Rozprawy doktorskie na temat „Densité de chiralité”

Le succès d’un catalyseur asymétrique n’est possible que si son ligand chiral est judicieusement conçu. La combinaison d’un carbène N-hétérocyclique avec un cycle oxazoline s’avère particulièrement prometteuse. Une nouvelle famille de sels d’imidazolium, où ces deux hétérocycles sont liés par un pont (diméthyl)méthylène a été générée. Les précurseurs imidazoliums sont obtenus par réaction d’un dérivé bromé avec un imidazole portant un cycle oxazoline. Sept différents précurseurs de carbènes ont pu être générés (rendements compris entre 60 et 90%), et les carbènes libres 1-(1-méthyl-1-((4S)-iso-propyl- et tert-butyl-4,5-dihydrooxazol-2-yl)éthyl)-3-(di(-naphtyl)méthyl) imidazole-2-ylidène (11a, 11b) ont pu être isolés. La réaction du sel d’imidazolium 9d avec le catalyseur de Karstedt en présence de KOtBu génère le complexe monodentate de platine(0) 13. Ce dernier peut être oxydé par CsBr3 pour former le complexe bidentate de platine(II) 15. Le complexe neutre de rhodium(I) 18 est quant à lui obtenu par déprotonation du sel d’imidazolium 9g puis réaction avec [Rh(nbd)Cl]2, et a pu être converti en son analogue cationique 19 par abstraction de bromure. La présence de groupements méthyles sur le pont (dimethyl)méthylène apporte une plus grande stabilité au complexe par rapport à l’air et renforce le pouvoir chélatant du ligand. De plus, pour la famille de ligands précédemment développée au sein du groupe où les deux hétérocycles sont directement liés, les limites de sa capacité à chélater un centre métallique ont été illustrées par la synthèse des complexes de cuivre(I) 12a et 12b, qui cristallisent sous la forme de dimère et d’oligomère de coordination. Les analogues cationiques des complexes de rhodium 16b, 18 et 20 ont été testés comme catalyseurs de la réaction d’hydrosilylation asymétrique des cétones. Les observations expérimentales ne pouvant pas être expliquées par le mécanisme communément accepté pour cette catalyse, une étude théorique fut menée par le biais de calculs DFT. Trois voies mécanistiques ont pu être établies : elles diffèrent par le mode d’insertion de la cétone, soit dans la liaison Rh-Si (mécanisme d’Ojima), soit dans la liaison Si-H (mécanisme de Chan) ou via la formation d’un intermédiaire silylène (nouveau mécanisme proposé). Ce dernier est énergétiquement favorisé par rapport aux mécanismes postulés jusqu’à maintenant (55 kJ. Mol-1 pour le mécanisme d’Ojima, 120 kJ. Mol-1 pour le mécanisme de Chan). De plus, n’étant accessible que lorsqu’un dihydrosilane est utilisé, ce nouveau mécanisme rend compte de l’accélération de la vitesse de réaction lorsqu’un silane secondaire est utilisé à la place d’un silane tertiaire. Enfin, seul ce mécanisme offre une interprétation possible de l’effet isotopique cinétique inverse observé
The efficiency of an asymmetric organometallic catalyst is determined by the appropriate design of the chiral ligand. The combination of the kinetic robustness of N-heterocyclic carbenes with oxazolines as stereodirecting elements appears to be very promising. A novel family of imidazolium salts, where both heterocycles are connected by a (dimethyl)methylene bridge was generated. Reacting various bromide derivatives with imidazoles bearing an oxazoline unit has afforded a family of seven different ligand precursors (60-90% yield). The free carbenes 1-(1-methyl-1-((4S)-iso-propyl- and tert-butyl-4,5-dihydrooxazol-2-yl)ethyl)-3-(di(-naphtyl)methyl)imidazole-2-ylidene (11a, 11b) could be isolated by simple deprotonation of the imidazolium salt. Reaction of the imidazolium salt 9d with the Karstedt catalyst in the presence of potassium tertbutoxide led to the formation of the monodendate trigonal planar Pt(0) complex 13, which could be oxidised to the bidendate Pt(II) complex 15 by reaction with CsBr3. Subsequent deprotonation of the imidazolium salt 9g and reaction with [Rh(nbd)Cl]2 gave the neutral square-planar Rh(I) complex 18 that is converted into the cationic bidendate complex 19 by bromide abstraction. The methyl substituents on the methylene bridge proved to provide more stability to complexes towards air and to enhance the chelating capacity of the ligand in solution. At the same time, the limit of the chelating capacity of the ligands previously developed in the group, where both heterocycles are directly connected, was emphasised by the generation of the Cu(I) complexes 12a and 12b, which crystallised as dimer and coordination oligomers. The cationic analogues of the rhodium complexes 16b, 18 and 20 were tested in the catalytic asymmetric hydrosilylation of ketones and afforded different activities and selectivities. The commonly accepted Ojima mechanism not accounting for some of the experimental observations, a comprehensive theoretical investigation of the catalysis mechanism via DFT calculations was carried out. Three viable mechanistic pathways could be established. They all involve a first oxidative addition step and differ in the mode of insertion of the ketone, either into the Rh-Si bond (Ojima mechanism), into the Si-H bond (Chan mechanism) or via the formation of a silylene intermediate (new mechanistic pathway). The latter is energetically favoured with regard to the postulated ones, by respectively 55 kJ. Mol-1 (Ojima mechanism) and 120 kJ. Mol-1 (Chan mechanism). Being only accessible when a dihydrosilane is used, this explains the observed rate enhancement when secondary silanes are used instead of tertiary silanes. Moreover, it accounts for the inverse kinetic isotope effect

