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.

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Ce travail de thèse porte sur l'étude de la commutation ultrarapide de matériaux moléculaire photomagnétiques présentant des transitions entre états de spin. Ces cristaux moléculaires sont des prototypes de bi-stabilité moléculaire possédant deux états électroniques distincts, Haut Spin (HS) et Bas Spin (LS), entre lesquels les molécules peuvent commuter par la lumière. L'émergence des techniques ultrarapides nous permet d'étudier en temps réel ces processus de photo-commutation ainsi que les dynamiques hors équilibres associées jusqu'à l'échelle femtoseconde (10-15s). Nous avons combiné ici l'utilisation de sondes sensibles aux changements d'états électroniques et aux changements structuraux pour étudier ces processus de photo-commutation. Des mesures d'absorption optiques femtosecondes ont été effectuées sur notre plate forme laser et elles ont complétées par des mesures de diffraction et d'absorption des rayons X résolues en temps. La première partie de cette thèse se focalise sur la dynamique de commutation induite par la lumière au niveau moléculaire. Elle révélé l'intrication compliquée de degrés de liberté électroniques et structuraux. La génération et l'amortissement rapide de phonons optiques est identifié comme étant le processus clé dans le piégeage des molécules dans l'état Haut Spin. Les mesures réalisées sur différents types de composés ont prouvé le caractère local et linéaire de ce processus. La seconde partie de cette thèse présente les études de dynamique hors équilibre et des effets en cascade d'origine élastique et thermique résultant de ces perturbations initiales. Des effets coopératifs induits par la lumière sont ainsi mis en évidence. Cette dynamique hors équilibre pilotée par des phénomènes propagatifs et diffusifs est sensible aux effets de taille. L'étude de nano-cristaux démontre une grande efficacité et une réponse aux effets élastiques plus rapide que dans le cas des macrocristaux. Ces études apportent une compréhension nouvelle des phénomènes hors équilibre liés aux transitions de phase photo-induites sur des échelles de temps et d'espace allant de la molécule au matériau. / The main topic of this thesis is the study of the ultrafast photo-switching of photo-magnetic molecular materials showing transition between spin states. These molecular crystals are prototypes of molecular bistability between two distinct electronic states, HS and LS. The molecules can be switched between these two states by a light pulse. The emergence of ultrafast techniques allows us to study in real time these photo-switching processes and also the associated out-of-equilibrium dynamics down to the femtosecond scale (10-15s). We have combined probes sensitive to the change of electronic state, on the hand, and to structural rearrangements, on the other hand, in order to observe these photo-switching processes. The measurements of ultrafast transient absorption spectroscopy have been made using the laser plateform at the IPR. Complementary time resolved X-ray diffraction and absorption experiments have been performed on large facilities. The first part of this manuscript is focused on the photo-switching dynamics at molecular scale. It reveals a complicated interaction between electronic and structural degrees of freedom. The generation and damping of coherent optical phonons is identified as a key parameter in the trapping in HS potential. Several experiments on different compounds show the linear and local character of such ultrafast photo-switching. The second part of this thesis presents studies on the complete out of equilibrium dynamics. It reveals a cascading process with activation of elastic and thermal effects at different time scales. Cooperative processes following a light excitation are observed. These complexes dynamics are driven by propagating and diffusive process sensitive to the size of the sample. The study of nanocrystals yields high conversion and faster response to elastics effect than single-crystals. These studies further elucidate the out of equilibrium processes underlying the photo-induced phase transitions on time and length scales, from the molecule to material scale.

