que a os cálculos quânticos usaram abordagem semi-empírica com o funcional PM3 e teoria do funcional da densidade com o funcional BLYP e base def2-SV(P) incluindo efeitos de dispersão. Ensaios de docking molecular também foram realizados para determinar uma configuração de atracamento inicial para os cálculos de QM/MM. Os resultados propõem que as reações de troca de ligante ocorrem em duas etapas distintas, dependentes da acidez do meio. As selenuranas dicloradas eliminam cloro, em meio aquoso, e formam espécies tricoordenadas (DMeSeO, DMeOH+, DMeSH+, DMeCl+) que podem interagir com tiolato provinente de cisteína proteases provocando sua inibição em ambientes ácidos, com barreiras de energia muito pequenas (menor que 3 kcal) ou inexistentes. / Recently two centuries of the discovery of selenium have been completed, a controversial element that can be considered toxic and at the same time essential. Despite their antagonistic properties, selenium compounds have a great biological appeal since the report of their incorporation into enzymes, through selenocysteine. In this context, selenium and tellurium compounds have been prominent due to their anti-inflammatory, antioxidant, antiviral and antimicrobial properties. And therefore, as potential chemotherapeutics against cardiovascular, infectious, neurological and parasitic diseases. These compounds have also been shown to be promising in cysteine-cathepsin inhibition. These enzymes are ubiquitous and participate in various functions in the human body. However, the unregulated activity of cysteine proteases is related to the development of several pathologies, which make them important therapeutic targets in the planning of new drugs. Experimental trials with calcogenurans showed good inhibition of cysteine proteases. Although the mechanism of reaction of these compounds has not yet been fully elucidated, the literature proposes that inhibition occurs through the bound between the thiol group and the calcogen atom in its hypervalent form. In this approach, quantum mechanics calculations were used to investigate the reaction mechanism through the Gibbs free energy analysis involved to ligand exchanges reactions, using for this the density functional theory (DFT) with the B3LYP functional and base 6311-G+(d), considering dispersion effects and zero point correction. Hybrid calculations with Quantum Mechanics/Molecular Mechanics (QM/MM) were developed to evaluate the energy involved in the inhibition of papain by selenuran using AMBER software in interface with Orca software. For the molecular dynamics, the general Amber force field (GAFF) and the explicit solvation model TIP3P were used, while the quantum calculations used a semi-empirical approach with the PM3 functional and the DFT with the functional BLYP and base def2-SV (P) including dispersion effects. Molecular docking assays were also performed to determine an initial docking configuration for the QM/MM calculations. The results suggest that the ligand exchange reactions occur in two distinct steps, depending on the acidity of the medium. The dichlorinated selenuranes eliminate chlorine in aqueous medium and form tricoordinated species (DMeSeO, DMeSeOH+, DMeSeSH+, DMeSeCl+) which can interact with thiolate from cysteine proteases causing their inhibition in acid environments, with very small energy barriers (less than 3 kcal) or nonexistent.

