"Molecular engineering of some 2,4,6-(substituted biarylamino)-1,3,5-triazines and crystal data belonging to the products 2,4,6-(m,m’-ditolylamino)-1,3,5-triazine, 2,4,6-(p,p’-ditolylamino)-1,3,5-triazine and 2,4,6-(phenyl-p-tolylamino)-1,3,5-triazine were reported. Retrosynthetic analysis of trigonal octupolar networks led to the identification of tris-substituted diarylamino-triazines as molecular analogs of Piedfort units formed by cofacial dimers of 2,4,6-triaryloxy-1,3,5-triazine molecules. Synthesis of mono and diarylamiono triazines is achieved by coupling of the corresponding anilines with cyanuric chloride. Synthesis of diarylamines exhibiting different functional groups on two phenyl rings is attempted; the successful attempt in the case of phenyl-p-tolylamine is described. All the crystals obtained so far belong to centrosymmetric space group P21/c. Though none of the molecules retain trigonal symmetry in the crystal structures, pseudo-trigonal assembly of molecules is identified in some cases. The assembly of molecules within the crystals results in columnar structures formed by C-H..N and C-H..pi interactions."

Current research focuses on the effect of different continuous solid state shear based processing for the production of pharmaceutical amorphous system and cocrystals for poorly water soluble APIs. The S3M technology is getting first time reported for its application in pharmaceutical field and it is considered as technology with good potential for development of pharmaceutical dosage forms. The main objectives of this study include the effect of two solid state shear processes on the product properties in case of solid dispersions and cocrystals. Hot melt extrusion technology has been widely explored for the production of pharmaceutical solid dispersions and cocrystals, it would be helpful to compare how the new invented S3M technology will differ from the existing solid state shear process. The S3M has been also explored for the advantages over HME process in terms of residence time, plasticiser free dispersions, effect of process on degradation of drugs during processing. For this purpose, the process and material modifications during operation of these two technologies was important aspects of this study. The pharmaceutical drugs chosen for the solid dispersion purpose were carbamazepine, ibuprofen, glibenclamide which are BCS class II drugs and paracetamol from BCS class III drug was selected as model drug for solid dispersion manufacturing with PVP. VA64, HPMCP HP55, HPMCAS, Ethyl cellulose as polymers. In case of cocrystals selected drugs were carabamazepine, caffeine, paracetamol and ibuprofen with co-formers nicotinamide, saccharin, salicylic acid, glutaric acid, oxalic acid, maleic acid. The selections of co-formers were done on the basis of functional group complementarity between drug and co-former. All the details about the pairs for cocrystals and for solid dispersions are given in experimental section. Carbamazepine has been explored in depth for solid dispersions with different polymers and with different co-formers in case of cocrystals. The effect of process variables and amount of shear applied during processing was deciding factor in product output and quality. The end product in case of both the solid dispersions and cocrystals varied in their physicochemical, morphological and drug release properties HME process needed addition of plasticisers during preparation of solid dispersions whereas S3M was plasticiser free process which gave good insight on how this will affect the product performance during evaluation studies. The solid dispersions in case of HME were had smooth surfaces and which are non-porous in nature whereas in case of S3M the solid dispersions were highly porous in nature. The differences in the structural and morphological features of solid dispersions somehow did not affect the drug release of drug during in-vitro dissolution studies and both the solid dispersions did not show much difference in drug release. In case of cocrystals processing on S3M it was observed that the S3M process is dependent on the use of polymer as process aid. For this purpose PEO, PVP VA64 and HPMCP HP55 were selected as model polymer as process aid during processing of cocrystals, out of which PEO has been explored widely as processing aid due to its process suitability, low melting and ability to withstand high shear during processing. PVP VA64 was used only in case of carbamazepine cocrystals with salicylic acid and HPMCP HP55 in case of caffeine cocrystals with maleic acid. The effect of concentration of PEO in case of carbamazepine cocrystals as processing aid was studied (concentration range 5%, 10%, 15%, 25% w/w). The concentration of PEO in case of HME cocrystals had direct effect on the drug release of drug dissolution studies which was reduced in case of higher concentration of PEO (25% w/w), which was not observed in case of S3M processes carbamazepine cocrystals. The product in case of cocrystals by S3M was thread like structures whereas in case of HME cocrystals were in form of screw shaped compact mass. The difference in morphological and structural properties of cocrystals did not had major effect on drug release in case of S3M process but in case of HME processed cocrystals the higher amount of polymer slowed the drug release. The degradation studies in case of drugs carbamazepine, paracetamol were carried out whereas in case of polymer for HPMCP HP55 were carried out. It was found that HME processed samples showed higher degradation as compared to S3M processed one in both the cases solid dispersions and cocrystals. This can be attributed to high residence time in case of HME as compared to S3M process. The effect of two high shear processes HME and S3M had significant effect on the morphological and structural properties of the solid dispersions and cocrystals. The variation in the structural and morphological properties did not have direct effect on the drug release of drug during dissolution studies. HME and S3M both the processes had some positive and some negative aspects within them for processing of pharmaceutical dispersions and cocrystals. In case of HME the use of plasticiser is mandatory to maintain low torque levels during processing and to avoid blockage of extruder barrel, whereas in case of S3M the process is plasticiser independent and processing of solid dispersion is very easy as compared to HME with low residence time. Processing of plain drug or co-former was easy in case of HME whereas in case of S3M processing it was mandatory to use polymer as processing aid specially during processing of cocrystals. In case of process controls HME has excellent control over the process parameters which can be controlled and manipulated as per requirement, whereas S3M technology needs to have technical modifications to have better control over its processing parameters. The S3M can be a revolutionary technology for pharmaceutical industry once it is upgraded with better control and optimised process parameters.