En spectroscopie le couplage expérience-théone permet notamment la déterminatIon des structures des conformères les plus stables de (bio)molécules ainsi que l'analyse de mouvements de grande amplitude et de structures hyperfines. Nous avons réalIsé des expériences de spectroscopie à Impulsions mlcroondes par transformée de Fourier en jet supersonique et des calculs de chimie quantique (ab initio et DFT). Nos principaux résultats concernent l'étude de sucres CnH2nOn et de leurs complexes hydratés. Dans le complexe glycolaldéhyde-eau (n=2), la molécule d'eau s'insère avec unc sélectivité au niveau des liaisons hydrogéne en cassant la liaison intramoléculaire et en formant deux lIaisons intermoléculaires. De plus. Nous avons mis en évidence une flexibilité conformationnelle au sein du complexe, modélIsée avec une surface d'énergie potentielle rendant compte des mouvements de grande amplitude des groupes hydroxyles du complexe. Cette étude d intérêt général a été étendue aux complexes hydratés des sucres C3. Par ailleurs, la structure hyperfine spin nucléaire - spin nucléaire des sucres en C2 et C3 (1. 3-dihydroxyacétone) a été observée et modélisée. Ce modèle pourrait être appliqué à tous les sucres CnH2nOn. Enfm, nous avons développé une méthodologie pour caractériser les conformères les plus stables des sucres en C. Pour les amines avec liaison peptidique, nous avons résolu la controverse sur l'énergie relative des conforméres E et Z du N-phénylformamide, avec une méthodologie adaptée. Qui a ensuite été appliquée au benzamide et au complexe urée-eau. La structure hyperfine de la molécule chirale CHCIFI a été caractérisée et sa structure a l'équilibre calculée ab initio.

La réponse optique linéaire et non linéaire d'assemblages moléculaires et de nano particules métalliques bidimensionnels a été déterminée. Dans un premier temps, l'étude a porté sur des films moléculaires de DiA, un composé amphiphile ayant une forte réponse non linéaire. La conclusion marquante de cette partie est la mise en évidence par des mesures de génération de second harmonique de l'apparition de la chiralité dans les agrégats moléculaires initialement non chiraux à très forte compression. Dans la seconde partie, l'étude optique linéaire et non linéaire des films de particules métalliques d'or et d'argent révèle la présence d'agrégats dont la taille et la mobilité dépendent de la densité moyenne de particules en surface. L'observation de fortes fluctuations de l'intensité mesurée lors de la compression a nécessité la mise en œuvre d'une approche dynamique de ces mesures mettant en évidence les mécanismes à l'œuvre dans ces films et les temps caractéristiques associés.

