Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / A family of six β-diketone based ligands capable of simultaneously acting as halogen-bond (XB) donors (each of para and meta substituted chloro, bromo and iodo functionalities) and chelating ligands was synthesized. Four ligands were characterized by X-ray diffraction to identify the structural behavior of the ligand itself. The free ligands bearing bromine and iodine show XB interactions (C-X···O) whereas the ligand containing chlorine did not show XB interactions. The corresponding Cu(II) complexes for ligands were also synthesized in different solvents such as acetonitrile, ethyl acetate and nitromethane. Both acetonitrile and ethyl acetate participate in XB interactions with XB donors (Br or I) although nitromethane does not participate in such interaction. Metal-ligand complexes with iodine as XB donor in the para position engage in XB interactions to make extended supramolecular architecture when the solvent is nitromethane. When the XB donor attached in the meta position of the ligand, formation of extended supramolecular architecture was seen even in the presence of a strongly coordinating solvent such as acetonitrile. Two tetra functionalized molecules bearing hydrogen-bond (HB) donors (-OH) and XB donors (-C≡C-I) and one tetra functionalized molecule which has only HB donors (-OH and -C≡C-H) were synthesized. The donor molecules themselves show potential for making HB and XB interactions with the available acceptor sites present in the system. The competition between intermolecular HB and XB was explored by co-crystallizing with suitable nitrogen based acceptors. HB and XB donors showed equal competitiveness toward common acceptors when making HB/ XB interactions. Furthermore, the geometry and relative positioning of the donor sites can, in certain cases, change the balance between the competing interactions by favoring HB interactions. A series of cavitands functionalized with XB donors, HB/XB donors and β-diketone have been synthesized. Binding preferences of XB and HB/XB cavitands towards a series of suitable HB/XB acceptors were studied in solid state and they have confirmed the presence of interactions between donor and acceptors. Cavitands with β-diketone functionality were subjected to binding studies with metal ions in solution as well as in the solid state. Successful metal-ligand complexation in solid state as well as in solution state based on UV/Vis titrations have been confirmed. In order to stabilize chemically unstable energetic compound, pentaerythritol tetranitrocarbamate (PETNC), a co-crystallization approach targeting the acidic protons was employed. A co-crystal, a salt and a solvate were obtained and the acceptors were identified as supramolecular protecting groups leading to reduced chemical reactivity and improved stability of PETNC with minimal reduction of desirable energetic properties. Several potential tetrazole based explosives which are thermal and impact sensitive and solid propellants which are impact sensitive were subjected to co-crystallization experiment to stabilize and enhance their properties. Co-crystals and salts of the explosives were obtained with suitable nitrogen based and oxygen based acceptors. The impact sensitivity and thermal instability of the explosives were improved with the introduction of co-formers. Oxygen based acceptors have shown more favorable explosive property improvements compared to nitrogen based acceptors with significant retention of explosive nature of the parent explosives.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / A set of multifunctional molecules [isomeric forms of 1-(pyridylmethyl)-2,2'-biimidazole] was synthesized and subjected to systematic co-crystallizations with selected hydrogen- and halogen-bond donors in order to explore the impact of interaction type, geometry and electrostatics on the resulting supramolecular architectures. The structural outcome with hydrogen-bond donors (carboxylic acids) is somewhat unpredictable because of the presence of the acid···biimidazole heterosynthon that can compete with biimidazole···biimidazole homosynthon. In contrast, the solid-state supramolecular behavior of those probe molecules is largely unchanged in halogen-bonded co-crystals. Only two types of primary interactions, the two-point hydrogen bonds responsible for pairing biimidazole moieties, and the single-point halogen bonds responsible for the co-crystal formation and structure extension, are present in these systems. The results highlight that, by incorporating geometric biases along with orthogonal interactions, one can effectively prevent synthon crossover which is of paramount importance in complex crystal engineering endeavors. Heterobifunctional ligands pave the way for elaborate metallo-supramolecular systems, and are also useful for combining metal-ligand bonding with other types of non-covalent interactions. Nine new acetylacetonate ligands featuring either pyridyl- or thiophenyl-heterocycles were successfully prepared, and their metal binding abilities were studied with selected di- and tri-valent transition metal ions. As expected, the acetylacetonate ligation to metal dications remains consistent. In each case, the metal is four-coordinate and resides in a square planar environment. Differences in the overall architectures arise from the role played by the terminal heterocycles and the solvent. In seven (out of nine) structures, the heterocyclic end is involved in a structure-directing interaction and it is more prevalent in ligands bearing 4-pyridinyl unit. Divergent molecules containing bulky substituents tend to produce porous materials via frustrated packing. Two rigid tetrahedral cores, tetraphenylmethane and 1,3,5,7-tetraphenyladamantane, grafted peripherally with four (trimethylsilyl)ethynyl moieties were found to have only isolated voids in their crystal structures. Hence, they were modified into tecton-like entities, tetrakis(4-(iodoethynyl)phenyl)methane [I₄TEPM] and 1,3,5,7-tetrakis(4-(iodoethynyl)phenyl)adamantane [I₄TEPA], and the effect of motif-forming characteristics of iodoethynyl units on molecular arrangement and crystal porosity was analyzed. I₄TEPM not only holds increased free volume compared to its precursor, but also forms one-dimensional channels. Furthermore, it readily co-crystallizes with Lewis basic solvents to afford two-component porous materials even though they suffer from stability issues. As the binding sites in I₄TEPM and I₄TEPA are tetrahedrally-predisposed, they can be further utilized for the modular assembly of highly symmetric, three-dimensional extended architectures. With that in mind, these two building blocks were subsequently allowed to react with various halide salts, and it was found that the reactions between I₄TEPM and tetraphenylphosphonium halides readily yield four-fold interpenetrated diamondoid networks sustained by C–I⋯X⁻ (X⁻ = chloride, bromide, iodide) halogen-bonding interactions. The halide anions exhibit mutual-induced fitting of their coordination and act as four-connecting tetrahedral nodes, while the tetraphenylphosphonium cations render essential templating information and structural support.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / A methodology for estimating hydrogen-bond preferences and binding affinities in solution, based on molecular electrostatic potential surfaces (MEPS), is presented using tritopic hydrogen bond acceptor and a series of aromatic carboxylic acids. The plot of calculated MEPS values against experimentally determined binding constants produces a goodness-of-fit of over 0.93 and a similar positive correlation is obtained between MEPS values and binding enthalpies. A series of tritopic N-heterocyclic compounds were synthesized and subjected to systematic co-crystallizations with selected multi-topic aliphatic and aromatic carboxylic acids to determine if ditopic and tritopic donors formulate assemblies with desired stoichiometries. The co-crystals formed contained the COOHᐧᐧᐧBzim synthon, and we observe vacant sites on the acceptor molecules. A series of co-crystallizations between tritopic N-heterocyclic compounds and perfluoroiodoarenes were carried to map out structural landscapes. At least one potential binding site on the acceptor is left vacant on all the four structures obtained. The absence of halogen bonds to all sites can be ascribed primarily due to deactivation of the σ-hole on the iodo-arene donors and partially due to steric hindrance. Four nonsteroidal anti-inflammatory (NSAID) drugs were chosen due to the presence of the COOH moiety, to establish if aqueous solubility can be modulated by systematic solubility measurements of the complex. Two different solids were obtained with a 1:1 and 1:3 stoichiometry. The solubility of the 1:1 co-crystal decreased by 12-fold compared to pure aspirin (3mg/mL at 20 °C) indicating that co-crystals can offer promising new solid forms of pharmaceutically relevant compounds. A series of hydrogen- and halogen bonding Tröger’s base derivatives were synthesized using aromatic N-heterocycles and the iodoethynyl functionality, followed by a series of co-crystallization between aliphatic dicarboxylic acids and symmetric ditopic acceptors. The results suggest that reducing the number of binding sites from three to two facilitates the formation of co-crystals with the desired stoichiometry. The results indicate that directed assembly can be achieved more easily when the molecular building blocks are conformationally rigid.