We have presented a thorough experimental investigation of electroabsorption spectroscopy on quasi-one-dimensional organic molecular crystals such as PTCDA and MePTCDI vapor deposited thin films to clarify the involvement of the charge-transfer exciton in the lowest excited state. By a self-built experimental setup, two kinds of electroabsorption measurements, called "perpendicular" and "parallel" measurements, were conducted at room temperature in ambient air. The crystalline texture of PTCDA and MePTCDI thin film samples are characterized by X-ray diffraction measurements. Current-voltage, capacitance-frequency and capacitance-voltage measurements are performed to clarify the electric field distribution inside organic layers. The results from electrical measurements show that only under certain conditions (electroabsorption measurements with proDC bias), the perpendicular and parallel electroabsorption meaurements can be directly compared. The electroabsorption spectra of MePTCDI and PTCDA thin films can be interpreted by neither pure Frenkel exciton nor pure charge-transfer exciton model. Essential features of electroabsorption spectra of MePTCDI and PTCDA thin films can be understood by the the mixture of Frenkel and charge-transfer exciton model. However, there is still a discrepancy in the directional properties of electroabsorption signals between experimental results and modle calculations. This small discrepancy suggests that a full interpretation of electroabsorption spectra of quasi-one-dimensional organic molecular crystals needs further experimental and theoretical investigations.

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The main topic of this thesis is the study of the ultrafast photo-switching of photo-magnetic molecular materials showing transition between spin states. These molecular crystals are prototypes of molecular bistability between two distinct electronic states, HS and LS. The molecules can be switched between these two states by a light pulse. The emergence of ultrafast techniques allows us to study in real time these photo-switching processes and also the associated out-of-equilibrium dynamics down to the femtosecond scale (10-15s). We have combined probes sensitive to the change of electronic state, on the hand, and to structural rearrangements, on the other hand, in order to observe these photo-switching processes. The measurements of ultrafast transient absorption spectroscopy have been made using the laser plateform at the IPR. Complementary time resolved X-ray diffraction and absorption experiments have been performed on large facilities. The first part of this manuscript is focused on the photo-switching dynamics at molecular scale. It reveals a complicated interaction between electronic and structural degrees of freedom. The generation and damping of coherent optical phonons is identified as a key parameter in the trapping in HS potential. Several experiments on different compounds show the linear and local character of such ultrafast photo-switching. The second part of this thesis presents studies on the complete out of equilibrium dynamics. It reveals a cascading process with activation of elastic and thermal effects at different time scales. Cooperative processes following a light excitation are observed. These complexes dynamics are driven by propagating and diffusive process sensitive to the size of the sample. The study of nanocrystals yields high conversion and faster response to elastics effect than single-crystals. These studies further elucidate the out of equilibrium processes underlying the photo-induced phase transitions on time and length scales, from the molecule to material scale.

