Noncovalent and reversible covalent interactions have long been exploited in catalysis and supramolecular chemistry. Examples of such noncovalent interactions include hydrogen bonding, halogen bonding and CH-π and π-π interactions. Reversible covalent interactions that have been employed towards these ends comprise the formation of imines, acetals, ketals and boronate esters. This thesis describes the investigation of various noncovalent and reversible covalent interactions, and their possible applications in catalysis and novel reaction development. Chapter 1 describes the investigation of anion receptors composed of hydrogen- and halogen- bond donor groups. Binding studies of these molecules have indicated that they are capable of interacting with an anion simultaneously through hydrogen and halogen bonding. Receptor design was found to have a profound effect on the strength of the halogen bonding interaction. Receptors containing halogen-bond donors showed selectivity for halide anions over oxyanions. In Chapter 2, potential halogen bonding catalysts were synthesized and screened in a series of reactions. Incorporating halogen-bond donors into the catalysts appeared to have no beneficial effect in terms of reactivity. Explanations for these observations are discussed along with suggestions for designing future catalysts that could exploit halogen bonding interactions. Chapter 3 discusses attempts to use hydrogen-bond donor catalysts to effect catalyst-controlled stereoselective additions to 2-nitroglycals. While stereoselective additions were observed in some cases, they were not catalyst-controlled. The results from these experiments suggested that catalysts and reactions developed for simple nitroalkenes could not be easily adapted to 2-nitroglycal substrates. A review of interactions between boron containing compounds and saccharides is presented in Chapter 4. Their applications in drug delivery systems, cellular imaging and the sensing and separation of carbohydrates are discussed, in addition to their uses as protecting and activating groups in oligosaccharide synthesis. Finally in Chapter 5, the development of a regioselective boronic acid-mediated glycosylation reaction is described. This methodology was applied in the synthesis of two key intermediates used in the synthesis of a pentasaccharide derivative isolated from the plant Spergularia ramosa.

Noncovalent and reversible covalent interactions have long been exploited in catalysis and supramolecular chemistry. Examples of such noncovalent interactions include hydrogen bonding, halogen bonding and CH-π and π-π interactions. Reversible covalent interactions that have been employed towards these ends comprise the formation of imines, acetals, ketals and boronate esters. This thesis describes the investigation of various noncovalent and reversible covalent interactions, and their possible applications in catalysis and novel reaction development. Chapter 1 describes the investigation of anion receptors composed of hydrogen- and halogen- bond donor groups. Binding studies of these molecules have indicated that they are capable of interacting with an anion simultaneously through hydrogen and halogen bonding. Receptor design was found to have a profound effect on the strength of the halogen bonding interaction. Receptors containing halogen-bond donors showed selectivity for halide anions over oxyanions. In Chapter 2, potential halogen bonding catalysts were synthesized and screened in a series of reactions. Incorporating halogen-bond donors into the catalysts appeared to have no beneficial effect in terms of reactivity. Explanations for these observations are discussed along with suggestions for designing future catalysts that could exploit halogen bonding interactions. Chapter 3 discusses attempts to use hydrogen-bond donor catalysts to effect catalyst-controlled stereoselective additions to 2-nitroglycals. While stereoselective additions were observed in some cases, they were not catalyst-controlled. The results from these experiments suggested that catalysts and reactions developed for simple nitroalkenes could not be easily adapted to 2-nitroglycal substrates. A review of interactions between boron containing compounds and saccharides is presented in Chapter 4. Their applications in drug delivery systems, cellular imaging and the sensing and separation of carbohydrates are discussed, in addition to their uses as protecting and activating groups in oligosaccharide synthesis. Finally in Chapter 5, the development of a regioselective boronic acid-mediated glycosylation reaction is described. This methodology was applied in the synthesis of two key intermediates used in the synthesis of a pentasaccharide derivative isolated from the plant Spergularia ramosa.