Only within the last decade has supramolecular chemistry begun to adopt the Group 15 elements into its field of research. This dissertation presents a supramolecular approach to the self-assembly and reactivity of Group 15 metalloids, specifically arsenic and antimony, with organothiolate ligands. Investigating the self-assembly of pnictogen-based coordination complexes allows for in-depth characterization of the chemical behavior of arsenic, antimony and other Group 15 elements. Currently, the infiltration of arsenic into global groundwater systems has developed into a worldwide health concern. There are no chelating agents available for public use in the treatment of arsenic poisoning which are capable of binding arsenic (III) in its preferred coordination geometry thereby hindering the selectivity for rapid chelation. Chapter I is a review covering two important characteristics observed in the Group 15 elements: 1) a stabilizing, non-covalent cation-π interaction aiding in the formation of pnictogen-aryl thiolates, and 2) an observed lack of selectivity in environments containing multiple pnictogen ions which enables transmetalation of the complexes to occur or the generation of heterometallic assemblies. Based on the discovery of this new transmetalation reactivity, the remainder of the dissertation explores the effects of external additives during self-assembly in order to understand how they may affect the reactivity of these self-assembled complexes and provide insight into formation mechanisms. Chapter II identifies a catalyst for the acceleration of a slow self-assembly reaction between AsCl3 and a dithiolate ligand to give an As2L3 cryptand. Chapter III examines the oxidation of the arsenic cryptand using iodine, which leads to the self-assembly of a series of differently sized, discrete disulfide-bridged macrocycles. In Chapter IV, the self-assembly of the first trinuclear arsenic- and antimony-based coordination complexes was studied, revealing interesting solvent dependent conformational isomerism in solution. Chapter V applies the pnictogen-enhanced iodine oxidation to the synthesis of known and new cyclophanes using supramolecular chemistry, including the self-assembly and covalent capture of an unprecedented tetrahedral thiacyclophane. Additionally, an unusual trithioorthoformate capped tricyclophane cage was also synthesized and isolated by pnictogen-activated oxidation. Chapter VI includes the conclusion and future directions for the project. This dissertation includes co-authored material and previously published results. / 10000-01-01

"Self-assembled monolayers (SAMs) are organized molecular assemblies that are formed by spontaneous adsorption of a compound in solution to a surface (e.g. alkanethiols on gold). The design, preparation, and characterization of several self-assembled monolayers and multilayers on surfaces (gold, indium tin oxide and quartz) are described. The systems were chosen based on their ability to form ordered films and to perform a given device function. SAMs were fabricated with selected functional groups at the air-monolayer interface, capable of complexing metal ions (e.g. dicarboxypyridine, dicarboxybenzene, imidazole, 4-hydroxypyridine) with the purpose of using these SAMs to construct multilayered films. Deposition of a second layer consisting of metal ions (e.g. Cu(II), Co(II) and Fe(III)), occurs by non-covalent metal ligand binding interactions between the metal ion layer and the different organic ligands on the surface. Deposition of subsequent layers was achieved by the incorporation of the appropriate organic ligands and metal ions. These monolayers and multilayered films were characterized by contact angle measurements, ellipsometry, grazing angle FT-IR, cyclic voltammetry and impedance spectroscopy following deposition of each layer on the film. Electrochemical analysis of the multilayered films shows alternating insulating/conducting behavior (cyclic voltammetry) and alternating changes in films capacitance (impedance spectroscopy) depending on the outermost layer of the film. Films capped with an organic layer show low conductivity, while films capped with a metal layer show conducting behavior. The electrochemical behavior of the films is related to the degree of “leakiness” or electrolyte solution permeation through the film, which is high for films with metal layers as the top layer and decreases once the film is capped with an organic layer. The alternating conducting/insulating behavior of the films allows for fabrication of multilayered thin films of variable thickness and tunable conducting properties. Ordered films were fabricated with up to seven layers of dicarboxypyridine and Cu(II), and 4-hydroxypyridine and Fe(III) metal-ligand units. The construction of these films provides an example of molecular