Crystal engineering is widely applied in the design of new solids with desired physical and chemical properties based on an understanding of intermolecular interactions in terms of crystal packing. The understanding of such structure-property correlations increased my interest in the modulation of macroscopic properties of solid compounds. Establishing connections between structure and macroscopic properties is a classical aspect of materials science and engineering. With the advent of the nanoindentation technique, it is now possible to make such a link between micro-level structures with mechanical properties of molecular solids - in other words, between chemistry and engineering. Nanoindentation is a quantitative probe for the assessment of mechanical behavior of small volume materials. In this technique, applied load and indenter depth penetration are measured simultaneously for a molecular crystal specimen, with high precision and resolution. From this data, one can obtain the elastic modulus and hardness of molecular crystals. Being able to accordingly assess the relative strengths of intermolecular interactions, such a technique has become relevant to the subject of crystal engineering. We have used nanoindentation to study the packing anisotropy of molecular crystals and to establish structure-property relationships. This thesis demonstrates that nanoindentation is a state-of-the-art technique to probe the mechanical properties of molecular crystals and assists the development of the subject of crystal engineering towards property design. Chapter 1 gives an overview of the development of crystal engineering from solid state organic chemistry and a brief introduction of the nanoindentation technique which has become relevant to the subject of crystal engineering to establish structure-property relationships. The study of the mechanical properties of molecular solids as a function of their crystal structures is a very active branch of crystal engineering. Chapter 2 explores the insights of well-known odd-even alternative mechanical, physical and thermal properties of α,ω-alkanedicarboxylic acids such as elastic modulus, hardness and melting temperature through nanoindentation technique. These properties are well correlated with their crystal structure packing. The odd acids were found to be softer and lower melting temperature as compared to the even ones, possibly due to the strained molecular conformations in the odd acids in easier plastic deformation. Shear sliding of molecular layers past each other during indentation is a key to the mechanism for plastic deformation in the molecular crystals. Relationships between structural features such as interplanar spacing, interlayer separation distance, molecular chain length and signatures of the nanoindentation responses, discrete displacement bursts have also been discussed in this chapter. Chapter 3 explores the use of the nanoindentation measurement as a signature response to study the microstructure that exists in a single crystal of organic solids. The analysis of microstructure through X-ray crystallography can be misleading. This is because crystal structures as determined from the single-crystal diffractometer data represent only space- and time-averaged structures. Thus, due to higher spatial resolution of the nanoindentation technique compared to X-ray diffraction (XRD) it become a local probe, which allows for discrimination between different microstructure or domains in the single crystal. Chapter 4 attempts to explore an understanding of the underlying relationship between crystal structure and the mechanical properties of molecular crystals which are relevant for the systematic design of organic solids with a desired combination of mechanical properties such as elasticity and hardness through crystal engineering. Elastic properties in molecular solids are largely determined by the isotropy of crystal packing. By using the techniques of crystal engineering, seven halogenated N-benzylideneanilines (Schiff bases) crystals have been systematically designed and observed common underlying structural features which lead to high flexibility and elasticity. Elasticity in those crystals arises from a criss-cross packing of molecular tapes in isotropic structures with energetically comparable halogen bonds (Cl···Cl or Cl···Br). The chapter also demonstrates that the solid solution strengthening can be effectively employed to engineer hardness of organic solids. High hardness can be attained by increasing lattice resistance to shear sliding of molecular layers during plastic deformation. Chapter 5 demonstrates the broad applications of mechanical properties of molecular solids in the context of the pharmaceutical industry, which can be understood through nanoindentation. Crystal engineering is applied in designing active pharmaceutical ingredients (APIs) so as to obtain materials that exhibit optimum combinations of important physicochemical properties such as solubility, dissolution rate, and bioavailability. In the context of industrial-scale pharmaceutical manufacturing, it can also be used to tune mechanical properties such as grindability and tabletability, which often determine the processing steps that are adopted. Hence, there is always interest in the crystal structure−mechanical property correlations of APIs. The study of the mechanical properties of polymorphic drugs is an important for developing an understanding of their stability in the solid state. Overall, the main aim of this thesis is to explore an understanding for establishing structure-mechanical properties correlations of molecular crystals with recent advances in the nanoindentation technique and to gain knowledge for the design and synthesis of new materials using the crystal engineering approach. Nanoindentation of molecular crystals provides insights related to crystal packing, interaction characteristics, polymorphism and topochemistry.