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The impact of the molecular electrostatic potential values (MEPs) in halogen and hydrogen bond interactions were explored using two acceptors with multiple acceptor sites with twelve hydrogen-bond donors, five halogen bond donors and four mixed halogen and hydrogen bond donors. The results suggested if the difference between the two acceptor sites is above 38 kJ/mol both hydrogen and halogen bond donors prefer the acceptor site with the highest MEP value and this selectivity was lost if the difference is below 26 kJ/mol. To examine the potential of halogen-bond donors in organocatalysis, a halogen-bond donor molecule was synthesized and the catalytic activity was measured using a benchmark Ritter type solvolysis reaction. Results suggested the catalytic activity of the halogen-bond donor molecule with > 90 % conversion of the product with the use of a stoichiometric amount of the catalyst for 96 hrs. Successful use of the control molecules confirm that the catalytic activity is an outcome of having halogen-bond donors in the molecule. The benefit of using a structural mimic in landscaping the structural outcomes of poorly soluble molecules was explored using an anticancer drug erlotinib. A structural mimic was synthesized by maintaining all binding sites that are important to design a structural landscape and the structural outcomes were analyzed using five FDA approved dicarboxylic acids. The results suggested that the structural outcomes of the mimic can be related to the actual drug erlotinib. Solubility and thermal behavior analysis of the co-crystals also suggested that with the systematic changes of the co-crystallization agent, it is possible to make predictable changes to the physical properties. To observe the effect of co-crystallization technology in reducing the chemical reactivity and sensitivity of an energetic compound dinitrobenzotriazole, a series of co-crystallization experiments was carried out using fourteen nitrogen and oxygen based acceptors. Four co-crystals were obtained and the acceptors were identified as supramolecular protecting groups which led to successful diminish of chemical instability and decreased impact sensitivity. Hygroscopicity and chemical reactivity of tetranitrobisimidazole, a potential RDX replacement, was successfully decreased by protecting the acidic N-H protons in the molecule by introducing suitable co-formers. Introduction of the N-oxide based acceptors into the system enhanced the stability while retaining most of the desirable energetic properties.

The halogen bond has recently risen in prominence as a non-covalent interaction for use in supramolecular chemistry, allowing for the rational design of materials, pharmaceuticals, and functional molecules. The occurrence of the σ-hole opposite to the C-X covalent bond (X = F, Cl, Br, I) renders the halogen bond a highly directional and tuneable interaction, offering desirable features to crystal engineers. The halogen bond can be divided into its two components: the halogen bond donor bearing the halogen atom, and the electron-rich halogen bond acceptor. In this thesis, we investigate the nature of the halogen bond, its role in supramolecular assembly and impact on the local dynamics, along with developing synthetic methods to prepare this class of materials. We begin by fully characterizing the halogen bond donor by using 35Cl ultra-wideline solid-state nuclear magnetic resonance (NMR) spectroscopy on a series of single-component chloronitriles exhibiting the C-Cl···N halogen bond. We then perform the first modern nuclear quadrupole resonance (NQR) investigations of the halogen bond, observing the 79/81Br and 127I nuclei in a series of cocrystals exhibiting the C-Br···N and C-I···N halogen bond, respectively. Computational results attribute the observed increases in the quadrupolar coupling constants (CQ) to a reduction in the carbon-halogen σ-bonding contribution to V33 and an increase in the lone-pair and core orbital contributions, providing the first model of the electronic changes occurring on the halogen bond donor upon the formation of the halogen bond. Attention is then turned on characterizing the halogen bond acceptor and its surrounding environment, beginning by investigating a solid-state NMR approach relying on the 19F nucleus to characterize perfluorinated cocrystals. This strategy has reduced analysis times from hours to minutes while providing higher sensitivity and resolution, with the resulting chemical shifts permitting the unambiguous identification of the halogen bond and allowing for the refinement of X-ray crystal structures. The halogen bond acceptor is then investigated in a series of isomorphous dimers exhibiting both the halogen bond and hydrogen bond in the C≡C-I···X-···H-N+ motif, revealing the halogen bond’s relative contribution to the electric field gradient increasing in the order of Cl- > Br- > I-, contrasting the contributions of the hydrogen bond. We then explore the impact of the halogen bond on the surrounding