films that could function as molecular wires or junctions due to their controllable electrochemical properties. Photocurrent generating films were fabricated by incorporation of chromophore groups (e.g. pyrene, porphyrins) into the multilayered structures. These films generate cathodic or anodic current upon photoexcitation of the chromophores. The monolayers functionalized with different organic ligands were also used to study lanthanide complexation on the surfaces. Successful deposition of different lanthanide ions was achieved from DMSO solutions. Monolayers of a bicyclic structure, 4, 7, 13, 16-tetraoxa-1,10,21-triaza-bicycle[8.8.5] tricosane-19,23-dione, attached to a hexadecanethiol molecule were used to study the ability of metal ion detection on the surface using electrochemical (cyclic voltammetry and impedance spectroscopy) techniques. The SAMs show higher complexation affinity for Li+ than for Na+ or K+. Preliminary studies were also carried out to investigate the ability of different SAMs to cell adhesion interactions. Future experiments will help elucidate a systematic relation of cell adherence and the bulk and molecular-level properties of the functionalized surfaces. The different multilayered films described in this dissertation served as preliminary models for different molecular scale device applications. Current work is focused in the design and preparation of more efficient photocurrent generating films, highly selective sensors for different types of ions, surfaces for cell adhesion and microbial interactions, and the study of other potential applications such as the design of micro and nanofluidic devices. "

Metabolism of xenobiotic drug molecules can result in the formation of metabolites which are more chemically reactive than the parent drug from which they are derived. These reactive species have the potential to covalently modify biological macromolecules if they are not detoxified. The formation of drug-protein adducts carries a potential risk of clinical toxicities and idiosyncratic adverse drug reactions which can, in severe cases, result in hospitalisation and even death. Current methods for the evaluation of the risk for a drug to cause adverse drug reactions due to drug-protein binding rely on risk factors such as quantitative covalent binding value, structure, dose etc. The objective of this project was to develop methods for the detection of reactive metabolites directly bound to proteins, which could be used in future evaluations of the mechanisms of binding of candidates in drug development. Three compounds known to produce reactive metabolites, acetaminophen, SB-648969 and amodiaquine, were used as tool substrates. In vitro incubations with human liver microsomes and individual cytochrome P450 enzymes (as Supersomes ) were used to produce reactive metabolite species and binding with the incubation proteins evaluated. Analysis of the intact proteins, peptides generated via trypsin digestion of the incubation protein, and amino acids generated via digestion with pronase were evaluated using a combination of LC/MS and LC-MS/MS. Reactive metabolite trapping experiments with glutathione were used to provide information about the likely structure of the bound species and the specificity of binding, and were useful in the development of sensitive targeted precursor ion scanning and multiple reaction monitoring methods. [14C] radiolabelled acetaminophen and SB-649868 were used to assess the quantitative levels of binding (<5% modification of protein in both cases). Radiodetection using accelerator mass spectrometry (AMS) was used to evaluate the stoichiometry of binding and aid the identification of adducted peptides through retention time comparison. Chemical and electrochemical methods were utilised to produce stable solutions of N-acetyl-p-benzoquinone imine (NAPQI) and amodiaquine quinone imine (AQQI), reactive metabolites of acetaminophen and amodiaquine, respectively, which were bound to selected proteins and used as chromatographic and mass spectrometric standards. These methods were used to successfully identify an acetaminophen-modified peptide (T56) of cytochrome P450 CYP2E1. No modified proteins were observed for the SB-649868 incubations, however, examination of the AMS chromatograms for the incubations with acetaminophen and SB-649868 revealed a difference in the stoichiometry of binding, with one modified peptide observed with acetaminophen, and several for the incubations with SB-649868. The detection and identification of drug-protein adducts remains extremely challenging due to the low levels of any adducts observed, which can be exacerbated by binding on multiple sites of a protein; however this project has demonstrated that sensitive and selective LC/MS methods can be successfully developed to identify drug-protein adducts.

