Dissertations / Theses on the topic 'Catalyst screening'

Les protéines Ras jouent un rôle majeur dans le développement cellulaire. Faisant partie de la catégorie de petites GTPases, elles sont dotées d'un mécanisme fonctionnant tel un interrupteur moléculaire qui, dans leur cas, contrôle la transmission de signaux de croissance cellulaire. Liées au GTP, ces protéines adoptent une conformation leur permettant d'interagir avec des effecteurs en aval et, ainsi, activer la réplication et différenciation cellulaires. La réaction d'hydrolyse du GTP qui se déroule en leur centre, est accompagnée d'un changement conformationnel qui met fin à ces interactions, conduisant ainsi à l'état inactif de Ras, lié au GDP. Des mutations spécifiques de résidus bien déterminés entraînent une baisse du taux d'hydrolyse, laissant ainsi Ras liée au GTP. Or, de fortes concentrations de cette forme active de Ras ont été associées à une prolifération cellulaire anormale, caractéristique de la dissémination de tissus cancéreux. Il apparaît alors que l'élucidation des mécanismes employés par Ras pour accélérer le clivage du GTP constitue une étape majeure dans le développement de thérapies ciblées contre le cancer. Elles consisteraient à rétablir, au sein des mutants oncogéniques, un taux d'hydrolyse proche à celui mesuré au sein du type sauvage. Dans le but de mieux comprendre au niveau atomique les propriétés catalytiques de Ras, nous avons mené des simulations de dynamique moléculaire (MD) en décrivant le domaine G à différents niveaux de théorie (Mécanique Moléculaire (MM), Semi-empirique et Théorie de la Fonctionnelle de la Densité (DFT)). Ces calculs ont été réalisés pour les formes sauvage et mutées au niveau du résidu 61 de NRas. Ils ont été couplées à des caractérisations biomécaniques des complexes protéine-ligand étudiés, en utilisant la méthode des modes statiques. Cette méthode permet d'identifier des points chauds, réactifs, de la biomolécule et qui, suivant le critère de contrainte choisi, ont une influence mécanique sur la fonction GTPase de la protéine. Par conséquent, ils pourraient servir en temps que sites appropriés pour héberger des molécules médicamenteuses contenant des groupes chimiques spécifiques qui faciliteraient l'hydrolyse du GTP. Tout d'abord, les résultats obtenus montrent que le positionnement des molécules d'eau dans le cite actif est crucial pour catalyser efficacement la réaction. En effet, la répartition précise du solvant, observée dans le type sauvage, est perdue au sein des mutants de NRas considérés ici. Cette distribution différente des molécules d'eau ainsi que les modifications structurales du site actif engendrées par les substitutions du résidu Gln 61, ont un impact direct sur la densité électronique du GTP. Cette dernière présente un profil de type GDP au sein de la protéine de type sauvage uniquement, comme déterminé expérimentalement dans des études précédentes. Il apparaît donc que les mutations oncogéniques de Gln 61 perturbent cet effet catalytique majeur de NRas. Parmi trois propositions faites au cours de cette thèse sur des modifications à apporter à la forme mutée Q61R de NRas, une est présentée pendant la soutenance tandis que toutes les trois sont décrites dans le manuscript. Les groupes chimiques insérés au niveau du site identifié permettent de rétablir une distribution de l'eau comme celle observée dans le type sauvage. Pour terminer, lors de la soutenance uniquement, un chemin réactionnel alternatif de l'hydrolyse enzymatique du GTP est proposé<br>Ras subfamily of small GTPase proteins holds a key position in cell proliferation pathways. Indeed, the transmission of cell growth signals is controlled by proteins belonging to it. In their GTP-bound conformation, these proteins interact and activate downstream effectors of cell replication and differentiation. The hydrolysis reaction that takes place in their center, terminates these interactions, thereby leading to the GDP-bound inactive state. Point mutations of key residues lead to a hydrolysis rate drop that keeps Ras in a GTP-bound active state. Now, high concentrations of active Ras have been associated to abnormal cell proliferation, emblematic of cancerous tissues dissemination. With this into consideration, the elucidation of Ras mechanisms for accelerating GTP cleavage appears as a major step in the development of cancer targeted therapies that would consist in restoring the hydrolysing capabilities within oncogenic Ras to a wild-type rate. In an attempt to gain insight into Ras catalysing properties at the atomic level, unconstrained Molecular Dynamics (MD) simulations describing the G domain at different levels of theory (Molecular Mechanics (MM), Semi-empirical and Density Functional Theory (DFT)) were carried out for NRas member in its wild-type and Gln 61 mutated forms. These simulations were coupled to biomechanic characterisations of the complexes under inspection employing the static modes approach. The latter method, allows the identification of hot spots {\it i.e.} responsive residues of the biomolecule, that have a mechanical influence on the GTPase function of the protein. Hence, they could serve as suitable sites to host drug-like molecules containing specific chemical groups that would facilitate GTP hydrolysis. The obtained results show that water molecules positioning is crucial for efficiently catalysing the reaction that takes place in NRas center. Indeed, the precise positioning observed within the wild-type is lost within the mutants studied here. Furthermore, the active site structural modifications undergone upon Gln 61 substitutions, together with solvent distribution in it, impact directly GTP electronic density. The latter is accommodated to a GDP-like state within the wild-type protein only, as experimentally determined in previous investigations. Thus, oncogenic Gln 61 mutations impair this major catalysing effect. Among three engineered NRas proteins of the Q61R mutated form, proposed during this thesis, one is presented during the defence while the three are described in the manuscript. The chemical groups inserted at the identified site enable the recovery of water distribution as within the wild-type. To end, during the defence only, an alternative reaction pathway of the enzymatic reaction is proposed

