Herein we describe a straight-forward and reproducible method for the preparation of homogeneous, multicomponent cocrystals and supramolecular solid solutions. We prepared these multicomponent materials based on small organic molecules that employ a two-point supramolecular hydrogen bond synthon. We report the creation and characterization of two, three, four, five, and seven component crystals containing a variety of 2-aminopyridines and monosubstituted benzoic acids. These systems exhibit the ability to accommodate multiple components in varying proportions while coordinating into an identical packing structure. The flexibility of the system to incorporate multiple components also gives rise to gradual modulation of physical properties.

The supramolecular chemistry and crystal structures of four Bis(imidazolium 2,4,6-pyridinetricarboxylate) metal(II)dihydrate complexes, where M=Co2+, Ni2+, Cu2+, or Zn2+ (1-4, respectively), are reported. These complexes serve as supramolecular building blocks that self-assemble when crystallized to generate a single, well defined structure in the solid state. 2,4,6-Pyridinetricarboxylate anions and imidazolium cations form strong ionic hydrogen bonds that dominate crystal packing in compounds 1-4 by forming three-dimensional (3-D) networks of molecules. These networks consist of hydrogen-bonded layers of molecules defined by N-H…O interactions that are joined in the third dimension by O-H…O interactions. This 3-D network provides a supramolecular framework with which to control and predict molecular packing by design for engineering the structures of crystals. Furthermore, compounds 1-4 create a robust organic host lattice that accommodates a range of different transition metals without significantly altering the molecular packing. Growth of crystals from solutions that contain two or more different metal complexes results in the formation of mixed crystals in which the different metal complexes are incorporated into the crystalline lattice in the same relative molar ratio present in solution. Epitaxial growth of crystals involving deposition of one metal complex on the surface of a seed crystal that contains a second metal complex generates composite crystals in which the different metal complexes are segregated into different regions of the crystals. Compounds 1-4 form crystalline solids that represent a new class of modular materials in which the organic ligands serve as a structural component that defines a single packing arrangement that persists over a range of structures, and in which the metal serves as an interchangeable component with which vary the physical properties of material.

Crystal engineering is a rapidly developing area of research with goals aimed at designing molecular solids with desired physical and chemical properties. By utilizing reliable intermolecular interactions, the principles of supramolecular chemistry are exploited in the solid state in order to achieve favorable arrangements of molecules in a crystal lattice. We have applied crystal engineering strategies to further develop the strategy of template-directed reactivity in the solid state. An evaluation of catechol, a regioisomer of the commonly used resorcinol template, was performed. Co-crystallization of the template candidate with a bis-pyridyl olefin produced a discrete self-assembled architecture wherein hydrogen-bonded dimers of catechol pre-organize the olefins for a [2+2] photodimerization in the solid state. The dimerization was determined to proceed quantitatively and X-ray studies of a partial single-crystal-to-single-crystal reaction supported the hypothesis of the reaction proceeding exclusively within the discrete assemblies, despite the infinite stacking of the olefins. A study of substituent effects on the conformational bias of additional catechol- based template candidates was carried out. Candidates with bulky substituents a the 3- and 4-positions were observed to adopt a favorable syn-anti or syn-gauche conformer in most cases. Though conformational bias was induced and discrete assembly achieved, only one of the synthesized cocrystals met the geometric requirements for a photodimerization, however, extended UV exposure produced no evidence of product formation. We discuss the fortuitous discovery of a catechol-based cocrystal system that produces an infinite linear assembly. The fluorine atom of 3-fluorocatechol was observed to be too small to induce conformational bias in the template candidate. However, the system was observed to progress through a three-step solvent-mediated phase transformation. The second and third crystal phases were isolated and characterized by single-crystal X-ray diffraction. The X-ray data revealed that the zig-zag assembly of the first phase spontaneously transforms to a double helix topology in the second phase, before transforming to the final phase, which exhibits a quadruple helix topology. In our studies of pharmaceutical cocrystals, we sought to perform a systematic study of the solid-state behavior of the anti-cancer drug 5-fluorouracil. Inspired by previously published cocrystal structures, we performed co-crystallization experiments with a small series of structurally similar coformers. Comparison of the three structures revealed an inconsistent degree of synthon disruption between the coformers. Curiously, one of the cocrystals obtained displayed a packing arrangement consistent with the requirements of a [2+2] cycloaddition. Irradiation of the sample with UV light resulted in the quantitative formation of a cross-photocycloaddition product. The product was characterized as a pyrimidine-fused cyclobutane, the first reported synthetic derivative of 5-fluorouracil obtained from a solid-state reaction. Lastly, we utilize crystal engineering strategies to study the behavior of 2- iodohippuric acid, a common radio-imaging target. The pharmacokinetic properties of 2- iodohippuric acid make it an ideal target for renal imaging. We sought to approach a solid formulation of the target in a similar manner to that of a drug or other metabolized pharmaceutical. In doing so, we hoped to study the compound’s behavior in the solid state so that we may eventually use co-crystallization as a means of altering the properties of the target for the purpose of generalizing its use in imaging the body.