environment, using the rotating methyl groups of 2,3,5,6-tetramethylpyrazine as a model. Upon the introduction of a halogen bond, we observe a reduction in the rotational energy barrier of 56% on average, overshadowing the 36% reduction observed in the hydrogen bonded cocrystals. This is the first instance of the halogen bond directly catalyzing the local dynamics, coining the term “dynamics catalyst”. These results provide an effective strategy of enhancing the dynamics in molecular systems, such as molecular machines, supramolecular catalyst, as well as correcting the faulty dynamics encountered in diseased proteins. The role of halogen bonding in crystal engineering is then explored, reporting the first supramolecular triangle, a series of discrete charged dimers, and supramolecular architectures built from 1,3,5-tri(iodoethynyl)-2,4,6-trifluorobenzene, with the potential of creating fully organic porous structures for gas absorption. Mechanochemistry is then investigated as a synthetic method, allowing for the preparation of cocrystals featuring 3-iodoethynylbenzoic acid as the donor, with the resulting structures exhibiting concurrent halogen and hydrogen bonding. Mechanochemical ball milling is shown to reduce preparation times of powdered cocrystals from days to a single hour, while using a fraction of the organic solvent. Lastly, we pioneer cosublimation as a solvent-free synthetic technique for rapidly preparing halogen bonded cocrystals, yielding quality single crystals within a few hours, and a microcrystalline product within 15 minutes. Among its advantages, cosublimation offers a significant acceleration of discovery, while eliminating the environmental footprint associated with conventional synthetic methods.

This thesis describes the synthesis of interlocked anion host systems which exploit hydrogen bonding, halogen bonding, and lanthanide-coordination for anion recognition and sensing in aqueous solution. Chapter 1 introduces the field of anion supramolecular chemistry, with particular focus on areas of particular relevance to this thesis, namely anion recognition and sensing, anion templation and the synthesis of interlocked structures. Chapter 2 describes the synthesis of hydrogen bonding rotaxane and catenane hosts for recognising and sensing oxoanions in aqueous solvent media. The novel use of nitrate anion templation for the synthesis of interlocked molecules is reported, and the unprecedented selective recognition of nitrate in aqueous solvent media is demonstrated. Chapter 3 details the preparation of water soluble permethylated β-cyclodextrin-stoppered rotaxane hosts that utilise halogen bonding and hydrogen bonding interactions to bind anions in pure water. The first thermodynamic investigation into halogen bonding in water is reported, and the relative capabilities of halogen and hydrogen bonding for anion recognition in water are compared. Chapter 4 investigates the incorporation of lanthanide cations into rotaxane hosts for optical anion sensing. The seminal use of lanthanide cation templation for interlocked molecule synthesis is described, before anion templation approaches towards the synthesis of lanthanide-based rotaxanes are discussed. The luminescence anion sensing capabilities of these interlocked hosts are investigated. Chapter 5 describes the experimental procedures used in this work, and details the characterisation of compounds presented in Chapters 2–4. Chapter 6 summarises the conclusions of this thesis.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / A family of three 2-aminopyrazine derivatives were prepared and co-crystallized with thirty carboxylic acids. Our theoretical charge calculations and experimental results from 90 reactions demonstrated that decreasing the charge on the hydrogen-bond acceptor sites results in a decrease of the supramolecular yield (the frequency of occurrence of the desired outcome). However, synthon crossover (undesired connectivity) was observed 7/12 times and was unavoidable due to competitive binding sites present in the N-heterocyclic bases chosen. To avoid synthon crossover, we used a strategy based on geometric bias. We utilized hydrogen-bonding two-point contacts and halogen-bonding single-point contacts for supramolecular reactions with the 2-aminopyrazine family of compounds. The desired two-point contact and single-point contact (N•••I or N•••Br) appeared in 9/9 times even in the presence of other potentially interfering intermolecular interactions. In addition, the role of charge in controlling the presence/absence of proton transfer was also highlighted. To establish a hierarchy in halogen-bonding interactions we designed and synthesized a library of eight molecules equipped with two different halogen bond donors and combined with variety of halogen-bond acceptors. 