The distinct response of biological systems to the two enantiomers of a chiral chemical has led to a large market for enantiopure pharmaceuticals and raised fundamental issues about the origin of biological homochirality. It is therefore important to understand the interactions of chiral molecules with chiral environments. Chiral environments associated with solid surfaces could potentially play a useful role in chirally specific chemical processing. There are a variety of routes for creating chiral solid surfaces. Surfaces of materials whose bulk crystal structure is enantiomorphic can be used as one type of chiral solid surfaces. Metal surfaces that are intrinsically chiral due to the presence of kinked surface steps provide another route for creating chiral solid surfaces. Alternatively, we can impart chirality onto surfaces by attaching irreversibly adsorbing chiral organic species on otherwise achiral surfaces. Understanding and ultimately controlling enantiospecific interactions of molecules on this kind of surfaces requires detailed insight into the adsorption geometries and energies of these complex interfaces. To tackle these issues, we performed density functional theory (DFT) calculations that have proved to be a useful tool for quantitative prediction of these effects. Besides our main topic above, we theoretically examine the effects of K atoms as a promoter coadsorbed with small molecules on Mo2C surfaces, a promising catalyst for a range of chemicals applications. Our results in this thesis provide fundamental information about these systems and demonstrate that using DFT for this purpose can be a useful means of identifying the phenomena that control chiral surface chemistry.

Cationâ Ï interaction is an important determinant in protein structure and function. Among the three proteinogenic aromatic amino acids, tryptophan (Trp) is the strongest cationâ Ï donor. We reported the asymmetric syntheses of tryptophan regioisomers in which the amino acid side chain is attached at different position of the indole moiety. These new tryptophan regioisomers can effect a different mode of cationâ Ï interaction. In nature, dramatic increases in binding affinity can be achieved through multivalent binding. Following a fragmentation-dimerization approach, we synthesized Taxol-based dimer in which the baccatin III core of Taxol is coupled with flexible PEG linker. However, microtubule assembly assay suggested that these new dimers are not capable of effecting bivalent binding to the Taxol binding sites in microtubules. Memory of chirality (MOC) is an emerging theme in asymmetric synthesis in which the dynamic chirality of the reactive intermediate "memorizes" the static chirality of the reactant. Using dynamic 1D and 2D NMR and density functional theory (DFT) methods, we studied the MOC effect of 1,4-benzodiazepin-2-ones. Reconstruction of the reaction pathway using DFT calculations supported our proposed contra steric, retention of configuration mechanism.
Ph. D.

Doctor of Philosophy
Department of Chemistry
Christine M. Aikens
Gold and silver particles with dimensions less than a nanometer possess unique characteristics and properties that are different from the properties of the bulk. They demonstrate a non–zero HOMO–LUMO gap that can reach up to 3.0 eV. These differences arise from size quantization effects in the metal core due to the small number of atoms. These nanoparticles have attracted great interest for decades both in fundamental and applied research. Small gold clusters protected by various types of ligands are of interest because ligands allow obtaining gold nanoclusters with given sizes, shapes and properties. Three main families of organic ligands are usually used for stabilization of gold nanoclusters: phosphine ligands, thiolate ligands and DNA. Usually, optical properties of these NPs are studied using optical absorption spectroscopy. Unfortunately, sometimes this type of spectrum is poorly resolved and tends to appear very similar for different complexes. In these cases, circular dichroism (CD) and magnetic circular dichroism (MCD) spectroscopy can be applied. However, the interpretation of experimental CD and MCD spectra is a complicated process. In this thesis, theoretically simulated CD and MCD spectra were combined with optical absorption spectra to study optical activity for octa– and nona– and undecanuclear gold clusters protected by mono– and bidentate phosphine ligands. Additionally, optical properties of bare and DNA protected silver NPs were studied. Theoretical CD spectra were examined to learn more about the origin of chirality in chiral organometallic complexes, and to contribute to the understanding of the difference in chiroptical activity of gold clusters stabilized by different phosphine ligands and DNA–stabilized silver clusters. Furthermore, optical properties of the small centered gold clusters Au₈(PPh₃)₈²⁺ and Au₉(PPh₃)₈³⁺ were examined by optical absorption and MCD spectra using TDDFT. Theoretical MCD spectra were also used to identify the plasmonic behavior of silver nanoparticles. These results showed that CD and MCD spectroscopy yield more detailed information about optical properties and electronic structure of the different chemical systems than optical absorption spectroscopy alone. Theoretical simulation of the CD and MCD spectra together with optical absorption spectra can be used to assist in the understanding of empirically measured CD and MCD and provide useful information about optical properties and electronic structure.