Uranyl hybrid materials attract interest owing to promise of synthesizing functional materials, but typically experience limitations in extending dimensionality. This is due to the tendency of the uranyl cation to oligomerize along its equatorial plane, leading to the formation of flat secondary building units. One way to overcome these limitations is to utilize weak interactions to hold a structure together. This can be achieved through using ligands to build secondary building units through strong coordinative bonds that simultaneously provide supramolecular interactions as a means to extend dimensionality in the structure. We examined amino acids as a ligand choice because of its dual features of having a carboxyl group for coordination to the uranyl cation and an amino group that can be protonated to provide charge-assisted hydrogen bonding between to secondary building units in the structure. Aqueous benchtop chemistry in ambient conditions were used to synthesize and crystallize thirteen uranyl-glycine coordination compounds whose structures were elucidated with single crystal X-ray diffraction. Under these conditions, 1D coordination polymers form. The structural features in these compounds were varied to investigate their effects on the hydrogen bonding, including the presence/absence of metal center hydrolysis, the presence of other H-bond accepting carboxylate ligands, the use of dicarboxylic acid ligands to connect uranyl centers, and the addition of a secondary metal. The compounds provide insight into how the charge-assisted hydrogen bonding provided by zwitterionic amino acids is a viable means to extending the dimensionality of uranyl hybrid materials in a variety of chemical systems.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / Tailoring the properties of a bulk material such as a pharmaceutical compound, through non-covalent interactions, could lead to the enhancement of its physical properties without chemically modifying the individual molecules themselves. In order to obtain a degree of control and reliability of these non-covalent interactions, we must develop a series of synthons - patterns of non-covalent interactions between molecules. A family a N-heterocyclic amides were synthesised and an assessment of their binding selectivities was made, by evaluation of the supramolecular yield, (the frequency of occurrence of the desired connectivities). It was found that the supramolecular yield increased with increasing basicity of the heterocyclic nitrogen atom. However, there is a point where the heterocycle becomes basic enough to produce salts, which often leads to unpredictable connectivity and stoichiometry. Once the effectiveness of the N-heterocyclic amides as supramolecular reagents was established, a series of more closely-related ditopic hydrogen-bond acceptor molecules were synthesized. The supramolecular reagents contained imidazole and pyridine binding sites, so that the two sites differ in terms of their basicity and geometry. An assessment of the ability of these molecules to induce selectivity when a hydrogen bond donor such as a cyanoxime or a carboxylic acid is introduced was made. A total of nineteen crystal structures were obtained, of which one yielded a salt with unpredictable connectivity, and eighteen were cocrystals. Ten of these were 2:1 co-crystals, which shows that the two sites are accessible for binding. Eight were 1:1 stoichiometry, with five out of eight (63%) forming a hydrogen bond to the best acceptor. In addition, a series of molecular electrostatic potential calculations were employed to investigate the binding preferences and probe the best donor/best acceptor hypothesis. A ternary supermolecule was also constructed from a central, asymmetric hydrogen-bond acceptor and two different hydrogen-bond donor molecules. It was found that the best donor, the cyanoxime, bound to the best acceptor, the imidazole nitrogen atom, while the second best donor, a carboxylic acid, bound to the second best acceptor. The calculated molecular electrostatic potential values were used to rationalize this event. A series of substituted cyanophenyloxime, hydrogen bond donor molecules were synthesized and their effectiveness at forming co-crystals was examined. It was found that simple R group substitution could have a significant effect upon the co-crystal forming ability of the hydrogen bond donors, having improved the yield from 4% and 7% in a series of co-crystallizations with closely-related oximes, to 96% with the cyanoximes. A series of di- and tritopic cyanoximes were synthesized and an assessment of their co-crystal-forming ability was made. They were found to be equally effective at producing co-crystals as the monotopic cyanoximes, having done so in 23 out of 24 cases. In contrast to their carboxylic acid counterparts, the polycyanoximes also exhibited excellent solubility. Finally, a series of ditopic ligands (N-heterocyclic amide and pyridyl cyanoximes) were employed in the synthesis of metal complexes. The amide-based ligands were found to be very effective at organizing the metal architectures with coordination through the heterocyclic nitrogen atom and propagation of one-dimensional chains through carboxamidecarboxamide interactions. These interactions prevailed even in the presence of potentially disruptive species such as solvent molecules, (in Ag(I) complexes) counterions, or other hydrogen bond acceptors. The self-complementarity of the oxime moiety was found not to prevail in any of the cases, but the pyridyl cyanoximes were consistent in their behaviour, forming an O-H…O (oxime-oxygen) hydrogen bond to a carboxylate or acac moiety.