11 Halogen-bonded co-crystals were obtained; however, positional disorder of I/Br atoms obscures a complete analysis. This problem was solved by introducing asymmetry in the halogen-bond donor molecules. Finally, successfully demonstrated an unprecedented hierarchy in halogen-bond interactions based on electrostatics. We developed high-yielding Suzuki-Miyaura coupling reactions of tetraboronic pinacolyl ester cavitand to iodoarenes with a range of functional groups (electron withdrawing/donating group and a heterocycle) that show robustness and versatility, making it a ‘launch pad’ for the synthesis of many new cavitands in a facile manner. We have also successfully demonstrated cavitand functionalization from tetraaldehyde to tetraoximes using ‘solvent assisted grinding’, irrespective of the position of the aldehyde. Finally, we prepared tetra-substituted pyridyl and carboxylic acid cavitands having an ellipsoidal cavity capable of encapsulating asymmetric guest molecules and was subsequently obtained the first of its kind, C[subscript]2v symmetric molecular capsule with encapsulated asymmetric guest molecule.

Au cours de ces travaux de thèse, nous avons exploré de nouvelles applications des proazaphosphatranes et de leurs dérivés, en particulier leur confinement dans une cage moléculaire. Dans la première partie, une bibliographie présente la littérature concernant (i) la découverte et les applications de proazaphosphatranes, (ii) les catalyseurs confinés dans des cages covalentes et (iii) la liaison halogène - une interaction non covalente émergente-. Par la suite, l’utilisation de proazaphosphatranes comme organocatalyseur très efficace pour la réaction de Strecker est décrit. Ensuite, un système FLP (paire de Lewis frustrée) comprenant un proazaphosphatrane encagé comme base de Lewis et du TiCl4 comme acide de Lewis a été utilisé pour catalyser la réaction de MBH (Morita-Baylis-Hillman). Finalement, un azaphosphatrane chloré a été synthétisé, et ses propriétés de reconnaissance vis à vis de différents anions halogénures, par liaison halogène, a été étudié. / In this dissertation, our goal is to explore new applications of proazaphosphatranes and their derivatives, especially in a confined space. In the first part, a comprehensive literature review regarding 1) discovery and application of proazaphosphatranes, 2) confined covalent cages based organo- and metal-catalysts, and 3) halogen bonding – an emergent noncovalent interaction has been demonstrated. Subsequently, proazaphosphatrane as highly efficient organocatalyst for the Strecker reaction is discussed. And a FLP (frustrated Lewis pair) system comprising an encaged proazaphosphatrane as Lewis base and TiCl4 as Lewis acid for MBH (Morita–Baylis–Hillman) reaction is reported. In the end, chlorinated azaphosphatrane is synthesized and studied in the recognition of different halide anions by halogen bonding, exhibiting a preferable affinity for chloride over bromide and iodide.

Halogen bonding (XB), the interaction between electron deficient halogen compounds and electron donors, is an established non-covalent interaction in the solid and gaseous phases. Understanding of XB in the solution phase is limited. This thesis describes experimental studies of XB interactions in solution, and the application of XB interactions in anion recognition. Chapter 1 is a brief review of current understanding of XB interaction: theoretical models, studies of XB in solid and gaseous phases and examples in biological systems are discussed. At the end of this chapter, halogen bonding in the solution phase is discussed, along with applications of halogen bonding in organic syntheses. In chapter 2, linear free energy relationships involving the thermodynamics of halogen bonding of substituted iodoaromatics are studied. The utility of substituent constants and calculated molecular electrostatic potential values as metrics of halogen bond donor ability are discussed. Density Functional Theory (DFT) calculations are shown to have useful predictive values for trends in halogen bond strength for a range of donor-acceptor pairs. Chapter 3 describes the development of new multidentate anion receptors based on halogen bonding. Bidentate and tridentate receptors were found to exhibit significantly higher binding constants than simple monodentate donors. These receptors show selectivity for halide anions over oxyanions. Using 19F NMR spectra at different temperature, the enthalpies and entropies of anion bindings for monodentate and tridentate receptors were determined. The results indicate a positive entropy contribution to anion binding for both mono and tridentate receptors in acetone solvent. Finally in chapter 4, some mesitylene based receptors with 3-halopyridinium and 2-iodobenzimidazolium donors are introduced. The receptors perform halide anion recognition in aqueous solvent system through charge-assisted XB interactions. These findings can allude to utility in organic synthesis, supramolecular chemistry and drug design.

