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The thesis entitled “Exploring Intermolecular Space by Charge Density Analysis in Molecular Crystals” consists of five chapters. A short introductory note highlights the importance of intermolecular interactions and presents the current status of charge density analysis to obtain insights into such interactions. Charge density analysis of crystalline materials by using high resolution X-ray diffraction data has become routine and enables derivation of reliable one electron properties associated with the electron density. The results obtained from single crystal X-ray diffraction data at low temperature have been compared with periodic theoretical calculations using B3LYP/6-31G** methods to unequivocally establish the nature of weak interactions. Chapter 1 describes the quantitative analysis of Cl∙∙∙Cl intermolecular interactions in compounds 2-chloro-3-quinolinyl methanol, 2-chloro-3-hydroxypyridine and 2-chloro-3-chloromethyl-8-methylquinoline, which are corresponding to type I (trans and cis) and type II (L) geometries of Cl∙∙∙Cl interactions respectively. The 3D static deformation density plots from charge density analysis unequivocally suggest that both ‘cis’ and ‘trans’ type I geometries show decreased repulsion whereas type II geometry is attractive based on the nature of “polar flattening” of the electron density around the Cl atom. The topological features derived at bond critical point (BCP) of Cl∙∙∙Cl interactions also support the observed results. Chapter 2 discusses hetero-halogen (Cl∙∙∙F) and homo-halogen (F∙∙∙F) intermolecular interactions involving “organic fluorine” in compounds 2-chloro-4-fluorobenzoic acid and 4-flurobenzamide respectively. Charge density distributions show polar flattening effects at both atoms Cl and F, however the extent of polarization is small on F in comparison with that of the Cl atom. 3D static deformation density plots depict δ+ ∙∙∙δ− interactions for Cl∙∙∙F intermolecular interactions while F∙∙∙F interactions show small decreased repulsion features. The topological properties of F∙∙∙F interactions bring out the similarity between F∙∙∙F and Cl∙∙∙Cl interactions. Chapter 3 describes the nature of C−Cl∙∙∙O=C halogen bond in 2, 5-dichloro-1, 4-benzoquinone, a molecule specifically chosen to depict this interaction dominantly. The topological values at bond critical point, three dimensional static deformation density features and electrostatic potential isosurfaces unequivocally establish the attractive nature of C−Cl∙∙∙O=C halogen bond in the crystalline lattice. Chapter 4 discusses the generation of multi-component systems (for example cocrystals and salts) of active pharmaceutical ingredients (API). Two systems associated with nicotinamide, one with salicylic acid and the other with oxalic acid as coformers resulting in 1:1 molecular complexes have been analyzed. The charge density analysis, particularly at the proton transfer region clearly bring out the differences between cocrystal and salt thus providing insights into the continuum in the proton transfer pathways in molecular crystals. Chapter 5 describes a new methodology [supramolecular synthon based fragment approach (SBFA)] concerning transferability of experimental charge density multipole parameters and building a database using well defined supramolecular synthons. The modularity and robustness of supramolecular synthons are used to transfer experimental charge density multipole parameters of synthons derived from a high resolution X-ray diffraction study to target molecules possessing these synthons as fragments in the crystalline lattice. The synthesized charge density and derived topological properties on target molecules using routine single crystal diffraction data are comparable with both experimental and theoretical charge density results. SBFA thus is expected to provide an additional database which can be applied to include intermolecular interactions space in the modeling directly unlike the available ones such as ELMAM, INVARIOM and UBDB. Further, SBFA approach can be extended to the determination and synthesis of charge density properties in macromolecules such as polypeptides, nucleic acids and proteins. APPENDIX contains reprints of the articles published which comprises of the work carried out in addition to the above five chapters.