Crystal engineering has recently emerged as a method of choice for the design and the construction of functional materials. Solid-state synthesis, of the most commonly studied aspects of crystal engineering, has been shown to provide access to molecular targets that are hardly obtainable using principles of conventional (i.e. solution-based) organic synthesis. Reactions in the solid state are, however, not routinely used in organic synthetic chemistry. The scarce use of solid-state reactions can be attributed to the difficulty of predicting molecular arrangements in the solid state, as well as to the lack of methodologies to control crystal packing. Template-directed solid-state synthesis is a recently developed modus operandi that enables control over reactivity within multi-component crystals. The thesis is focused on the application of template-directed solid-state approach to [2+2] photocycloaddition reactions in the solid state, as well as on the understanding of intermolecular interactions in crystals. Synthetic templates have been utilized to construct cocrystals that enable a class of hitherto underdeveloped organic solid-state reactions, namely [2+2] cross-photoaddition reactions. In addition, products derived form templated solid state reactions, namely tetrapyridylcyclobutanes, have been utilized to generate exceptional materials, such as thixothropic hydrogels based on nano-dimensional metal-organic particles. The utility of crystal engineering has also been expanded to the nanoscience and the development of nanomaterials. A crystallization method for the preparation of nano-dimensional cocrystals has been developed. The method has been shown to enable single-crystal-to-single-crystal [2+2] photodimerizations of olefins. In addition, nano-dimensional cocrystals have been shown to exhibit distinctive mechanical properties upon single-crystal-to-single-crystal transformations. In addition to solid-state reactions and materials derived therefrom, we systematically studied hierarchies of supramolecular synthons in pharmaceutical cocrystals comprised of multi-functional molecules. Pharmaceutical cocrystals have been recently shown to exhibit physical properties superior to those of parent drugs. Our studies involved xanthine alkaloids as pharmaceutical agents and a series of hydroxylated benzoic acids as cocrystal formers. Synthon hierarchies have been established for three xanthine alkaloids. We also discovered pharmaceutical salts that formed where cocrystallization was expected to occur. Reasons contributing to such unexpected salt formation were investigated using X-ray crystallography and computational methods. The established synthon hierarchies are expected to contribute to a better understanding of self-assembly processes in cocrystals that is crucial for the development of state-of-art drugs, and the design of organic reactions in the solid state.

The synthesis of new molecules is often initiated with the desire to create unique materials that have specific functions and/or properties. The materials are often used in areas such as pharmaceuticals, medical imaging, and energetics. Preparation of these materials utilizes fundamental rules that define how molecules interact with each other in a solid. My research focuses on employing the established concepts to predict how certain molecules interact and assessing the solid form that results (crystal structure) from these interactions. The solids investigated in my research are composed of two different molecules that can combine in various ways based on complementary interactions. Once the two molecules interact to form a crystal structure, external stimuli, such as heat, can cause the atoms within the crystal to move in specific directions to allow for events such as water loss, or it can initiate atoms to rearrange completely to form a new molecule. My work evaluates how the crystal structure changes when the atoms move and how the interactions between the molecules are impacted. The results of my research indicate the crystal structure can be controlled by aspects such as physical size and the properties of the individual molecules within the crystal. Additionally, my work involves assessing new ways to synthesize the described molecules by using technology that avoids the use of harmful solvents. My research has demonstrated a new mixing method that can prepare molecules in the lab and production facilities that reduces the amount of solvent needed and improves sustainability through chemistry.

