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Yes / The creation of salts is a frequently used approach for the modification of physicochemical properties of an active pharmaceutical ingredient. Despite the frequency of application, there has been little research into the structural-property relationships of the final material and the nature of the counterion present. This work reports on five new salts of sulfathiazole and compares the energetics of the intermolecular interactions with variation in the crystal packing motifs.

no / Crystallisation is a widely used technique for purification and manipulation of the final crystal form of therapeutic agents. In particular, potential exists to control the mechanical properties of ibuprofen through control of crystal habit. The aim of this study was therefore to understand the influence of crystallisation conditions on the morphology of ibuprofen to enable production of crystals with different habits.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The work presented in this thesis has demonstrated that supramolecular synthons can be used to make multicomponent crystals, and various synthons can be combined to make supermolecules. The synthons can also be used to construct nanoscale assemblies. Molecules containing single and multiple hydrogen-bond (HB) and halogen-bond (XB) acceptor sites have been synthesized in an effort to carry out supramolecular synthesis in order to establish a reliable hierarchy for intermolecular interactions. Pyrazole-based molecules have been made, combined with various carboxylic acids, and characterized using infrared (IR) spectroscopy to give a success rate of 55-70%. Reactions that gave a positive result were converted to solution experiments, and crystals were grown and characterized using single-crystal X-ray diffraction (XRD). The co-crystals display infinite 1-D chains with the intended stoichiometry and structural landscape on 6/6 occasions. The salts, on the other hand, display unpredictable stoichiometry and structural landscape on 5/5 occasions. Furthermore, the electrostatic charge on the primary hydrogen-bond acceptor, N(pyz), can be altered by adding a nitro, R-NO2, covalent handle to the backbone of the pyrazole molecule. Addition of a strongly electron withdrawing group significantly lowered the charge on the pyrazole nitrogen atom and, in turn, lowered the supramolecular yield to 10%. Ditopic molecules containing pyrazole and pyridine on the same molecular backbone were synthesized and characterized using 1H NMR. The molecules were co-crystallized with carboxylic acids, and the resulting solids were characterized using IR spectroscopy. The solids could then be classified as co-crystal or salt using specific markers in the IR spectrum. Single-crystal XRD was used to observe the intermolecular interactions in the co-crystals and salts, and the co-crystals were assigned to two groups: Group 1 (2) and Group 2 (2). The salts (4) show more unpredictability with stoichiometry and structural landscape. A library of ditopic molecules containing triazole and pyridine acceptor sites were synthesized and characterized using 1H and 13C NMR. The molecules were co-crystallized with carboxylic acids and the resulting solids were characterized using IR spectroscopy which demonstrated a 100% supramolecular yield whenever a pyridine moiety was present, consistent with results from Chapter 3. Single-crystal XRD was used to identify the intermolecular interactions in the co-crystals (2) and salt (1), and the results show that triazole can compete with pyridine for hydrogen bond donors. A library of ditopic molecules was also used for halogen-bonding (XB) studies with a series of activated iodine and bromine-based donors. The results show that iodine donors have a higher success rate range (12.5-75%) compared to bromine donors (16.7-50%) based on results obtained from IR spectra. Furthermore, the results from the XRD show that pyrazole nitrogen atoms can compete with pyridine for forming XB, and two groups of supramolecular synthons were observed. Finally, relatively weak non-covalent interactions, HB and XB, can influence the assembly of nanoparticles based on IR spectroscopy and TEM images. The assembly of the particles is influenced by specific capping ligands, which were synthesized and characterized using 1H, 13C and 19F NMR. The results demonstrate that relatively weak non-covalent interactions based on HB and XB interactions can influence nanoparticle assembly.