The thesis entitled “Addressing subtle physicochemical features exhibited by molecular crystals via Experimental and Theoretical Charge Density Analysis” consists of five chapters. An introductory note provides a brief description of experimental and theoretical charge density methodology, followed by its utilization in obtaining certain physical and chemical properties in molecular crystals. Chapter 1 addresses not so easily accessed molecular property arising due to electron conjugation, highlighting antiaromaticity in tetracyclones. A systematic study of six tetracyclone derivatives with electron withdrawing and electron donating substituents has been carried out using experimental and theoretical charge density analysis. A three pronged approach based on quantum theory of atoms in molecules (QTAIM), nucleus independent chemical shifts (NICS), and source function (SF) has been employed to establish the degree of antiaromaticity of the central five-membered ring in all the derivatives. Electrostatic potentials mapped on the is density surface reveal the finer effects of different electron withdrawing and electron donating substituents on the carbonyl group. Chapter 2 presents a temperature induced reversible first order single crystal to single crystal phase transition (Room temperature Orthorhombic, P22121 to low temperature Monoclinic, P21) in a  hybrid peptide, Boc-γ4(R)Val-Val-OH. The thermal behavior accompanying the phase transition of the dipeptide crystal was characterized by differential scanning calorimetry, visual changes in birefringence of the sample during heating and cooling cycles on a hot-stage microscope with polarized light. Variable-temperature unit cell check measurements from 300 to 100 K showed discontinuity in the volume and cell parameters near the transition temperature, supporting the first-order behavior. The reversible nature of the phase transition is traced to be due to an interplay between enthalpy and entropy. Chapter 3 brings out an unusual stabilizing interaction involving a cooperative -hole and ¬hole character in a short NCS···NCS bond. This chapter describes structural features of four isothiocyanate derivatives, FmocXCH2NCS; X=Leu, Ile, Val and Ala. Among these it is observed that only FmocLeuCH2NCS which crystallizes in a tetragonal space group, P41, (a=b=12.4405(5) Å; c= 13.4141(8) Å) transforms isomorphously to a low temperature form, P41, (a=b=17.4665(1) Å; c= 13.1291(1) Å). The characteristics of the phase transition have been monitored by Differential Scanning Calorimetry, variable temperature IR and temperature dependent unit cell measurements. The short NCS···NCS intermolecular interaction (3.296(1) Å) is analyzed based on detailed experimental charge density analysis which reveals the nature of this stabilizing interaction. Chapter 4 explains a comparative study of syn and anti conformations of carboxylic acids in peptides from both structural aspect and charge density features. Single crystal structures of four peptides having syn conformations [BocLeuγ4(R)Valγ4(R)ValOH, BocLeuγ4(R)ValLeuγ4(R)ValOH, Boc3(S)Leu3(S)LeuOH] and one with anti conformation, BocLeuγ4(R)ValValOH have been analyzed. Experimental charge density analysis has been carried out exclusively on BocLeuγ4(R)ValValOH having anti form, because of its rare occurrence in literature. However, low temperature datasets on the four peptides with syn conformations were collected and theoretical charge density analysis has been carried out on two of these compounds. Electrostatic potentials mapped on is density surface bring out a significant difference at the oxygen atoms of the carboxyl group in the two conformations. However, lone pair orientation of different types of Oxygen atoms in the two forms (urethane, amide, acid) doesn’t exclusively indicate the differences in the corresponding charge density features. Chapter 5 addresses the issue of how sensitive are the charge density features associated with amino acid residues when the backbone conformational angles are varied. Three model systems, 1, L-alanyl–L-alanyl–L-alanine dehydrate; 2, anhydrous L-alanyl–L-alanyl–L¬alanine and 3, cyclo-(D,L-Pro)2(L-Ala)4 monohydrate have been chosen for this evaluation. Compound 1 has ant parallel alignment of tripe tide strands, and compound 2 has parallel alignment. All the alanine residues in compound 1 and 2 are in the -sheet region of the Ramachandran plot, whereas, the four Alanine residues in the cyclic hex peptide 3 span different regions of the Ramachandran plot. Theoretical multipole modelling has been carried out in order to explore the plausibility of transferring multipole parameters across different regions of Ramachandran Plot. Appendix I contains a brief description of charge shift bonding in Ph-CH2-Se-Se-CH2-Ph, as determined based on both experimental and theoretical charge density analysis. Appendix II contains a reprint of a published article on “Conformation-Changing Aggregation in Hydroxyacetone: A Combined Low-Temperature FTIR, Jet, and Crystallographic Study”.

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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.