Pour contrôler les systèmes chimiques complexes, les outils de la chimie supramoléculaire s’avèrent puissants et représenteront certainement une des technologies clef du 21e siècle. En effet, la réversibilité intrinsèque des liaisons chimiques impliquées dans la formation d'assemblages supramoléculaires apporte à ces systèmes un caractère "adaptatif", capable de réorganiser leur structure en fonction des conditions environnementales. Ce comportement s’avère totalement inédit malgré le grand nombre d’études effectuées sur cette famille de molécules du fait de ses propriétés photoactives. Au cours des dernières années, notre groupe a synthétisé de nombreux dérivés de triarylamines (TAAs), qui ont été utilisés pour produire des architectures supramoléculaires multifonctionnelles. En fonction des différents groupements qui substituent ce coeur TAA, diverses morphologies ont pu être observées et les propriétés physiques de ces auto-assemblages produits dans des solvants non polaires tels que les solvants chlorés ou le toluène se sont également révélées variées (propriétés cristal-liquide, conductrices, plasmoniques...). A partir de ces travaux, mon projet de thèse consistait en deux objectifs: a) étudier l'auto-assemblage et les propriétés de ces composés TAA dans des solvants polaires comme l'eau ou le méthanol. Pour cela, comme tenu du caractère hydrophobe des TAAs, il s'avérait nécessaire de synthétiser de nouvelles molécules incorporant des groupements latéraux favorisant la solubilité dans de tels solvants; b) stabiliser les auto-assemblages de triarylamine par polymérisation covalente et étudier les propriétés physiques associées à ces nouvelles structures. Pour cela, il convenait de synthétiser de nouvelles molécules incorporant des groupements polymérisables sur les chaines latérales, qui n'influençaient pas les propriétés d'auto-assemblages des TAAs. [...] / Based on the unique directionality and reversibility of non-covalent interactions, supramolecular self-assembly works as an elegant methodology to construct multifunctional hierarchical architectures. Inspired by nature, where water provides a vital environment for biological process such as biomacromolecular folding, water-soluble supramolecular polymers have been prepared and studied so as to mimic related biological systems. On the other hand, owing to the dynamic nature of their non-covalent bonds, supramolecular polymers often lack mechanical robustness. Thus, cross-linking strategies have been developed in order to combine highly ordered molecular arrangement inherent to the sef-assembly and mechanical robustness of the covalent backbone, which might bee promising to reach functional materials for practical applications. In this thesis, we focus on well-designed triarylamine molecules which are known to self-assemble into supramolecular polymers with excellent physical properties, as discovered by our group. In particular, molecules studied in this manuscript are based on tris-amide triarylamine scaffold known to produce self-assemblies with metallic conductivity and self-healing behavior. First, we studied the self-assemblies of three novel tris-amide triarylamine derivatives decorated with either poly(ethylene glycol) (PEG), peptide or cyanine dyes side chains on the three amide positions in polar solvents, i.e. either water or methanol. Characterizations by various physico-chemical techniques (NMR, UV-Vis absorption, fluorescence, infrared spectroscopies, microscopies, scatterings) demonstrated the formation of fibrillar aggregates for all molecules in such polar environments. Overall, this study suggest that the triarylamine core act as the main driving force for the self-assembly into columnar aggregates while side chains ensure solubility in these solvents and/or favor the formation of chiral architectures. In a second study, we investigated the formation of tris-amide triarylamine supramolecular polymers decorated with norbornene and siloxane end side chains, which could be further used to freeze the self-assembled structures by ring opening metathesis polymerization and sol-gel methods, respectively. [...]

