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.

Crystallographically solids with well defined crystal structures are normally assumed to be highly ordered. However, it is not uncommon to find considerable degree of disorder amongst many of these crystalline substances. Disorder among crystalline substances often arise from the rotational motion which leads to the well known class of plastic crystalline substances. Typically, globular molecules such as methane, carbon tetrachloride or adamantane exhibit plastic crystalline phase with significant amount of orientational disorder. In many other substances, disorder arises from torsional motion as in the case of biphenyl, p- or o-terphenyls, stilbene or azobenzenes. In case of molecules with flexible segment, such as alkanes or surfactants, motion of the terminal methyl group or terminal ethyl group is responsible for the observed disorder. Chapter 1 discusses various aspects of disorder in crystals. A new pressure induced solid phase of biphenyl is reported at room temperature. Isothermal-isobaric ensemble variable shape simulation cell Monte Carlo calculations are reported on biphenyl at 300K as a function of pressure between 0-4 GPa. The potential proposed by Williams for inter-molecular and Benkert-Heine-Simmons(BHS) for intramolecular interactions have been employed. Different properties indicating changes in the crystal structure, molecular structure, distributions of inter- and intra-molecular energy are reported as a function of pressure. With increase in pressure beyond 0.8 GPa, the dihedral angle distribution undergoes a change from a bimodal to an unimodal distribution. The changes in IR and Raman spectra across the transition computed from ab initio calculations are in agreement with the experimental measurements. It is shown that at pressures larger than 0.8 GPa, competition between inter-molecular interactions with intra-molecular terms v/z., conjugation energy and the ortho-ortho repulsion favors a planar biphenyl due to better packing and consequently a predominant inter-molecular term. The exact value of the transition pressure will depend on the accuracy of the inter- and intra-molecular potentials employed here. p-terphenyl has been modeled at 300K and atmospheric pressure with different potential models. Modified Fihppini parameters for mtermolecular interactions and BHS potential for inter-ring torsion predict the structure of p-terphenyl reasonably well. Pressure variation calculations are carried out with this combination of inter- and intra-molecular potential. The structure as a function of pressure upto 5 GPa has been compared with experimental structure provided by Puschnig et al. The transformation of functional form of the potential energy curve (associated with the inter-ring flipping) from W-shaped to [/-shaped form as a function of pressure has been observed. This is in excellent agreement with previous studies of polyphenyls including biphenyl and p-hexaphenyl. The complete planarization of molecules occurs when the pressure range is 1.0 GPa-1.5 GPa. Molecular simulation of solid stilbene in the isothermal-isobaric ensemble with variable shape simulation are reported. Structure has been characterized by means of lattice parameters and radial distribution functions. Simulations show existence of pedal-like motion at higher temperatures in agreement with the recent X-ray diffraction measurements by Ogawa and co-workers and several others previously. Difference in energy between the major and minor conformers, barrier to conformational change at both the crystallographic sites have been calculated. Temperature dependence of the equilibrium constant between the two conformers as well as the rate of conversion between the con-formers at the two sites have been calculated. These are in agreement with the recent analysis by Harada and Ogawa of non-equilibrium states obtained by rapid cooling of stilbene. Volume and total intermolecular energy suggest existence of two transitions in agreement with previous Raman phonon spectroscopic and calorimetric studies. They seem to be associated with change from order to disorder at the two sites. Ab initio calculations coupled with simulations suggest that the disorder accounts for only a small part of the observed shortening in ethylene bond ength. A Monte Carlo simulation with variable shape simulation cell has been carried out on stilbene. The study attempts to investigate the disorder at various pressures upto 4 GPa. It is seen that the population of minor conformers at sites 1 and 2 decrease with increase in pressure. Population of minor conformers at site 2 decreases to zero by 1.5 GPa. In contrast, the population of minor conformers at site 1 remains finite for the runs reported here. It is seen that the population of minor conformers at site 1 is higher than at site 2 at room temperature which is to be expected on the basis of the activation energies. Associated changes in the unit cell as well as molecular conformation are discussed. Isothermal-isobaric ensemble Monte Carlo simulation of adamantane has been earned out with variable shape simulation cell. Low temperature crystalline phase and the room temperature plastic crystalline phases have been studied employing the Williams potential. We show that at room temperature, the plastic crystalline phase transforms to the crystalline phase on increase in pressure. Further, we show that this is the same phase as the low temperature ordered tetragonal phase of adamantane. The high pressure ordered phase appears to be characterized by a slightly larger shift of the first peak towards lower value of r in C-C, C-H and H-H rdfs as compared to the low temperature tetragonal phase. Co-existence curve between the crystalline and plastic crystalline phase has been obtained approximately upto a pressure of 4 GPa. We investigate the equation of state, variation of lattice parameters and the distortion of molecular geometry of low temperature phase of adamantane upto 26 GPa pressure. A rigid and a flexible model of adamantane have been studied using variable shape simulation within the isothermal-isobaric ensemble. Including six low frequency modes obtained from density functional theory carried out on a single-molecule has incorporated the flexibility. These calculations used Becke 3-parameter method and Lee-Yang-Parr electron correlation functional with 6-31G(d) basis set. The simulated equation of state and variation of c/a ratio as a function of pressure are compared with the experimental results. The results are in good agreement with high pressure experiments. Nature of distortion in molecular geometry obtained from the calculation are also in good agreement with the experiment.