The thesis entitled “Organic fluorine in crystal engineering: Consequences on molecular and supramolecular organization” consists of six chapters. The main theme of the thesis is to address the role of substituted fluorine atoms in altering the geometrical and electronic features in organic molecules and its subsequent consequences on crystal packing. The thesis is divided into three parts. Part I deals with compounds that are liquids under ambient conditions, crystal structures of which have been determined by the technique of in situ cryocrystallography. Part II demonstrates the utilization of in situ cryocrystallography to study kinetically trapped metastable crystalline phases that provide information about crystallization pathways. In part III, crystal structures of a series of conformationally flexible molecules are studied to evaluate the consequences of fluorine substitution on the overall molecular conformation. The genesis and stabilization of a particular molecular conformation has been rationalized in terms of variability in intermolecular interactions in the crystalline state. Part I. In situ cryocrystallography: Probing the solid state structures of ambient condition liquids. Chapter 1 discusses the crystal structures of benzoyl chloride and its fluorinated analogs. These compounds have been analysed for the propensity of adoption of Cl···O halogen bonded dimers and catemers. The influence of conformational and electronic effects of sequential fluorination on the periphery of the phenyl ring has been quantified in terms of the most positive electrostatic potential, VS,max (corresponding to σ-hole) on the Cl-atom. It is shown that fluorine also exhibits “amphoteric” nature like other heavier halogens, particularly in presence of electron withdrawing groups. Although almost all the derivatives pack through C–H···O, C–H···F, C–H···Cl, Cl···F, C–H···π and π···π interactions, the compound 2,3,5,6-tetrafluorobenzoyl chloride exhibited a not so commonly observed Cl···O halogen bonded catemer. On the other hand, the proposed Cl···O mediated dimer is not observed in any of the structures due to geometrical constraints in the crystal lattice. Chapter 2 presents the preferences of fluorine to form hydrogen bond (C–H···F) and halogen bonds (X···F; X= Cl, Br, I). Crystal structures of all three isomers of chloro-, bromo-and iodo-fluorobenzene have been probed in order to gain insights into packing interactions preferred by fluorine and other heavier halogens. It has been observed that homo halogen…halogen (Cl···Cl, Br···Br and I···I) contacts prevail in most of the structures with fluorine being associated with the hydrogen atom forming C–H···F hydrogen bond. The competition between homo and hetero halogen bonds (I···I vs I···F) is evident from the packing polymorphism exhibited by 4-iodo fluorobenzene observed under different cooling protocols. The crystal structures of pentafluoro halo (Cl, Br, I) benzenes were also determined in order to explore the propensity of formation of homo halogen bonds over hetero halogen bonds. Different dimeric and catemeric motifs based on X···F and F···F interactions were observed in these structures. Chapter 3 focuses on the effect of different cooling protocols in generating newer polymorphs of a given liquid. The third polymorph (C2/c, Z'=6) of phenylacetylene was obtained by sudden quenching of the liquid filled in capillary from a hot water bath (363 K) to the nitrogen bath (< 77 K). Also, different polymorphs were obtained for both 2¬fluoro phenylacetylene (Pna21, Z'=1) and 3-fluoro phenylacetylene (P21/c, Z'=3) when crystallized by sudden quenching in contrast to the generally followed method of slow cooling which results in isostructural forms (P21, Z'=1). The rationale for these kinetically stable “arrested” crystalline configurations is provided in part II of the thesis. Part II. Tracing crystallization pathways via kinetically captured metastable forms. Chapter 4 explains the utilization of the new approach of sudden quenching of liquids (detailed in chapter 3) to obtain kinetically stable (metastable) crystalline phases that appear to be closer to the unstructured liquids. Six different examples namely, phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorobenzoyl chloride, 3-chloro fluorobenzene and ethyl chloroformate are discussed in this context. In each case, different polymorphs were obtained when the liquid was cooled slowly (100 K/h) and when quenched sharply in liquid nitrogen. The relationship between these metastable forms and the stable forms (obtained by slow cooling) combined with the mechanistic details of growth of stable forms from metastable forms provides clues about the crystallization pathways. Part III. Conformational analysis in the solid state: Counterbalance of intermolecular interactions with molecular and crystallographic symmetries. Chapter 5 describes the crystal structures of a series of conformationally flexible molecules namely, acetylene and diacetylene spaced aryl biscarbonates and biscarbamates. While most of the molecules adopt commonly anticipated anti (transoid) conformation, some adopt unusual cisoid and gauche conformations. It is shown that the unusually twisted conformation of one of the compounds [but-2-yne-bis(2,3,4,5,6¬pentafluorocarbonate)] is stabilized mainly by the extraordinarily short C–H···F intermolecular hydrogen bond. The strength of this rather short C–H···F hydrogen bond has been authenticated by combined single crystal neutron diffraction and X-ray charge density analysis. It has also been shown that the equi-volume relationship of H-and F-atoms (H/F isosterism) can be explored to access various possible conformers of a diacetylene spaced aryl biscarbonate. While biscarbonates show variety of molecular conformations due to absence of robust intermolecular interactions, all the biscarbamates adopt anti conformation where the molecules are linked with antiparallel chains formed with N–H···O=C hydrogen bonds. Chapter 6 presents a unique example where the commonly encountered crystallographic terms namely, high Z' structure, polymorphism, phase transformation, disorder, isosterism and isostructuralism are witnessed in a single molecular species (parent compound benzoylcarvacryl thiourea and its fluorine substituted analogs). The origin of all these phenomenon has been attributed to the propensity of formation of a planar molecular dimeric chain mediated via N–H···O [R2 (12)] and N–H···S [R2 (8)] dimers.

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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