Small molecule walkers developed to date take advantage of the reversibility of dynamic covalent bond formation to transport molecular fragments along molecular tracks using both diffusion processes and ratchet mechanisms. However, external intervention (the addition of chemical reagents and/or irradiation with light) is required to mediate each step taken by the walker unit in systems reported so far. In this Thesis, the first synthetic small molecule able to walk back-and-forth upon an oligoethylenimine track without external intervention via intramolecular Michael and retro- Michael reactions is described. The 1D random walk is highly processive and exchange takes place between adjacent amine groups in a stepwise fashion. The walker is used to perform a simple task: quenching of the fluorescence of an anthracene group situated at one end of the track as a result of the walking progress. In the presence of excess of base, the molecule preferentially ‘walks’ towards the favoured final foothold of tracks of increasing length and it is possible to monitor the population of all or a few positional isomers over time. In each case the molar fraction of walkers reaching the final foothold is determined quantitatively by 1H NMR. Control over the rate of exchange is achieved by varying the amount of base added. The dynamic migration of a small molecule upon the track is a diffusion process limited to one dimension and as such can in principle be described using the one dimensional random walk. Chapter I identifies a set of fundamental walker characteristics and includes an overview of the DNA-based and small molecule transporting systems published to date. Chapter II describes the inspiration for this work and model studies which lay the groundwork for the research presented in this thesis. The initial track architecture and optimisation of reaction conditions are demonstrated using a simple model compound which then led to the development and a detailed investigation of a first synthetic small molecule able to walk upon an oligoethylenimine track without external intervention. Chapter III presents a modified synthetic route towards the desired walker-track architectures and a comprehensive investigation of the dynamic properties of a series of tracks of increasing length upon which the walker migrates in a unidirectional fashion. The Outlook contains closing remarks about the scope and significance of the presented work as well as ideas for the design of novel small-molecule walkers, some of which are well under way in the laboratory. Chapter II (with the exception of model studies included at the beginning of the chapter) is presented in the form of article that has recently been published. No attempt has been made to re-write this work out of context other than merging content of the article with the supplementary information published together with the article. Chapter II is reproduced in the Appendix in its published format.

Non-covalent interactions in solution are subject to modulation by surrounding solvent molecules. This thesis presents two experimental molecular balances that have been used to quantify solvent effects on non-covalent interactions, including electrostatic and dispersion interactions. The first chapter introduces literature where non-covalent interactions have been studied in a range of solvents, particularly those where the effects of aqueous or fluorous solvents have been investigated. These solvents are of particular interest as they both invoke solvophobic effects on organic molecules, but have differing chemical and physical properties. The second chapter describes the adaptation of the Wilcox molecular torsion balance to study interactions between organic and fluorinated carbon chains in a range of solvents. Solvent cohesion was found to be the principle force driving both the alkyl and fluorous chains together in aqueous solvents, where no contribution to the interaction energy arising from dispersion forces could be detected. In fluorous and polar organic solvents evidence was found for weak favourable dispersion interactions between the alkyl chains. In contrast dispersion forces between the chains were found to be disrupted by competitive van der Waals interactions with surrounding solvent molecules in apolar organic solvents. Association of the fluorous chains was found to be solely driven by solvent cohesion. The final chapter describes the design and synthesis of a novel synthetic molecular-balance framework and describes its application to simultaneously measure solvent and substituent effects on the position of conformational equilibria. Despite the simplicity of the model system, surprisingly complicated behaviour emerged from the interplay of conformational, intramolecular and solvent effects. Nonetheless, a large data set of experimental equilibrium constants was analysed using a simple solvent model, which was able to account for both the intuitive and more unusual patterns observed. A means of dissecting electrostatic and solvent effects to reveal pseudo gas-phase behaviour has resulted from the analysis of experimental data obtained in many solvents.

L'intégration de molécules électroactives dans des composants électroniques suscite un intérêt croissant en raison de la miniaturisation constante des dispositifs de microélectronique. Dans ce contexte les propriétés redox des polyoxométallates (POMs) en font des candidats potentiellement attractifs. Ce mémoire présente les différents travaux effectués lors de cette thèse dans le but d'immobiliser des POMs de manière covalente sur des surfaces conductrices. Des composés hybrides organique/inorganique à base de tungstène et de molybdène ont été synthétisés et immobilisés sur des surfaces de carbone, d'or et de silicium, puis la vitesse de transfert électronique entre la surface et le POM a été mesurée par électrochimie. Des études complémentaires ont montré que la densité de greffage a peu d'influence sur la constante de transfert électronique, à l'inverse de paramètres comme la nature du lien covalent ou la présence d'acide en solution. Enfin, la dispersion contrôlée de POMs sur des surfaces d'or a été effectuée. / Introduction of redox active molecules in electronic devices is currently attracting a lot of attention due to the unceasing downscaling of microelectronics components. In this context, the redox properties of polyoxometalates (POMs) make them interesting candidates. This thesis presents the results of this PhD work aiming at covalently grafting POMs on conductive surfaces. Organic/inorganic hybrids based on tungsten and molybdenum cores have been synthesised and grafted onto carbon, gold and silicon surfaces. The electron transfer rate between the electrode surface and the POM has been measured by electrochemistry. Whereas parameters such as the covalent link or the presence of acid have an important effect on the transfer rate, the grafting density does not impact it noticeably. In a last study, POMs were spread on gold surfaces in a controlled manner.

