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 “In situ crystallography and charge density analysis of phase transitions in complex inorganic sulfates” consists of six chapters. Structural changes exhibited by ferroic and conducting materials are studied as a function of temperature via in situ crystallography on the same single crystal. These unique experiments bring out the changes in the crystal system resulting in subtle changes in the complex polyhedra, distortions in bond lengths and bond angles, rotation of sulfate tetrahedral around metal atoms, phase separations and charge density features. The results provide new insights into the structural changes during the phase transition in terms of coordination changes, variable bond paths and variability in electrostatic potentials while suggesting possible reaction pathways hitherto unexplored. Chapter 1 gives a brief review of the basic features of structural phase transitions in terms of types of phase transitions, their mechanisms and related properties and outlines some of the key characterization techniques employed in structural phase transition studies like single crystal diffraction, thermal analysis, conductivity, dielectric relaxation, Raman spectroscopy and charge density studies. Chapter 2 deals with the group of compounds A3H(SO4)2, where A= Rb, NH4, K, Na which undergoes ferroelastic to paraelastic phase transitions with increase in temperature. Crystal structures of these compounds have been determined to a high degree of accuracy employing the same single crystal at room temperature at 100K and at higher temperatures. The data collection at 100K allows the examination of the ordered and disordered hydrogen atom positions. Rb3H(SO4)2 show two intermediate phases before reaching the paraelastic phase with increase in temperature. However, in case of (NH4)3H(SO4)2 and K3H(SO4)2, the paraelastic phase transition involves a single step. Chapter 3 deals with variable temperature in situ single crystal X-ray diffraction studies on fast super protonic conductors AHSO4, where A= Rb, NH4, K to characterize the structural phase transitions as well as the dehydration mechanism. The structure of KHSO4 at room temperature belongs to an orthorhombic crystal system with the space group symmetry Pbca and on heating to 463K it transforms to a C centered orthorhombic lattice, space group Cmca. The high temperature structure contain two crystallographically independent units of KHSO4 of which one KHSO4 unit is disordered at oxygen and hydrogen sites an shows a remarkable increase of sulfur oxygen bond distance – 1.753(4)Å. On heating to 475K, two units of disordered KHSO4 combine and loose one molecule of water to result in a structure K2S2O7 along with an ordered KHSO4 in a monoclinic system [space group P21/c]. On further heating to 485K two units of ordered KHSO4 combine, again to lose one water molecule to give K2S2O7 in a monoclinic crystal system [space group C2/c]. In the case of RbHSO4, both the high temperature structural phase transition and a serendipitous polymorph have been characterized by single crystal X-ray diffraction. The room temperature structure is monoclinic, P21/n, and on heating the crystal insitu On the diffractometer to 460K the structure changes to an orthorhombic system [space group Pmmn]. On keeping the crystallization temperature at 80°C polymorph crystals of RbHSO4 were grown. In case of NH4HSO4 both the room temperature and high temperature structures are structurally similar to those in RbHSO4, but the transition temperature is found to be 413K. Chapter 4 deals with the crystal structure, ionic conduction, dielectric relaxation, Raman spectroscopy phase transition pf a fast ion conductor Na2Cd(SO4)2. The structure is monoclinic, space group C2/c, and is built up with inter connecting CdO6 octahedra and SO4 tetrahedra resulting in a framework structure. The mobile Na atoms are present in the framework, resulting in a high ionic conductivity. The conductivity measurement shows two phase transitions one at around 280°C, which was confirmed later from DTA, dielectric relaxation, high temperature powder diffraction and Raman spectroscopy. Chapter 5 describes the structure and in situ phase separation in two different bimetallic sulfates Na2Mn1.167(SO4)2S0.33O1.1672H2O and K4Cd3(SO4)5.3H2O. These compounds were synthesized keeping them as mimics of mineral structures. The structure of Na2Mn1.167(SO4)2S0.33O1.1672H2O is trigonal, space group R . The stiochiometry can be viewed as a combination of Na2Mn(SO4)22H2O resembling the mineral Krohnkite with an additional (Mn0.167S0.333O1.167) motif. On heating the parent compound on the diffractometer to 500K and keeping the capillary at this temperature for one hour, a remarkable structural phase separation occurs with one phase showing a single crystal-single crystal transition and the other generating a polycrystalline phase. The resulting single crystal spots can be indexed in a monoclinic C2/c space group and the structure determination unequivocally suggests the formation of Na2Mn(SO4)2, isostructural to Na2Cd(SO4)z. The mechanism follows the symmetry directed pathway from the rhombohedral → monoclinic symmetry with the removal of symmetry subsequent to the loss of the two coordinated water molecules. In case of K4Cd3(SO4)5.3H2O the structure belongs to the space group P21/n at room temperature and on heating to 500K and holding the capillary at this temperature for 60 minutes as before, the CCD images can be indexed in a cubic P213 space group after the phase separation, generating K2Cd2(SO4)3, belonging to the well known Langbeinite family, while the other phase is expected to be the sought after K2Cd(SO4)2. The possible pathways have been discussed. Chapter 6 reports the charge density studies of phase transitions in a type II langbeinite, Rb2Mn2(SO4)3. The structure displays two different phases, cubic at 200K, orthorhombic at 100K respectively. After multiple refinements it is found that there are significant differences in the actual bond path (Rij) and the conventional bond length. In the cubic phase the distortions in sulfate tetrahedral are more than in the orthorhombic phase which could be the expected driving force for the phase transition to occur. Appendix contains reprints of the work done on the structures of the following: a) Rb2Cd3(SO4)3(OH)2.2H2O: structural stability at 500 K b) Structure of (NH4)2Cd3(SO4)4.5H2O c) Structure of Rb2Cd3(SO4)4.5H2O

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.