Yes / A systematic study of the influence of solvent on the crystal packing behaviour of Reichardt's dye demonstrates that the structure of the assembly formed in the solid state depends on the nature of the solvent–solute interactions present in the solution phase. Apolar aprotic solvents lead to solvates with a hexagonal channel topology, but this supramolecular assembly is perturbed by the presence of aromatic or polar protic solvents.

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.

The English translation of the chapters written in French is available in Appendix. / La motivation initiale de ce travail provient de l'importance que les composés de coordination ont dans notre vie quotidienne. Leurs propriétés les rendent attrayants pour un large éventail d'applications, dans des domaines allant de la catalyse et de la conversion et stockage de l'énergie solaire jusqu’au domaine des matériaux et des sciences de la vie. Poussée par l'évolution et le progrès général de notre société, la recherche en chimie de coordination moderne évolue vers la complexité au niveau moléculaire, où la Nature représente une source majeure d'inspiration, comme dans le cas de la photosynthèse artificielle et de la chimie métallo-supramoléculaire. Dans le même temps, l'étude des complexes de coordination nourrit la curiosité scientifique et les approches pluridisciplinaires ouvrent de nouveaux mondes fascinants, tout en repoussant les frontières de la connaissance à des niveaux sans précédent. En continuité avec l'étude et le développement de composés de coordination pour des applications spécifiques, le thème central de cette thèse est l'interaction Métal - Ligand et les moyens de la moduler par le design du ligand, afin de générer les propriétés nécessaires pour les applications ciblées. Le design de complexes de coordination est considéré comme un «ensemble de composants modulables» – le ligand: les groupes fonctionnels des atomes donneurs, les substituants et leurs effets électroniques et stériques, le type et la dimension du cycle chélate; l’ion métallique; l'environnement. Les ligands étudiés ici sont les oxydes d’amidines N,N’-disubstitués (AMOXs) (aussi appelés α-aminonitrones ou hydroxyamidines). L'influence du motif de substitution du ligand sur les propriétés des composés est étudiée pour des complexes bis(AMOX) de cobalt(II) et de zinc(II). Les bis(chélates) de cobalt(II) sont plan carré (bas spin) à l'état solide, mais présentent une isomérisation de la structure plan carré (bas spin) vers une structure tétraédrique (haut spin) en solution dans des solvants non-coordinants. L'équilibre d'isomérisation est fortement influencé par le motif de substitution sur le ligand, du fait d’une combinaison de facteurs stériques et électroniques. Une approche théorique (DFT/ TD-DFT) et expérimentale combinée a montré que, dans la famille des chélates bis(AMOX) de zinc(II), le gap optique peut être finement modulé pour de potentielles applications dans des dispositifs optoélectroniques par la modification spécifique des ligands. Un cas spécial de solvatomorphisme a été identifié: des modifications de la géométrie et de l’état de spin sont induites par la présence ou l’absence de liaisons hydrogènes dans un même composé de cobalt(II). L’influence de l'environnement est ainsi illustrée. Les interactions faibles sont les principaux facteurs responsables pour la stabilisation du système vers une combinaison spécifique géométrie - état de spin à l'état fondamental, de façon similaire au contrôle allostérique et aux interactions hôte-invité dans les systèmes biologiques. Des études préliminaires vers des systèmes supramoléculaires à base des ligands AMOX ont été effectuées (assemblées multimétalliques vers des matériaux fonctionnels et des systèmes photocatalytiques pour conversion d'énergie solaire, en particulier la photocatalyse pour la production de H2). J’espère que les résultats et les perspectives présentées dans cette thèse incitent à la poursuite de la chimie de coordination des AMOXs. / The underlying motivation for this work stems from the importance that coordination compounds play in our daily lives. Their properties make them suitable and attractive for a wide range of applications in fields going from catalysis and solar energy conversion/ storage to materials and life sciences. Driven by the general progress of our society, research in modern coordination chemistry evolves toward complexity at the molecular level, with Nature representing a major source of inspiration as shown by artificial photosynthesis and metallosupramolecular chemistry. At the same time, the study of coordination complexes nurtures scientific curiosity, and multidisciplinary approaches are opening fascinating new worlds, while pushing the frontiers of knowledge to unprecedented depths. In line with the study and the development of coordination compounds for specific applications, the central theme of this thesis is the Metal-Ligand interaction and how it can be modulated through ligand design to generate the properties targeted for particular applications. The design of coordination complexes is seen as a ‘collection of adjustable components’ (e.g. the ligand: the donor atoms and their functional groups, the type and the size of the chelating ring, the ring substituents and their electronic and steric effects; the metal-ion; the environment). The ligands under study are the N,N’-disubstituted amidine oxides (AMOXs) (also known as α-aminonitrones/ hydroxyamidines). The influence of the ligand substitution pattern on the properties of the compounds is investigated in series of cobalt(II) and zinc(II) bis(AMOX) complexes. The cobalt(II) bis(chelates) are square-planar (low spin) in the solid state, but show square-planar (low spin) to tetrahedral (high spin) isomerization in solution of non-coordinating solvents. The isomerization equilibrium is highly sensitive to the substitution pattern on the ligand due to a combination of steric and electronic influences. A combined experimental and theoretical approach [DFT and time dependent (TD-DFT)] has shown that in the family of zinc(II) bis(AMOX) chelates, by specific modification of the ligands, the optical band gap can be fine-tuned for potential applications in optoelectronic devices. A special case of hydrogen-bonding-induced geometry and spin change at a cobalt(II) centre within a same cobalt(II) bis(chelate) has been identified. It highlights the influence of the environment on the properties of the complex. Weak interactions are the main factors responsible for biasing the system toward a specific geometry – spin state combination in the ground state, in a similar fashion to allosteric control and host-guest interactions in biological systems. Preliminary studies were conducted toward AMOX-based supramolecular systems: multimetallic assemblies toward functional materials and photocatalytic systems for solar energy-conversion (in particular photocatalysis for H2 production). It is my hope that the above results and the perspectives presented in this work motivate further developments in AMOX coordination chemistry.