A natural Maghnia clay was pillared by Al13 and impregnated by 3-10 wt.% Me (Me = Rh, Ni, Pd, Ce) to be used as catalysts in the reforming of methane with carbon dioxide to synthesis gas. The structural and textural properties of materials calcined at 450°C were determined by several techniques (XRD, FT-IR, 27Al magic angle spinning (MAS) NMR, X-ray photoelectron spectroscopy (XPS), BET, thermogravimetric analysis (TGA)- DSC, H2-temperature programmed reduction (TPR) and NH3-TPR). Although impurities are present in the Al-pillared layered clay (PILC) support, most properties are close to those of pure Al-pillared Na-montmorillonite. Impregnation and calcination leads to the plugging of most micropores by clusters or microparticles of oxides. The NMR resonances of AlVI and AlIV specie are not modified after impregnation, and AlVI/AlIV ratio only varies on loading when compared to Al-PILC. Catalytic experiments show that the most active catalyst is 3%Rh/Al-PILC on which 88 mol.% of methane is converted at 650°C with a minimum amount of carbon deposit. The conversions decrease along the 3% Rh-10% Ni > 3%Pd > 3% Ni > 3% Ce series. The H2/CO ratio amounts to 1.1 with Rh and to 0.85 with Pd which are metallic at the temperature of reaction, but it has a lower value with Ni and Ce due to the RWGS reaction known to proceed in the presence of oxides.

Nature has always served as a model for mimicking and inspiration to humans in their efforts to improve their life. Researchers have been inspired by nature to produce biomimetic materials with molecular recognition properties by design rather than evolution. Molecular imprinting is one way to prepare such materials. Such smart materials with new functionalities are at the forefront of the development of a relevant number of ongoing and perspective applications ranging from consumer to space industry. Molecularly imprinted polymers were developed by mimicking the natural enzymes or antibodies that serve as host for binding target molecules. These imprints were used as a recognition element to substitute natural biomolecules in biosensors. The concept behind molecular imprinting is to mold a material (with the desired chemical properties) around individual molecules. Upon removal of the molecular templates, one is left with regions in the molded material that fit the shape of the template molecules. Thus, molecular imprinting results in materials that can selectively bind to molecules of interest. Imprinted materials resulted in applications ranging from chemical separation to bioanalytics. In this work attempts were made particularly in the development of molecularly imprinted polymer based thermometric sensors. The main effort was focused towards the development of an covalently imprinted polymer that would be able to selectively bind fructosyl valine (Fru-Val), the N-terminal constituent of hemoglobin A1c ß-chains. Taking into account the known advantages of imprinted polymers, e.g. robustness, thermal and chemical stability, imprinted materials were successfully used as a recognition element in the sensor. One of the serious problems associated with the development of MIP sensors and which lies in the absence of a generic procedure for the transformation of the polymer-template binding event into a detectable signal has been addressed by developing the "thermometric" approach. In general the developed approach gives a new insight on MIP/Analyte interactions. / In dem Bestreben, ihr eigenes Leben zu verbessern, haben die Menschen stets die Natur nachgeahmt und sich von ihr inspirieren lassen. Die Natur hat Forscher zur Erzeugung smarter biomimetischer Stoffe mit molekularen Erkennungseigenschaften nach dem Vorbild der Evolution inspiriert. Eine der Methoden zur Herstellung solcher Substanzen ist das molekulare Prägen. Smarte Materialien mit neuen Eigenschaften stehen an der Spitze der Entwicklung potentieller Anwendungen vom Verbraucher bis hin zur Raumfahrtindustrie. Durch Nachahmung von natürlichen Enzymen oder Antikörpern wurden molekular geprägte Polymere (MIPs) entwickelt, die der Bindung von Zielmolekülen dienen. Diese geprägten Polymere (imprints) wurden anstelle von Biomolekülen als Erkennungselemente in Biosensoren eingesetzt. Das Konzept, das dem molekularen Prägen zugrunde liegt, besteht in der Formung eines Polymers (mit den entsprechenden chemischen Eigenschaften) um einzelne Zielmoleküle herum. Nach Entfernen dieser molekularen Template bleiben Abdrücke im Polymer übrig, die der Form der Templatmoleküle entsprechen. Mit Hilfe des molekularen Prägens kann man also Stoffe herstellen, die