Crystal engineering is a rapidly developing area of research with goals aimed at designing functional molecular solids using reliable intermolecular interactions. By designing these intermolecular interactions using principles of supramolecular chemistry, favorable molecular arrangements can be achieved, which is manifested in desirable properties. We have applied crystal engineering strategies to the synthesis of unique materials for advanced applications including a metal-organic semiconductor, photochromic co-crystals, and a co-crystalline thin film for photolithography. We designed a metal-organic complex based on Ag(I) that exhibits π-π stacking interactions in the organic ligands, which is favorable for electrical conductivity in organic-based semiconductors. The nanocrystalline complex exhibits remarkable electrical conductivity and is also designed to undergo a [2+2] cycloaddition reaction, resulting in over a 70% increase in electrical conductivity. The increase in conductivity is supported by an increased contribution of Ag(I) ions to the top edge of the valence band, as well as new Ag···C(phenyl) interactions that can provide a charge transport pathway. Co-crystallization strategies were used to switch a non-photochromic compound photochromic upon incorporation into a series of co-crystals. Previously in our group, a co-crystalline thin film was applied for photolithography, and here, the crystal structure of the co-crystalline film is elucidated. We have also applied principles of crystal engineering to the synthesis of materials that are candidates for electrical property characterization measurements. First, we utilize Ag(I) to synthesize 0D and 1D metal-organic complexes. These complexes are also designed to undergo [2+2] photocycloaddition reactions and upon reaction, an increase in dimensionality by at least one order (i.e. 0D to 1D) is achieved. In one complex, photodimerization resulted in a 3D metal-organic framework (MOF), and we successfully applied a ‘green’ synthetic method to the synthesis of the 3D MOF via vortex grinding. We also report the X-ray crystal structure and solid-state packing of an organic molecule involving tetrathiafulvalene, a classic organic semiconductor. The molecule is susceptible to solvent uptake/loss and exhibits π-π stacking arrangements that are not ideal for favorable electrical properties. Through co-crystallization strategies, we achieve a unique ‘lock-arm’ motif that results in infinite stacking in the tetrathiafulvalene core, an ideal property for semiconductivity. This thesis will also focus on the solid-state [2+2] photodimerization reactions of styrylthiophenes, molecules that rarely undergo the reaction in either the solution or solid state. There have been very few efforts to attain regiocontrol of the products and high yielding photodimerizations of thiophenes are rare. We utilized a ditopic resorcinol template to afford the head-to-head photodimerization product, and by using a dicarboxylic acid-based co-crystal former, we were able to synthesize the head-to-tail photodimer. Both products were achieved in quantitative yield. We have also expanded our approach by employing silver templates, which have previously been successfully applied to photodimerizations of olefins substituted with six-membered rings (i.e. phenyl). We examined photoreactivity in Ag(I) coordination complexes with both α- and β-substituted thiophenes. Both head-to-head and head-to-tail products can be achieved and, in some complexes, both products are produced. In our studies examining thiophene photoreactivity with dicarboxylic acid templates, we discovered a unique co-crystal wherein two strong supramolecular synthons contribute equally to the solid-state packing. Due to this rare observation, we performed a survey of the Cambridge Crystallographic Database for co-crystals dominated equally by the same two strong supramolecular synthons. We found that co-crystals including both of these synthons are quite rare, and our co-crystal was the first to include a monopyridine. We discuss differences in pKas between the hydrogen-bond donor and acceptor to understand situations where these interactions do not form. We also highlight optimization of crystal symmetry and favorable secondary interactions, such as weak hydrogen bonding and π-π stacking, which may lead to and support the unique synthon formation. Lastly, we utilize co-crystallization strategies to modify the degree of dynamic molecular motion in the azo functional group, a group that is known to exhibit pedal motion in the solid state. The molecular motion is related to the thermal expansion behavior of the crystals and only upon co-crystallization with a ditopic receptor is the molecular motion capability of the azo group unlocked and ‘colossal’ thermal expansion properties achieved. By systematically modifying the non-azo component, we achieve thermal expansion ranging from ‘colossal’ to nearly zero, as well as rare negative thermal expansion.