Memory of chirality (MOC) is an emerging strategy for asymmetric synthesis which relies upon the intermediacy of transiently non-racemic reactive species. In these reactions the configuration of the sole stereogenic center of the enantiopure starting material is "memorized" by a chiral non-racemic conformation in the intermediate; trapping then captures the stereochemical information, and generates a new stereogenic center with high fidelity. We experimentally and computationally studied the highly retentive deprotonation/alkylations of 1,4-benzodiazepin-2-ones (BZDs) that rely upon this strategy. We captured a transiently non-racemic BZD enolate intermediate in enantiopure form, then released the enolate and observed its subsequent reaction. This approach allowed the first ever step-wise observation of the stereochemical course of such a MOC process. Approximately 2 million deaths are caused by malaria every year in the world. In total roughly 3.2 billion people are living under the risk of malaria transmission. Current use of anticholinesterase insecticides has been limited by their toxicity to human beings. A major African malaria insect vector, Anopheles gambiae (Ag), was targeted. Based on sequence alignment and homology models of AgAChE, a strategy of dual-site binding was adopted that targets Trp84 in the active site and Cys286 at the peripheral site. Selective AChE inhibitors have been designed and synthesized.
Ph. D.

Bivalent drug design is an efficient strategy for increasing potency and selectivity of many drugs. We devised a strategy to prepare agonist-benzodiazepine heterodimers that could simultaneously bind to agonist and BZD sites of the GABAAR. We synthesized a benzodiazepine-MPEG model compound that relied on physiological GABA to elicit flux. We established that a tether at the N1 position of the BZD would not prevent binding to the receptor. However, coupling of GABA amides with long chain PEG tethers studied by another group member resulted in complete loss of agonist activity. We therefore ceased research in this particular area. 1,4-Benzodiazepin-2,5-diones display a wide range of pharmacological activities. Compounds containing the tricyclic proline-derived subtype have received attention as potent anxiolytic agents and as starting materials for anthramycin-inspired anticancer agents. More recently enantiopure (S)-proline-derived 1,4-benzodiazepin-2,5-diones have been recognized as selective α5 GABAA receptor ligands. Despite the impressive diversity of 1,4-benzodiazepine-2,5-diones prepared to date, enantiopure examples possessing a quaternary stereogenic center have been largely unexplored. "Memory of chirality" (MOC) is an emerging strategy for asymmetric synthesis. This technique enables the memory of a sole chiral center in the substrate to be retained in a process that destroys that center. We have used this technique to prepare a library of quaternary proline-derived, thioproline-derived and hydroxyproline-derived 1,4-benzodiazepin-2,5-diones, in high ee. We have developed an efficient synthetic method for preparing oxaproline-derived 1,4-benzodiazepin-2,5-diones in high yields, and by applying the MOC strategy we have prepared quaternary derivatives in acceptable %ee. We envision oxaproline-derived 1,4-benzodiazepin-2,5-diones may exhibit similar or more potent pharmacological properties than proline-derived 1,4-benzodiazepin-2,5-diones. Using density functional theory (DFT) methods, we modeled the formation of an enantiopure, dynamically chiral enolate intermediate and the slow racemization of the enolate on the alkylation reaction time scale.
Ph. D.

Over the past 20 years’ researchers have tried to utilize the remarkable properties of single-walled carbon nanotubes (SWCNTs) to create new high-tech materials and devices, such as strong light-weight composites, efficient electrical wires and super-fast transistors. But the mass production of these materials and devices are still hampered by the poor uniformity of the produced SWCNTs. These are hollow cylindrical tubes of carbon where the atomic structure of the tube wall consists of just a single atomic layer of carbon atoms arranged in a hexagonal grid. For a SWCNT the orientation of the hexagonal grid making up the tube wall is what determines its properties, this orientation is known as the chirality of a SWCNT. As an example, tubes with certain chiralities will be electrically conductive while others having different chiralities will be semiconducting. Today’s large scale methods for producing SWCNTs, commonly known as growth of SWCNTs, gives products with a large spread of different chiralities. A mixture of chiralities will give products with a mixture of different properties. This is one of the major problems holding back the use of SWCNTs in future materials and devices. The ultimate goal is to achieve growth where the resulting product is uniform, meaning that all of the SWCNTs have the same chirality, a process termed chirality-specific growth. To achieve chirality-specific growth of SWCNTs requires us to obtain a better fundamental understanding about how they grow, both from an experimental and a theoretical point of view. This work focuses on theoretical studies of SWCNT properties and how they relate to the growth process, thereby giving us vital new information about how SWCNTs grow and taking us ever closer to achieving the ultimate goal of chirality-specific growth. In this thesis, an introduction to the field is given and the current state of the art experiments focusing on chirality-specific growth of SWCNTs are presented. A brief review of the current theoretical works and computer simulations related to growth of SWCNTs is also presented. The results presented in this thesis are obtained using first principle density functional theory. The first study shows a correlation between the stability of SWCNT-fragments and the observed products from experiments. Calculations confirm that in 84% of the investigated cases the chirality of experimental products matches the chirality of the most stable SWCNT-fragments (within 0.2 eV). Further theoretical calculations also reveal a previously unknown link between the stability of SWCNT-fragments and their length. The calculations show that at specific SWCNT-fragment lengths the most stable chirality changes. Thus, introducing the concept of a switching length for SWCNT stability. How these new results link to the existing understanding of SWCNT growth is discussed at the end of the thesis.