No description available.

Doctor Of Philosophy / Department of Chemistry / Christer Aakeröy / Crystal engineering, or non-covalent synthesis in the solid state, requires an understanding of intermolecular forces, and the hydrogen bond has become a reliable non-covalent tool in the construction of supramolecular architectures. In the same way that synthetic chemists refer to a “yield” to quantify a desired product, crystal engineers typically determine the successful formation of a supramolecular product according to the frequency or occurrence of preferred intermolecular interactions between molecules under certain reaction conditions, thus, the supramolecular yield. These non-covalent reactions can be effectively carried out using supramolecular reagents (SR’s). A family of ditopic bis-imidazol-1-yl/benzimidazol-1-yl compounds were synthesized and used as SR’s in combination with a variety of dicarboxylic acids to produce binary solids in 100% yield through the primary acid···imidazol-1-yl/benzimidazol-1-yl synthons even in the presence of potentially disruptive intermolecular interactions. We furthermore noted that secondary C–H···O interactions within and between 1-D chains were of equal structural importance based upon an analysis of the metrics displayed by these interactions. The use of these SR’s as ligands with neutrally charged metal complexes was also investigated. SR’s containing benzimidazol-1-yl and carboxamide moieties were synthesized and combined with two different carboxylic acids to make ternary solids through acid···benzimidazol-1-yl and carboxamide···acid hydrogen bonds using a hierarchical approach – the best donor-best acceptor, second best donor-second best acceptor guidelines. These SR’s were also employed as ligands for high-yielding syntheses of linear metal complexes where neighboring complexes are linked via carboxamide···carboxamide hydrogen bonds. Asymmetric SR’s possessing two different N-heterocycles were synthesized and employed in the construction of ternary supermolecules with a high degree of structural selectivity and specificity when introduced to two different carboxylic acids. The stronger acid interacts at the more basic site, while the weaker acid hydrogen-bonds with the less basic nitrogen atom. Finally, an SR containing three different binding sites was designed and synthesized with the aim of producing quaternary co-crystals.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19182号 / 工博第4059号 / 新制||工||1626(附属図書館) / 32174 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 北川 進, 教授 杉野目 道紀, 教授 濵地 格 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