The interest in metal-organic materials namely, coordination polymers and metal-organic frameworks has risen dramatically over the past few years. To a certain extent this interest is a consequence of the realization chemists have discovered how to play a form of molecular Lego® in which metal cations or metal clusters represent the bricks (or nodes) and organic ligands such as 4,4-bipyridine (bipy) or benzene-dicarboxylate represents the glue (or spacers). The "node-and-spacer" approach to self-assembly can be invoked in such a manner that a plethora of infinite architectures and discrete polyhedra can be generated from geometric principles, some of which are unprecedented in either natural or synthetic materials. The research presented within this dissertation primarily involves the use of coordination chemistry and supramolecular chemistry in the context of synthesizing metal-organic materials and deals with how subtle variations in reactants and procedures can have dramatic effects upon the materials formed. The effect of aromatic guest molecules on the crystal packing of 1D and 2D "metal-4,4`-bipyridine" coordination polymers has been addressed in terms of structural analysis and fluorescence spectroscopy. The phenomena of supramolecular isomerism resulting from the use of metal-carboxylate clusters as building blocks for a variety of metal-organic materials will be discussed. Finally, an analysis of the Host:Guest and suprasupermolecular properties of discrete nanostructures will be provided.

Control of solid state ordering in conjugated small molecules is paramount to the continued development and implementation of organic materials in electronic devices. However, there exists no reliable method on which to predicatively determine how a change to the molecular structure will impact the solid-state packing. As such, the molecule must be synthesized before its solid-state packing can be definitively evaluated. However, once the packing structure of a material is known there exist both qualitative structure- function relationships derived from the literature, as well as quantitative computational methods that can be employed to suggest if a material will perform well in a given device. This type of bottom-up strategy is used in Chapter 2 to design and synthesize a high performance material for organic field effect transistors. A core molecule is synthesized, and through rigorous optimization of pendant and solubilizing groups a material with exceptional solid-state packing is developed and its performance in an organic field effect transistor is discussed. Chapter 3 discusses the use of conjugated organic molecules in conjunction with inorganic materials to develop hybrid organic/inorganic materials. A scalable synthesis is developed so derivatives can be rapidly synthesized and their properties evaluated. Two classes of materials are developed and synthesized: tetracene-based ligands for quantum dots and diammonium-substituted anthracene and tetracene derivatives for 2D-perovskites. Initial results for both classes of materials are presented. Chapter 4 discusses the topochemical photopolymerization of heptacene [4+4] dimers. Multiple derivatives were synthesized in order to give the ideal alignment of molecules in the crystal, followed by irradiation of crystals to give crystal templated polymerization. In Chapter 5, triarylmethane derivatives are synthesized and their performance as radiochromic sensors is evaluated. Chapter 6 involves the development of a robust synthetic scheme toward a difficult to attain π- extended regioisomer of pyrene. Photophysical characterization reveals that the direction of π-extension from the pyrene core has a profound effect on electron delocalization.

Supramolecular synthesis has gained much attention in recent years. Such an approach to synthesis represents an attractive alternative to traditional, multi-step synthesis, especially for making complex, nanoscopic structures. Of particular interest, in the context of this work, is the use of metal-organic interactions to direct the self-assembly of nanoscopic architectures. These interactions are highly directional, relatively "strong" (compared to other supramolecular interactions) and kinetically labile, which allows for "self-correction" and in turn the production, often in high yield, of defect-free products. This also means that a number of related, yet structurally diverse products (supramolecular isomers) could be isolated. The work presented herein demonstrates the supramolecular synthesis of related, yet structurally diverse family of metal-organic nanoscale supramolecular architectures that are based on the ubiquitous paddle-wheel dimetal tetracarboxylate secondary building unit (SBU) and angular dicarboxylate ligands. It also demonstrates that the SBU self-assembles into clusters of four (tetragonal) and three (trigonal) nanoscale secondary building units (nSBU), which further self-assemble into nanoscale structures that include discrete (0D) faceted polyhedra, tetragonal 2D sheets and another 2D sheet that conforms to the so-called Kagom lattice. In addition, the work herein demonstrates that synthesis under thermodynamic equilibrium conditions facilitates "self-correction" so that the most stable thermodynamic product is obtained. Synthesis, characterization and crystal structure analysis of these structures is presented herein.