This thesis deals with the design, formation and evaluation of dynamic systems constructed by means of sulfur-containing reversible reactions, in organic and aqueous media and under mild conditions. In a first part, the synthesis of thioglycoside derivatives, constituting the biologically relevant starting components of the dynamic systems, is described. In addition, the pD-profile of the mutarotation process in aqueous media for a series of 1-thioaldoses is reported and revealed an astonishing beta-anomeric preference for all the carbohydrate analogs under acidic or neutral conditions. In a second part, the phosphine-catalyzed or -mediated disulfide metathesis for dynamic system generation in organic or aqueous media is presented, respectively. The direct in situ 1H STD-NMR resolution of a dynamic carbohydrate system in the presence of a target protein (Concanavalin A) proved the suitability and compatibility of such disulfide metathesis protocols for the discovery of biologically relevant ligands. In a third part, hemithioacetal formation is demonstrated as a new and efficient reversible reaction for the spontaneous generation of a dynamic system, despite a virtual character of the component associations in basic aqueous media. The direct in situ 1H STD-NMR identification of the best dynamic beta-galactosidase inhibitors from the dynamic HTA system was performed and the results were confirmed by inhibition studies. Thus, the HTA product formed from the reaction between 1-thiogalactopyranose and a pyridine carboxaldehyde derivative provided the best dynamic inhibitor. In a fourth and final part, a dynamic drug design strategy, where the best inhibitors from the aforementioned dynamic HTA system were used as model for the design of non-dynamic (or “static”) beta-galactosidase inhibitors, is depicted. Inhibition studies disclosed potent leads among the set of ligands.<br>QC 20100621