No description available.

The results of the application of a density functional theory method incorporating dispersive corrections in the 2010 crystal structure prediction blind test are reported. The method correctly predicted four out of the six experimental structures. Three of the four correct predictions were found to have the lowest lattice energy of any crystal structure for that molecule. The experimental crystal structures for all six compounds were found during the structure generation phase of the simulations, indicating that the tailor-made force fields used for screening structures were valid and that the structure generation engine, which combines a Monte Carlo parallel tempering algorithm with an efficient lattice energy minimiser, was working effectively. For the three compounds for which the experimental crystal structures did not correspond to the lowest energy structures found, the method for calculating the lattice energy needs to be further refined or there may be other polymorphs that have not yet been found experimentally.

The knowledge of the packing behaviour of small organic compounds in crystal lattices is of great importance for industries dealing with solid state materials. The properties of materials depend on how the molecules arrange themselves in a crystalline environment. Crystal structure prediction provides a theoretical approach through the application of computational strategies to seek possible crystal packing arrangements (or polymorphs) a compound may adopt. Based on the chemical diagrams, this thesis investigates polymorphism of several small organic compounds. Plausible crystal packings of those compounds are generated, and their lattice energies are minimised using molecular mechanics and/or quantum mechanics methods. Most of the work presented here is conducted using two software packages commercially available in this field, Polymorph Predictor of Materials Studio 4.0 and GRACE 1.0. In general, the computational techniques implemented in GRACE are very good at reproducing the geometries of the crystal structures corresponding to the experimental observations of the compounds, in addition to describing their solid state energetics correctly. Complementing the CSP results obtained using GRACE with isostructurality offers a route by which new potential polymorphs of the targeted compounds might be crystallised using the existing experimental data. Based on all calculations in this thesis, four new potential polymorphs for four different compounds, which have not yet been determined experimentally, are predicted to exist and may be obtained under the right crystallisation conditions. One polymorph is expected to crystallise under pressure. The remaining three polymorphs might be obtained by using a seeding technique or the utilisation of suitable tailor made additives. / University of Bradford

The crystalline solid state is invaluable to both the pharmaceutical and fine chemical sectors. The advantages primarily relate to reducibility criteria required during processing of stable solid state materials and delivering purification, which is inherently performed by the crystal growth process. A major challenge is achieving control through crystallising solids with the desired physico-chemical properties. If this can be achieved the crystalline solid is of great financial and practical benefit. One emerging methodology for manipulating the solid crystalline form is the application of co-crystals. This work relates to key steps in the understanding of rational design of co-crystals utilizing crystal engineering concepts to determine systems before then applying screening criteria to the selected sub-set. 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. This led to the discovery of a number of co-crystal systems with the co-former nicotinamide, with the single crystal structures determined for the following systems; R/S ibuprofen: nicotinamide, S ibuprofen: nicotinamide, R/S flurbiprofen: nicotinamide and salicylic acid: nicotinamide. To assess the crystallization and phase behaviours of determined co-crystals the R/S ibuprofennicotinamide system was selected and successful studies were undertaken determining the aqueous ternary phase behavior and the pre-nucleation speciation in methanol. There have, as yet, been a limited number of published examples which are concerned with pharmaceutical property enhancement by co-crystals, as vast proportion of the literature concerns the growth and isolation of these novel phases. To elucidate further the pharmaceutical relevance of co-crystals the properties of the R/S ibuprofen- nicotinamide system were then assessed showing a positive profile for this material. / AstraZeneca and the University of Bradford / The accompanying "Experimental raw data files and cifs" are not available online.