Ge₂Sb₂Te₅ (GST) is an established phase-change material that undergoes fast reversible transitions between amorphous and crystalline states with a high electro-optical contrast, enabling applications in non-volatile optical and electronic memories and optically-switchable structured metamaterials. This work demonstrates that optical anisotropy can be induced and recorded in pure and doped GST thin films using circularly polarised light (CPL), opening up the possibility of controlled induction of anisotropic phase transition in these and related materials for optoelectronic and photonic applications. While the amorphous-to-crystalline phase transition in GST has generally been understood to proceed via a thermal mechanism, significant optical anisotropy (measured by circular dichroism (CD) spectroscopy in this work) strongly suggests that there is an electronic athermal component of the phase change induced by the handedness of circularly polarised nanosecond laser pulses and implies the existence of chiral structures or motifs. Optically active and inactive regions in the films have also been studied using X-ray and electron diffraction and spectroscopic techniques in order to obtain a structural picture that can be correlated to the optical changes observed and the findings offer surprising evidence of the nature of the phase transition. Regions exhibiting higher CD signal intensities were found to be mostly amorphous with elemental phase separation observed within modified surface features. Several mechanisms are proposed for the observed phenomena, including the retention of chiral crystalline fragments in laser- irradiated and melt-quenched amorphous regions, which could explain the results of CD spectroscopy. This may be extended to other material systems and harnessed in potential metamaterials, plasmonics, photonics or chiroptical applications.

Les modèles effectifs de type Nambu—Jona-Lasinio (NJL) peuvent être utilisés pour étudier les phases à densité et température finies de la chromodynamique quantique (QCD). Alors que les prédictions de ces modèles effectifs peuvent être comparées avec les résultats sur réseaux aux faibles densités, un tel garde-fou n'existe pas à plus haute densité où la discrétisation fait face à un problème de signe sévère. Dans cette thèse nous proposons une méthode systématique permettant de calculer la stabilité d'une prédiction par rapport aux données d'entrée du modèle. De cette manière un critère quantitatif est fabriqué permettant d'évaluer le pouvoir prédictif d'un modèle. La discussion est principalement orientée sur le point critique chiral.Enfin les phases très hautes densités, telles que pouvant exister à l'intérieur des étoiles compactes, sont abordées et la superconductivité de couleur est discutée dans le cadre des modèles NJL
Nambu--Jona-Lasinio models can be used to study finite density and finite temperature quantum chromodynamics phases. Finite temperature and low density predictions of these models can be compared to lattice results. Such a comparison is not possible at larger density because of the so called sign problem. In this thesis the proposed systematic method allows to compute the stability of a prediction with respect to the inputs of the model. In this way a quantitative criterium is constructed which can be used to evaluate the predictive power of the studied model. Finally the high density phases which can exist in the interior of compact stellar objects are discussed along with color superconductivity in NJL type models

Certain types of porphyrins can be used as achiral agent for determination of enantiomeric excess (ee) of chiral molecules. Particular organic chiral molecule (guest) and porphyrin (host) form host-guest complex while inducing nonequiv- alency of particular proton resonances in symmetrical host. It causes splitting of NMR signals linearly dependent on ee of guest. In this work we investigated com- plexation of di-brombenzylated oxoporphyrin with chiral camphorsulfonic acid. NMR titration revealed that they form complex with 1:1 stoichiometry with as- sociation constant K ≈ 5 × 104 l/mol. We confirmed linear dependence of split- ting of host β-protons on ee of guest. Low temperature measurements revealed two conformations of host-guest complex with population around 0.7:0.3 (at −60 ◦ C). DFT quantum mechanical computations at BLYP/3-21G* level revealed also two conformations with population 0.79:0.21. NMR shifts were computed on this geometries with method GIAO/PBE1PBE/6-31G(2df,2pd) and compared to experimental values. 1