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

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

Crystal engineering underlies the essence of natural affiliation between the molecule on the one side and the crystal as a supramolecular assembly on the other. Molecular recognition is the fundamental cause for this efficient transformation and if we consider the crystal as a supramolecular entity then it is not at all difficult to conceive crystallization as an outstanding example of molecular recognition. In general, organic compounds often facilitate closed packed crystal structures as described by A. I. Kitaigorodskii in the form of the close packing principle but based on chemical features, there is still a small window to understand, to rationalize and to fashion new crystal structures. Extending the chemical viewpoint as first proposed by J. M. Robertson, the supramolecular synthon model as a descriptor of collective crystal structures has been invoked that enables one to trail the molecular behaviour from an entropy dominated situation in solution to an enthalpy driven progression in the solid state. After 20 years, the concept of the supramolecular synthon has stood the test of time because of its simplicity and effectiveness towards the implementation in complex crystal structures and has led the scientific community to further handle complex and interesting ideas in structural chemistry and supramolecular synthesis. The complexity of dynamic and progressive behavior of molecules during crystallization may be understood by the analogous argument of protein folding; both these complex phenomena decode the emergence of multiple metastable forms before the final structures are attained. These intermediate kinetically driven species may be high energy polymorphs and pseudopolymorphs of the compound in question or semicompact random globules for proteins. Understanding the role of these species in their respective processes is of critical importance in elucidating mechanisms. As an alternative approach, crystal structure prediction (CSP) is also of fundamental importance in the context of understanding the crystallization process. All energy based computational methods of CSP address this problem by scanning the multi-dimensional energy hypersurface. This is performed by computing lattice energy changes with respect to parameters like unit cell dimensions, space group symmetry and the positional coordinates of atoms in the asymmetric unit. Further, the computational prediction of the crystal structure of an organic compound results in several choices, and it is possible that a collection of some of these when taken together forms a pattern that mimics the course of the crystallization process very much in the manner that structure correlation mimics covalent bond breaking and making. With all these developments, one is truly at the stage today when any experimental or computed crystal structure is just that, a crystal structure of the molecule in question and it is part of a complex and dynamic structural space which may include a part of the supramolecular reaction trajectory for crystallization itself. Accordingly, this thesis emphasizes the importance of kinetic events during crystallization and proposes some strategies to access the inaccessible domains of this structural space of a given compound. I have exploited the supramolecular synthon model to understand the kinetics of the crystallization process and have further extended this understanding towards the isolation of stoichiometric ternary solids. The synthon model also helps one to provide a logical step to explore these remote domains of the complex hyperenergy surface that have collectively been termed as the crystal structure landscape of the compound in question. The precise descriptions of the chapters are mentioned below. Chapter 2 describes fluorosubstitution as a unique chemical probe to explore the high energy crystal structures of benzoic acid in ambient conditions. This landscape exploration of benzoic acid is based on the robust (kinetically favoured) supramolecular homosynthon as well as consistent fluorosubstitution in native compound. This analysis is also supported by synthon based crystal structure prediction which is one of the best ways of monitoring high energy virtual crystal structures. Chapter 3 extends the idea of landscape exploration towards multicomponent systems. The incorporation of an additional compound during crystallization facilitates even complex kinetic environments but using fluorosubstitution as a chemical probe, it again helps to analyse the high energy virtual domains of the given multicomponent system. Similar to chapter 2, the landscape exploration of multicomponent system is also based on the robust (kinetically favoured) supramolecular heterosynthon as well as consistent fluorosubstitution in the native multicomponent system. Chapter 4 emphasizes the importance of synthon modularity as a chemical probe to traverse in the crystal structure landscape of the given multicomponent system. Here, I have quantified the role of the definitive synthon, by using the supramolecular synthon based fragment approach (SBFA), in the emergence of polymorphism in cocrystals. In latter part of this chapter, I utilized this collective kinetic information in order to realize the combinatorial nature of the crystallization process and showed the complex combinatorial synthesis of ternary solids which itself is considered to be an arduous exercise. Chapter 5 discusses the importance of kinetic information which were fetched from the corresponding multicomponent landscapes and were further utilized for combinatorial synthesis of ternary solids. Although the combinatorial idea is well established in solution, this chapter highlights the first experimental evidence of this idea in the solid state and shows preferred amplification of certain supramolecular synthons from corresponding libraries in the supersaturated crystallizing medium. Chapter 6 extends the combinatorial idea of crystallization even further by using highly flexible organic compounds that collectively provide larger structural space during crystallization. Using the delicate kinetic information about the molecular and supramolecular features, this chapter describes the preferential selection of molecular conformation and supramolecular synthons from the supersaturated solution during the molecule→crystal pathway. In summary, the idea of the crystal structure landscape provides an extended interpretation about some of the complex ideas namely, crystal energy landscape and polymorphism in modern crystal engineering. The crystallization of an organic compound often depends upon intrinsic chemical features and accordingly one selects optimized crystallization routes in the corresponding landscape through decisive experimental conditions. As a final note, the idea of the crystal structure landscape enables one to (at least qualitatively) understand the importance of crystallization kinetics which is understandably a difficult task.