La compréhension et le contrôle des interactions intermoléculaires est d'une importance fondamentale dans les domaines de la reconnaissance moléculaire et de l'ingénierie cristalline, ainsi que dans les systèmes biologiques. Parmi les contacts faibles les plus fréquents qui lient les molécules dans les solides organiques nous trouvons la liaison halogène, la liaison chalcogène, et la liaison hydrogène faible. Dans cette thèse, des études expérimentales et théoriques de densité de charge rhô(r) basées sur la méthodologie QTAIM ont été effectuées pour l'analyse des liaisons halogènes et chalcogènes, et pour leur comparaison avec les liaisons hydrogène faibles. Pour ce faire, nous avons réalisé l'affinement multipolaire de la densité électronique obtenue à partir de la diffraction des rayons-X sur monocristal, ainsi qu'à partir des calculs périodiques DFT. A l'issue de nos résultats, nous avons définie la nature de ces interactions faibles (électrophile-nucléophile) et caractérisé leur intensité et directionnalité. Basé sur la topologie de L(r) = ¬rhô delta inversé2 rhô(r), le descripteur électrostatique (delta(L/rhô)) nous a permis d'évaluer quantitativement l'interaction électrostatique entre les régions de concentration (CC) et de dilution (CD) de charge de la couche de valence des atomes. L'énergie d'interaction (Eint) a été décrite à partir de descripteurs topologiques de rhô(r). Nous nous sommes intéressés également à la formation de fragments structuraux récurrents, appelés synthons. Il a été prouvé que le synthon peut être créé non seulement par des groupements d'atomes similaires, mais aussi par des ensembles de sites CC et CD qui sont impliqués de façon similaire dans la formation de contact / Understanding and control of intermolecular interactions play a crucial role in molecular recognition, crystal engineering, and biological systems. Three very frequent weak contacts linking the molecules in organic solids are halogen, chalcogen, and weak hydrogen bondings. In this thesis, we perform experimental and theoretical charge density rho(r) studies based on the QTAIM methodology for analyzing halogen and chalcogen bonding, and for comparing them with weak hydrogen bonding, as derived from the high-resolution single crystal X-ray diffraction multipole-refined electron density and from density functional theory (DFT) calculations. Defining the nature of these weak interactions as electrophilic-nucleophilic, we particularly focus on their strength and directionality. Based on the topology of L(r) = ¬rho inverted delta2 rho(r), a proposed electrostatic descriptor (delta(L/rho)) permitted us to evaluate quantitatively the electrostatic intensity between charge concentration (CC) and charge depletion (CD) regions belonging to the valence shell of the interacting atoms. The interaction energy (Eint) was described from the topological properties of rho(r). The attention has been also paid to the formation of recurrent structural fragments, called synthons. By the developed approach, it is proved that the synthon arrangement can be created not only by groups of atoms, but also by sets of CC and CD sites similarly involved in the contact formation

The thesis entitled "Phase Behaviour in Crystalline Solids: Exploring the Structure Guiding Factors via Polymorphism, Phase Transitions and Charge Density Studies" consists of five chapters divided into two parts. A basic introductory section describes the topics relevant to the work and the methods and techniques utilized. Part A contains two chapters that discuss the structural aspects related to polymorphism, solvatomorphism, conformational preferences and phase transitions exhibited by active pharmaceutical ingredients (APIs). It also discusses the structure-property correlations in API crystal forms and the possible utility of second harmonic generation (SHG) for their bulk characterization. Part B has three chapters that discuss experimental and theoretical charge density analyses of intra-and intermolecular interactions that play structure guiding roles in some of the APIs discussed in Part A. The main focus of the present work is to characterize the interaction patterns devoid of strong classical hydrogen bonds. The case studies include multifurcated C - H …O hydrogen bonds, the “carbon bonding” and chalcogen interactions involving Se and S atoms. In addition to charge density studies, in situcryocrystallography and molecular complexation experiments have been employed to examine structural consequences of chalcogen bonding. Further, Appendices 1 and 2 describe phase transition studies on the inorganic mineral kröhnkite and its high temperature phase transitions leading to novel inorganic structural types. Part A: Polymorphism and phase behaviour in Active Pharmaceutical Ingredients (APIs) Chapter 1 discusses case studies of polymorphism, supramolecular preference sand phase transitions exhibited by active pharmaceutical ingredients (APIs). Section 1.1 deals with the polymorphism of an anti-oxidant drug candidate ebselen and its hydroxyl derivative. The potential of organoselenium compounds to form a Se…O chalcogen bonded supramolecular recognition unit (synthon) has been established in these polymorphs and its generality is substantiated with the help of a Cambridge Structural Database (CSD) analysis. Section 1.2 demonstrates the utility of the ‘chalcogen bonded supramolecularsynthon’ in