Supramolecular chemistry is a branch of chemistry that focuses on chemical systems that are made up of a discrete number of assembled molecular components held together by various non-covalent interactions. Supramolecular systems are rarely designed from first principles. Rather, chemists have a range of well-studied structural and functional building blocks that they are able to use to build up larger functional architectures. We have chosen tetraphenylethylene (TPE) as the supramolecular building block in designing various functional materials because of interesting optical and electronic properties of TPE derivatives. We have utilized several intermolecular interactions like hydrogen bonding, coordinate bonding and halogen bonding to obtain materials with remarkable optical and electronic properties in the solid state as well as solution phase that can have potential applications in fields like crystal engineering, material science and organic electronics. TPE functionalized with four carboxylic acid groups was synthesized and crystallized with various bis(pyridines) to yield organic semiconducting materials. These crystals have been characterized by single crystal X-ray diffraction and conducting properties have been studied using conducting probe-atomic force microscopy. Semiconducting properties of these materials can be tuned based on bis(pyridine) component. Two different tetrapyridyl substituted TPEs have been synthesized and their photoluminescent properties have been studied in solution. Fluorescence emission was found to be switchable as a function of solvent mixture as well as pH. Both compounds have been structurally characterized in their free base form as well as in their protonated form as tetraperchlorate salts via X-ray diffraction. These three compounds have been utilized as supramolecular building blocks in metal organic frameworks (MOFs) as well as organic co-crystals mediated by hydrogen bonding as well as halogen bonding. A fluorescent complex of the tetraacid with zinc has been obtained which crystallized in a non-centrosymmetric space group due to solvent and water ligands on the zinc center. A coordination polymer has been obtained via solvothermal synthesis using tetrapyridyl TPE and zinc chloride. Lewis basicity of tetrapyridyl TPE's has also been utilized in organic co-crystalline assemblies mediated by halogen bonding interactions with iodoperfluoroarenes. Finally, Halobenzoyl esters of TPE based compounds have been synthesized and halogen bonding properties of these compounds have been exploited to achieve solid state porous networks.

This study investigates the metallosupramolecular chemistry of functionalised 1,2-diazole ligands, by the preparation and characterisation of a range of first-row transition metal coordination polymers and discrete assemblies. To this end, twenty-six ligands containing 1,2-diazole functionality have been synthesised, twenty-one of which have not previously appeared in the coordination chemistry literature. Utilising these compounds, forty new coordination compounds have been prepared and characterised by single-crystal X-ray crystallography and other analytical techniques, and their solid-state structural features discussed in the search for reproducible new diazole-based synthons for the designed synthesis of new functional materials. Particular attention is paid to the contribution of the second nitrogen atom on the diazole ring, which participates in structure-directing hydrogen bonding interactions, or acts as a synthetic handle to easily append further functionality to the ligand system. The design of the ligands is separated into two primary categories, representing the different approaches adopted for the synthesis of the metallosupramolecular architectures. The combination of 1H-pyrazole and carboxylic acid functionality in mixed-ligand assemblies was investigated with the combination of bis-pyrazole and bis-carboxylic acid ligands, and with the preparation of ligands containing both functional groups. This approach was extended to the related heterocyclic species indazole, with all five possible isomers of indazole-carboxylic acid synthesised and used in coordination chemistry for the first time. The 1H-diazole-carboxylate synthon was employed in the synthesis of fourteen coordination polymers and three discrete assemblies. Heteroaryl substitution at the 1-position of pyrazole or indazole compounds was employed to generate chelating ligands containing pyridine or benzimidazole functionality, which were used to form nineteen discrete complexes, including dinuclear helicates and metallocycles, and five coordination polymers. The effect of flexibility and distance between coordination sites in bis-bidentate ligand systems was examined, in conjunction with studies into the effect of steric bulk and variation of the electronic nature of the coordinating groups. While this study is primarily concerned with the solid-state structural chemistry of 1,2-diazole coordination compounds, attention is paid where appropriate to solution-based measurements such as NMR and UV/Visible studies, and the pertinent behaviour of functional materials, such as thermogravimetric analysis for solvated species and gas uptake studies for stable void-containing materials.

Yes / The design of new functional crystalline materials requires an understanding of the factors that control salt and co-crystal formation. These states often only differ in the location of the proton and are influenced by chemical and crystallographic factors. The interaction between a carboxylic acid and a pyridine is a frequently used supramolecular synthon in crystal engineering which can exist as either a co-crystal (CO2H⋯N) or salt (CO2−⋯HN+). The results of a Cambridge Structure Database search indicate that the nature of the functional groups on the pyridine play a stronger role in selection of the phase than those of the acid. However, the nature of the local hydrogen bonding of the interaction also adjusts the potential for proton transfer. This was demonstrated by ab initio modelling of the energy landscape for binary and ternary co-crystals by inclusion of varying components of the local environment.