Halogen bonding (XB), the interaction between electron deficient halogen compounds and electron donors, is an established non-covalent interaction in the solid and gaseous phases. Understanding of XB in the solution phase is limited. This thesis describes experimental studies of XB interactions in solution, and the application of XB interactions in anion recognition. Chapter 1 is a brief review of current understanding of XB interaction: theoretical models, studies of XB in solid and gaseous phases and examples in biological systems are discussed. At the end of this chapter, halogen bonding in the solution phase is discussed, along with applications of halogen bonding in organic syntheses. In chapter 2, linear free energy relationships involving the thermodynamics of halogen bonding of substituted iodoaromatics are studied. The utility of substituent constants and calculated molecular electrostatic potential values as metrics of halogen bond donor ability are discussed. Density Functional Theory (DFT) calculations are shown to have useful predictive values for trends in halogen bond strength for a range of donor-acceptor pairs. Chapter 3 describes the development of new multidentate anion receptors based on halogen bonding. Bidentate and tridentate receptors were found to exhibit significantly higher binding constants than simple monodentate donors. These receptors show selectivity for halide anions over oxyanions. Using 19F NMR spectra at different temperature, the enthalpies and entropies of anion bindings for monodentate and tridentate receptors were determined. The results indicate a positive entropy contribution to anion binding for both mono and tridentate receptors in acetone solvent. Finally in chapter 4, some mesitylene based receptors with 3-halopyridinium and 2-iodobenzimidazolium donors are introduced. The receptors perform halide anion recognition in aqueous solvent system through charge-assisted XB interactions. These findings can allude to utility in organic synthesis, supramolecular chemistry and drug design.

There are currently three known crystal packing motifs of boronsubphthalocyanine derivatives. Each motif is associated with a particular class of BsubPc derivatives, and none are ideal for organic electronic applications according to the criteria we defined for evaluation: having a continuous pathway for charge-carrier conduction in the solid-state, resistance to hydrolysis, good electrochemical and optical properties, and possession of a robust crystal form. In this thesis, we present five methods for altering the crystal packing structure of phenoxy-BsubPc derivatives in order to meet the above four criteria. We find that neither addition of steric bulk to the axial derivative nor changing the symmetry of the compounds is sufficient for creating a new crystal packing motif. We do find that reducing the symmetry of the axial group does increase the solubility greatly, however. We identify a new motif for BsubPc crystals that occurs when the intermolecular interactions between the axial phenoxy segment and the BsubPc ligand are increased. We present two methods for achieving this new motif, one is through addition of a π-Br interaction and the other is through creation of a strong π-acid/ π-base stacking by making the axial phenoxy more π-electron rich. Unfortunately, the p-bromophenoxy-BsubPc forms this new motif as a kinetic product, isolation of which is unreliable. Attaching a naphthol fragment axially to the BsubPc creates a stable version of this new motif. We also synthesized a new class of BsubPc pseudohalides based on sulfonate derivatives. Of the derivatives in this new class, we found that mesylate-BsubPc forms into a crystal packing structure that possesses a one-dimensional pathway for charge carrier mobility, but is still resistant to hydrolysis under the conditions tested. Overall, we show four compounds that meet the criteria for further study as organic electronic materials: p-methoxyphenoxy-BsubPc, α-naphthoxy-BsubPc, β-naphthoxy-BsubPc, and mesylate-BsubPc.