generating molecular complexes of APIs. A series of salts and co-crystals of the amyotrophic lateral sclerosis drug Riluzole have been synthesized in order to evaluate the structure directing role of S…O chalcogen bonded synthon in their crystal structures. Section 1.3adescribes the generation of polymorphs and solvatomorphs of the antidepressant drug candidate fenobamand associated phase transitions. The tautomeric preference in this molecule has been rationalized from the crystal structure analysis and abinitioenergy calculations. Further, section 1.3b utilizes chemical derivatization as a means to experimentally simulate thetautomeric preference and molecular conformations in several derivatives of fenobam and thiofenobam. Section 1.4 describes the issue of solvatomorphism and the generation of the fifth solvatomorph of gallic acid, its structural complexity and temperature induced phase transitions. The ability of solvent water molecules to drive structural diversity, by forming ‘hydration synthons’,is demonstrated in this case. Chapter 2 presents a novel methodology for the detection of polymorphic impurities in APIs based on second harmonic generation (SHG).The SHG based method has been employed to polymorphic mixtures of fenobam, hydrochlorothiazide, pyrazinamide, tolbutamide, curcumin, febuxostat and nimesulide.The conventional methods such as powder X-ray diffraction (profile fitting analysis), FT-IR, Raman spectroscopy and thermal analysesto detect the presence of polymorphic impuritiesin bulk API samples are employed on the mixtures of these API samples and the impurity detection limits are compared with the proposed SHG methodology. The APIs used in these case studies were screened for their SHG efficiency using quantum chemical calculations of hyperpolarizability and HOMO-LUMO charge redistribution behaviour. Further, a correlation with the crystal symmetry, relative packing arrangement of molecules and the observed SHG efficiency have been discussed in of some of these cases. Part B: Exploring the nature and structural consequences of nonbonding interactions in molecular crystals Chapter 3 discusses the electron density features of quasi-trifurcated CH…Cl/CH…O interaction motifs leading to ‘carbon bonding’ and a trifurcated CH…O hydrogen bond motif. Section 3.1 describes the experimental and theoretical charge density analyses of quasi-trifurcated CH…Cl and CH…O motifsand investigates the existence of “carbon bonding” in solid state. The experimental charge density evidence for “carbon bonding” have been analyzed in cases of fenobam and dimethylamine: 4-hydroxybenzoic acid complex. The existence of this unconventional interaction, which roughly mimics the transition state geometry of SN2 (bimolecular nucleophilic substitution) reaction, is further established by a CSD analysis. Section 3.2 describes the experimental and theoretical charge density analyses of ferulic acid and compares the topological features associated with a trifurcated CH…O hydrogen bond motif, with corresponding strong classical OH…O hydrogen bonds. The study demonstrates the “Gulliver effect” of weak interactions in charge density terms. Charge density based interaction energy calculations via EPMM and EML methods have been utilized in this context to evaluate the relative strength of such interactions. Chapter 4 discusses the charge density features of intermolecular chalcogen bonding interactions involving selenium and sulphur atoms.Section 4.1 describes the experimental and theoretical charge density analyses of ebselen and its hydroxyl derivative. The charge density characterization of the conserved chalcogen bond synthon (discussed in chapter 1, section 1.1) has been carried out and electronic nature and geometric dependence of Se…O interactions have been explored. The mechanism of drug action of ebselen has been correlated with the experimentally observed charge density distribution around the intramolecular SeC and SeN bonds. Section 4.2 explores the homochalcogen interactions such as S…SandSe…Se in phenol analogues. In situ cryocrystallographic studies on thiophenol, selenophenol and their solid solutions are described. Veggard’s law-like behaviour observed in these solid solutions have been rationalized and the S…S and Se…Sehomochalcogen interactions have been evaluated in these liquid systems which are devoid of any other packing forces such as strong hydrogen bonds. Chapter 5 discusses the conformation locking potential of intramolecular S…O chalcogen bonding in sulfadrugs. Section 5.1 discusses conformation locking in the antibioticdrugsulfamethizole. A two pronged approach has been adopted in the study; a) generation of cocrystals and salts of sulfamethizole for the ‘experimental simulation’ of the molecular conformation, b) evaluation of charge density distribution around the intramolecular S…O interaction region in sulfamethizole. Section 5.2 describes the effect of ‘simple hybridized orbital geometry’ in the formation of intramolecular S…O chalcogen bonding. The experimental charge density analysis of the carbonic anhydrase inhibitor drug acetazolamide has been carried out and the two different intramolecular S…O geometries have been compared in terms of the charge density topology. The analysis highlights the advantage of “orbital geometry” consideration over the conventional distance-angle criteria in assessing nonbonded interactions.