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.

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.

<p>Peptides are a fundamental building-block of living systems and play crucial roles at both functional and structural level. Therefore, they have attracted increased attention as a platform to design and engineer new self-assembled systems that span the nano-to-meso scales. The rules of peptide design and folding enable the construction of suitable building-blocks to develop soft materials for biomaterial applications. Herein we present the use of the alpha-helical secondary structure to create two distinct structural motifs, namely coiled-coils and helical bundles. These peptide components can differ in size and incorporate a host of different functional moieties, the effects of which are described through their hierarchical assembly. </p> <p>First, we describe the self-assembly of coiled coil oligomers (trimer and tetramer) of the GCN4 leucine zipper peptide. The trimeric coiled coil was modified with varying number of aromatic groups (one to three) along each helical backbone, to facilitate higher order assemblies into banded nano- to micron-sized structures, the formation of which could be controlled reversibly as a function of pH. In addition, the electrostatic and aromatic interactions of the peptide material were harnessed for non-covalent binding of small drug molecules, followed by their subsequent pH-triggered release. Furthermore, these nanostructures are compatible with MCF-7 breast cancer cells, making them suitable drug-delivery agents for chemotherapeutics. In the absence of aromatic modifications, the coiled-coil trimer assembles into higher-order nanotubes that can be harnessed for selective encapsulation of high molecular weight biomolecules. With an increase in oligomerization from three to four, along with a single aromatic group modification on each helix, the tetrameric coiled-coil mutant successfully demonstrates a metal-assisted two-tier structural assembly into microbarrels and spheres.</p> <p>Second, we present the higher-order assembly of short tetrameric and pentameric helical bundle proteins, covalently stabilized by a belt of disulfide bridges, with metal-binding ligands at each helix termini. The addition of metals like Zn(II) and Cu(II) promote the assembly of the bundles into a 3D globular matrix, which upon thermal annealing transforms into microspheres. Additionally, these microspheres also demonstrate the metal-assisted inclusion of His-tagged fluorophores. Thus, peptide-based materials can be constructed by self-assembly of alpha-helical building blocks into systems with sophisticated, diverse morphologies and dynamic chemical properties, that can be further modulated to enhance performance for medical applications. </p>

Ce travail traite de la synthèse et de la caractérisation de nouvelles cages moléculaires discrètes riches en électrons préparées via la méthodologie d'auto-assemblage dirigée par les métaux, ainsi que de leurs propriétés redox et d’encapsulation. Les concepts généraux guidant la méthodologie d’auto-assemblage pilotée par les métaux sont présentés. Trois types de ligands tétratopiques rédox-actifs (L) constitués de tétrathiafulvalène (TTF), de dithiol-fluorène (DTF) ou de tétrathiafulvalène π étendu (exTTF) ont été conçus. Leur capacité à générer des cages auto-assemblées avec divers complexes (M) a été étudiée. Dans le premier cas, des métallacages M8L2 dont la géométrie offre une opportunité unique de favoriser des interactions inter-TTF étroites au cours du processus d’oxydation ont été décrites. Ces interactions ont été confirmées par des études électrochimiques ainsi que par DRX à partir d’un sel oxydé électrocristallisé. Dans le second cas, plusieurs auto-assemblages discrets MxLy (cages, clips) ont été obtenus à partir de nouveaux ligands électroactifs basés sur l'unité 9- (1,3-dithiol-2-ylidène) fluorène (DTF). Leurs propriétés rédox ainsi que leur capacité à complexer des unités électro-déficientes sont fortement dépendantes de la géométrie de l’auto-assemblage. Concernant le ligand exTTF, de grandes métallacages électroactives M12L6 (environ 4 000 Å3) ont été obtenus par combinaison avec des complexes trans de palladium ou d'argent. Ces dernières se désassemblent lors de l'oxydation, donnant lieu à une transformation sans précédent d'une cage métallique discrète en un polymère de coordination. Enfin, un nouveau squelette aromatique benzo[1,2-b:4,5-b'] dithiophène est décrit en tant qu’alternative aux dérivés riches en électrons π étendus. Le rôle critique des interactions non-covalentes 1,5 S ···S est démontré par une approche combinée expérimentale et théorique. / This work deals with the synthesis and characterization of new electron-rich discrete molecular cages, prepared via the coordination-driven self-assembly methodology, as well as on evaluating their redox and host-guest properties. The general concepts guiding the metal-driven self-assembly methodology are presented. Three types of redox-active tetratopic ligands (L) featuring either a tetrathiafulvalene (TTF), a dithiol-fluorene (DTF) or a π-extended tetrathiafulvalene (exTTF) have been designed. Their ability to generate self-assembled cages upon combination with various metal complexes (M) has been studied. In the first case, M8L2 metallacages were obtained, whose geometry offers a unique opportunity to promote close inter-TTF interactions upon oxidation, as confirmed through electrochemical studies as well as from single-crystal DRX from an electrocrystallized oxidized salt. In the second case, several discrete self-assemblies MxLy (cages, clips) were obtained and characterized from new electro-active ligands based on the 9-(1,3-dithiol-2-ylidene)fluorene (DTF) unit. Their redox properties as well as their binding ability towards electro-deficient planar species show a strong dependence to the self-assembly geometry. Considering the exTTF ligand, large (ca. 4000 Å3) electroactive M12L6 metallacages were obtained from combining with trans palladium or silver complexes. Le latter exhibits a disassembling process upon oxidation, giving rise to an unprecedented redox-triggered transformation of discrete metalla-cage into a coordination polymer. Finally, a new benzo[1,2-b:4,5-b'] dithiophene aromatic scaffold is investigated as an alternative π-extended electron-rich derivative. The critical role of non-covalent 1,5 S···S interactions is demonstrated by a combined experimental and theoretical approach.

No description available.

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.

Nature has inspired chemists to develop complex assemblies that perform functions in biologically relevant solutions. Yet this is not a trivial task. Not only does water act as a competitive medium but the salts that are inevitably present hamper supramolecular hosts from properly binding and carrying out their programmed function. This work was inspired by a serendipitous discovery of water-soluble functionalized calix[4]arenes that self-assemble into homodimers in salty water, mock serum and real urine. This thesis aims to explore this homodimerizing motif to learn more about self-assembly in salty water and to develop useful supramolecular tools. First the structural limits of the calixarene motif was explored by the transformation into a clip-like host that assembled similarly in water. NMR titrations revealed that the homodimers responded to hydrophobic cationic guests by dissociating to form new host-guest complexes. The resilience of the self-assembling motif was then tested against extreme co-solute conditions. In this part of the study, reversible covalent bonds were introduced within the dimer scaffold to afford a dynamic library of exchangeable hosts. Quantitative NMR was used to monitor each host in response to molar concentrations of urea and salt. This work also reports on a new class of salt-tolerant supramolecular chemosensors, called DimerDyes. These sensors form quenched homodimers in water but dissociate in the presence of hydrophobic cations to form new emissive complexes. Its mode of action was characterized by DOSY, 1H NMR and fluorescence spectroscopy. DimerDyes successfully monitored enzymatic reaction in real-time despite the presence of competitive salts and co-factors. The DimerDye concept was quickly expanded by the parallel synthesis of crude DimerDyes and efficient testing for illicit drugs without the need for purification. “Hit” dimers were then purified, characterized and were able to detect multiple different drug classes in real saliva. / Graduate / 2020-09-19