One of the major bottlenecks in catalyst development for proton exchange membrane fuel cell (PEMFC) is the lack of fast high-throughput testing methods. Fast screening techniques enable a large number of catalysts to be tested in a relatively short time under the same conditions. This project was focused on developing systems for screening catalysts used for the oxygen reduction reaction (ORR) at the cathode of PEMFCs. The first system developed was the 64 channel pin electrode array, using liquid electrolyte. The developed method improved both the quality and reproducibility of the data and has been used to rank catalyst samples, as well as to optimize loadings and the preparative methods of inks. The second system developed was a 25 channel array fuel cell, which operated under conditions analogous to real fuel cell environments. Both methods allowed trends in characteristics and activities of a series of catalysts to be established more rapidly than individual single-electrode methods such as half cell, rotating disc electrode (RDE) or fuel cell. The results from the two high-throughput methods are compared to those of the single channel systems. The mass and specific activities towards reduction of oxygen were studied using a series of Pt/C and PtCo/C catalysts. The catalytic properties of the Pt based carbon-supported catalysts were related to their structure e.g. particle size and lattice parameter, which were obtained mainly using Xray diffraction (XRD). It was found that the results acquired using parallel screening methods were similar to those collected with a RDE and a fuel cell. The thesis concludes with suggestions regarding the future improvement/development of high-throughput techniques. For the 64 channel array system the problem associated with the corrosion of the components should be solved. Similarly, the major changes for the array fuel cell would be to modify a heating system and further development of the anode flow field.

Le premier objectif de ce travail a consisté à développer la réaction CuSAC (découverte au laboratoire) pour la synthèse régiosélective de pyrazoles poly-substitués, dans un contexte de méthodologie de synthèse. Il existe de nombreux composés biologiquement actifs contenant le motif pyrazole et peu de méthodes régiosélectives décrites pour les synthétiser. Développer une nouvelle réaction pour obtenir des pyrazoles poly-substitués de façon contrôlée était donc très intéressant pour des applications synthétiques.Le deuxième objectif a été d’appliquer cette réaction à la bioconjugaison et notamment au développement de sondes profluorescentes Des coumarines-sydnones subissant un effet d’extinction de fluorescence par le phénomène PeT ont été développées. Suite au couplage avec un alcyne, le pyrazole formé n’éteint plus lafluorescence de la coumarine. Ce type de sondes est très intéressant pour le marquage de biomolécules, car il n’y a aucun parasitage de fluorescence et donc ne nécessite aucun lavage.Le troisième objectif de la thèse a été d’explorer la réactivité des composés mésoioniques pour un alcyne, sous une catalyse au cuivre, dans le but de découvrir de nouvelles réactions click. Un criblage de 24 composés dans 9 conditions de catalyses différentes, faisant plus de 200 réactions réalisées, a été effectué. Deux réactions ont été révélées, dont une très prometteuse. Celle-ci permet dans la même opération de lier deux partenaires tout en libérant un fragment d’un des deux partenaires. Cette réaction a été étudiée dans le but de développer un outil de théranostique où être utilisée pour la mise au point de nouveaux espaceurs clivables<br>The first aim of this work was the development of a new regioselective synthetic access to poly-substituted pyrazoles via the CuSAC reaction, previously discovered in the laboratory. The development of new reactions leading to poly-substituted pyrazoles with a full control of regioselectivity is highly interesting for synthetic applications.The second aim of this work was the application of this reaction for the labeling of complex biomolecules. To broaden the scope of the CuSAC, fluorogenic coumarin-sydnones which undergo fluorescence extinction via PeT have been designed and synthetized. Following the coupling reaction, the newly formed pyrazole core allows huge enhancement of the fluorescence signal.This kind of probes is highly interesting in the specific labelling of biomolecules avoiding washing steps.The last project of this thesis have been focused on the discovery of new [3+2] cycloaddition reaction implying a mesoionic compound and a terminal alkyne under copper catalysis. 24 mesoionic dipoles were screened for their ability to react with a terminal alkyne in 9 different catalytic conditions, yielding to more than 200 reactions screened. Two hits were identified, one of them holding great promise. This hit allows an efficient “click and release” reaction which should find tremendous applications, especially in the fields of theranostic and cleavable linker development

Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis. In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally. The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods. Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind. Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