Halide perovskites have recently emerged as the state-of-the-art semiconductors with the unique combination of outstanding optoelectronic properties and facile solution synthesis. Within only a decade of research, they have witnessed a remarkable success in photovoltaics and shown great potential for applications in light-emitting devices, photodetectors, and high-energy sensors. Yet, the majority of current perovskite-based devices still rely on polycrystalline thin films which, as will be discussed in Chapter 2, exhibit inferior charge transport characteristics and increased tendency to chemical degradation compared to their single-crystalline analogues. In this regard, unburdened from the effects of grain boundaries, single crystals demonstrate the upper limits of semiconductor performance. Their study is, thus, important from both fundamental and practical aspects, which present the major objectives of this dissertation. In Chapter 3, we study the intrinsic charge transport and recombination characteristics of single crystals of formamidinium lead halide perovskites. While, in Chapter 4, we investigate the mechanistic origins of rapid synthesis of halide perovskite single crystals by inverse temperature crystallization. Understanding the nucleation and growth mechanisms of halide perovskites enables us to design strategies toward integrating their single crystals into device applications. Namely, in Chapters 5 and 6, we demonstrate crystal engineering approaches for tailoring the thicknesses and facets of halide perovskite single crystals to make them suitable for, respectively, vertical and planar architecture optoelectronic devices. The findings of this dissertation are expected to benefit future studies on fundamental characterization of halide perovskites, as well as motivate researchers to develop perovskite-based optoelectronic devices with better crystallinity, performance and stability.

No / Of particular importance in recent years has been the development of techniques for producing nanoparticles (NPs) of poorly-water soluble drugs with dimensions less than 1000 nm for which their high surface area can lead to improvements in bioavailability. Furthermore, the small size of these particles can also enable cellular uptake, particularly for positively charged systems. Therefore, an overall objective of this part of the project was to produce nanoparticles with different levels of positive surface charge using the bottom-up method.

No / We report on the templated growth of 2:1 benzoic acid/isonicotinamide co-crystal on a benzoic acid subphase. The molecular basis for the template, registry between the phases, is presented. The template growth of behavior of the title compound was contrasted with that from melt and solution. This approach may be applicable as a precursor for the synthesis of bulk composite crystals.

No / Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Kofler mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.

No / In this feature article we will focus on the issues relating to the crystal growth of co-crystals, with a particular emphasis on drug development. The initial focus of this perspective is on the relevant literature examples that may be able to inform our understanding with regards co-crystal crystallisation and the allied supramolecular concepts. The second part of this perspective contains selected examples from our own work, which add to the literature perspective. Topics include; nucleation templates, in situ synchrotron XRD studies, solid-state synthesis through mixing and screening strategies.