The rational design of functional solids based upon the development of strategies for controlling intermolecular interactions and structural arrangement of simple molecular building units, represents a salient feature in the context of supramolecular chemistry and crystal engineering. Consideration of chemical functionality, geometrical capability and knowledge of the interplay between two or more sets of supramolecular interactions specific of preselected chemical components will facilitate further extension of crystal engineering towards the construction of supramolecular materials possessing valuable properties. Calixarenes represent excellent building blocks for the design of solid-state architectures, in particular calix-4-arenes crystallize easily and the introduction of a wide range of director functions is relatively simple. For example, amphiphilic and pseudo-amphiphilic calixarenes may be synthesized by selective functionalization at either face of the skeleton and a second functionality may then be introduced at the opposite face. Careful examination of the crystal packing of a series of calix-4-arene derivatives systematically modified with various alkyl chain lengths at the lower rim and selected functional groups at the upper rim will be considered in the broader perspective of crystal engineering strategies and development of novel materials. Metal-organic networks are typically based upon the cross-linking of transition metal-based nodes by "spacer" organic ligands. Since there is an inherent control over the chemical nature of the components of such metal-organic structures, it is possible to design infinite architectures that possess well-defined topologies and contain cavities suitable for incorporation of guest molecules. Investigation of metal-organic networks based upon rigid ligands possessing two types of coordination sites (nicotinate and dinicotinate) and conformationally labile ligands possessing saturated fragments (glutarate and adipate) will be addressed in the context of topological approaches to the design of multi-dimensional networks with particular emphasis upon their resulting properties.

The synthesis or the interaction between two or more molecules is known as supramolecular chemistry. The concept of supramolecular chemistry can be applied to the design of new pharmaceutical materials affording new compositions of matter with desirable composition, structure and properties. The design of a two-molecule, or binary, compound using complementary molecules represents an example of an application of crystal engineering. Crystal engineering is the understanding of intermolecular interactions, in the context of crystal packing, in the design of new solid materials. By identifying reliable connectors through molecular recognition or self-assembly, one can build predictable architectures. The study of supramolecular synthesis was accomplished using known pharmaceutical molecules such as Nifedipine (calcium channel blocker used for cardiovascular diseases) and Phenytoin (used as an anticonvulsant drug) and model compounds containing synthons common in pharmaceutical drugs (Crown ethers and Trimesic acid with ether linkages and carboxylic acid dimers, respectively) with complementary molecular additives. The co-crystals formed were characterized by various techniques (IR, m.p., XPD, single X-ray diffraction) and preliminary results were found to exhibit characteristics different from the parent compounds as a direct result of hydrogen bonding and self-assembly interactions. These crystalline assemblies could afford improved solubility, dissolution rate, stability and bioavailability.

This work endeavors to delineate modern paradigms for crystal engineering, i.e. the design and supramolecular synthesis of functional molecular materials. Paradigms predicated on an understanding of the geometry of polygons and polyhedra are developed. The primary focus is on structural determination by single crystal x-ray crystallography, structural interpretation using a suite of graphical visualization and molecular modeling software, and on the importance of proper graphical representation in the presentation and explanation of crystal structures. A detailed analysis of a selected series of crystal structures is presented. The reduction of these molecular networks to schematic representations that illustrate their fundamental connectivity facilitates the understanding of otherwise complex supramolecular solids. Circuit symbols and Schlafli notation are used to describe the network topologies, which enables networks of different composition and metrics to be easily compared. This reveals that molecular orientations in the crystals and networks are commensurate with networks that can be derived from spherical close packed lattices. The development of a logical design strategy for a new class of materials based on our understanding of the chemical composition and topology of these networks is described. The synthesis and crystal structure of a series of new materials generated by exploitation of this design strategy is presented, in addition to a detailed analysis of the topology of these materials and their relationship to a parent structure. In summary, this dissertation demonstrates that molecular polygons can self-assemble at their vertexes to produce molecular architectures and crystal structures that are consistent with long established geometric dogma. The design strategy represents a potentially broad ranging approach to the design of nanoporous structures from a wide range of chemical components that are based on molecular shape rather than chemical formula. In effect, this work represents another example of the molecular meccano approach to self-assembled structures. Most importantly, given that these materials are designed from first principles, they offer materials scientists the ability to control the chemical nature of the constituent components and therefore influence the bulk physical properties of materials.