sich selektiv an bestimmte Moleküle binden können. Geprägte Polymere finden breite Anwendung, etwa in chemischen Aufreinigungsprozessen und der Bioanalytik. Hauptanliegen der vorliegenden Arbeit war es, thermometrische Sensoren auf der Basis molekular geprägter Polymere zu entwickeln. Die Anstrengungen richteten sich vor allem auf die Entwicklung eines kovalent geprägten Polymers, das in der Lage ist, selektiv Fruktosyl-Valin (Fru-Val), den N-terminalen Bereich von Hämoglobin A1c, zu binden. Aufgrund der bekannten Vorzüge geprägter Polymere – z. B. Robustheit und thermische und chemische Stabilität – wurden geprägte Polymere erfolgreich als Erkennungselement im Sensor angewendet. Eine der größten Herausforderungen bei der Entwicklung von MIP-Sensoren, das Fehlen eines generischen Verfahrens zur Umwandlung der Bindungsreaktion in ein nachweisbares Signal, wurde mit der Entwicklung der thermometrischen Methode in Angriff genommen. Diese Methode führt allgemein zu neuen Einsichten in die Interaktionen zwischen MIP und Analyt.

<p>The detection and quantitation of protein-ligand binding interactions is important not only for understanding biological functions but also for the characterization of novel protein ligands. Because protein ligands can range from small molecules to other proteins, general techniques that can detect and quantitate the many classes of protein-ligand interactions are especially attractive. Additionally, the ability to detect and quantify protein-ligand interactions in complex biological mixtures would more accurately represent the protein-ligand interactions that occur in vivo, where differential protein expression and protein complexes can significantly affect a protein's ability to bind to a ligand of interest.</p><p> The work in this dissertation is focused on the development of new methodologies for the detection and measurement of protein-ligand interactions in complex mixtures using multiplex analyses. Methodologies for two types of multiplexed analyses of protein-ligand binding interactions are investigated here. The first type of multiplex analysis involves characterizing the binding of one protein target to many potential ligands, and the second type involves characterizing the binding of one ligand to many proteins. The described methodologies are derived from the SUPREX (stability of unpurified proteins from rates of H/D exchange) and SPROX (stability of proteins from rates of oxidation) techniques, which are chemical modification strategies that measure thermodynamic stabilities of proteins using a relationship between a protein's folding equilibrium and the extent of chemical modification. These two techniques were utilized in the development and application of several different experimental strategies designed to multiplex the analysis of protein-ligand interactions.</p><p> The first strategy that was developed involved a pooled compound approach for making SUPREX-based measurements of multiple ligands binding to a target protein. Screening rates of 6 s/ligand were demonstrated in a high-throughput screening project that involved the screening of two chemical libraries against human cyclophilin A (CypA), a protein commonly overexpressed in types of cancer. This study identified eight novel ligands to CypA with micromolar dissociation constants. Second, an affinity-based protein purification strategy was developed for the detection and quantitation of specific protein-ligand binding interactions in the context of complex protein mixtures. It involved performing SPROX in cell lysates and selecting the protein of interest using immunoprecipitation or affinity tag purification. A third strategy developed here involved a SPROX-based stable isotope labeling method for measuring protein-ligand interactions in multi-protein mixtures. This strategy was used in a proof-of-principle experiment designed to detect and quantify the indirect binding between yeast cyclophilin and calcineurin in a multi-component protein mixture. Finally, a quantitative proteomics platform was developed for the detection and quantitation of protein-ligand binding interactions on the proteomic scale. The platform was used to profile interactions of the proteins in a yeast cell lysate to several ligands, including the bioactive small molecules resveratrol and manassantin A, the cofactor nicotinamide adenine dinucleotide (NAD+), and two proteins, phosphoglycerate kinase (Pgk1) and pyruvate kinase (Pyk1). The above approaches should have broad application for use as discovery tools in the development of new therapeutic agents.</p> / Dissertation