Biodiesel is a renewable alternative to petro-diesel, derived from vegetable oils and animal fats. The use of biodiesel in place of petro-diesel leads to reduced emissions of greenhouse gases, especially CO2, and ensures energy security. The most commonly used technology for biodiesel production is based on a homogeneously catalysed liquid phase reaction. The disadvantages of this process are the ongoing costs of catalyst replacement, the large number of downstream purification steps and production of low quality glycerol with consequently low market value. In principle, heterogeneous catalysts can solve these problems. This research demonstrates that homogeneous alkali-catalysed biodiesel production was possible at an industrially acceptable level of conversion (> 96%) in ~ 5 min residence time, requiring a combination of high catalyst concentration and good mixing. Both the experimental and model simulations results clearly showed that rapid biodiesel production (reaction times below 2 min) at economically viable conversions can be achieved by increasing base catalyst and methanol concentrations without significant problems due to excess soap formation, even in the presence of water and free fatty acids. A heterogeneous strontium zirconate based (SZB) catalyst showed substantial activity towards rapeseed oil transesterification, but there was significant loss in activity with or without the presence of water due to leaching of the active sites, Sr(OH)2, into the methanol phase. The SZB catalyst cannot be re-used for triglyceride transesterification, as it acts in a similar manner to conventional homogeneous alkali catalysts. A PrSO3H-SBA-15 catalyst was active for carboxylic acids esterification with methanol, with the reaction rates increasing with reaction temperature and methanol molar ratio, but decreasing with water content and carboxylic acid chain length. Steric effects increased with carboxylic acid chain length, causing reductions in the esterification rates and turnover frequency. PrSO3H-SBA-15 has very narrow pores (5.1nm) that are not large enough for significant triglyceride transport. Therefore, PrSO3H-SBA-15 with expanded pore size, functionalised on a hydrophobic support would be required for simultaneous esterification of free fatty acids and triglyceride transesterification. Finally, a mesoscale oscillatory baffled reactor (meso-OBR) was constructed and used to suspend and screen solid catalysts for transesterification and esterification reactions, significantly reducing reagent required and waste generated due to the small volume (~10mL). This work is the first example of systematic screening of a solid-liquid-liquid reaction system in a meso-OBR. Continuous screening in the meso-OBR permits detailed kinetic studies, rapid optimisation of reaction conditions, and assessment of the reusability of the catalyst in a single experiment as opposed to multiple experiments in conventional batch reactor screening.

Actualment la creixent demanda de compostos enantiomèricament purs (fàrmacs, productes agroquímics, additius…) ha impulsat el desenvolupament de la catàlisi asimètrica, sobretot emprant compostos organometàl•lics quirals com a catalitzadors. La síntesi de nous lligands quirals és essencial per descobrir bons sistemes catalítics en catàlisi asimètrica. Els sucres són una font important de lligands per l’elevada disponibilitat i baix preu. Els objectius d’aquesta tesi son el desenvolupament de dues noves llibreries de lligands derivats de sucre. Concretament tioèter-fosfit i furanòsid monofosfit, per la seva aplicació en diverses reaccions asimètriques catalitzades per metall de transició, tals com la hidrogenació d’olefines funcionalitzades catalitzades per rodi, la hidrogenació d’olefines mínimament funcionalitzades catalitzada per iridi, les reacció de substitució al•lílica catalitzades per pal•ladi, i les adicions 1,2 a aldehids catalitzades per níquel.<br>The growing demand for enantiomerically pure compounds has led to important advances in asymmetric catalysis, especially using chiral organometallic compounds. In this context the search of new catalysts is very important, mainly focusing on the properties of the chiral ligands. This has led to the development of new chiral ligands. An important source of chiral ligands is derivatives carbohydrate derivatives because of their high availability, their low cost and their high functionality. The objectives of this thesis are to develop two new chiral ligands carbohydrate derivatives. Specifically thioether-phosphite and furanoside monophosphite, for application in several important asymmetric catalytic reactions as Rh- and Ir-catalyzed hydrogenation of functionalized and unfunctionalized olefins, respectively; Pd-catalyzed allylic substitution; and Ni-catalyzed 1,2-addition of trialkylaluminum reagents to aldehydes.

High throughput methods are valuable for decreasing the time needed for the development of new asymmetric reactions. Catalyst discovery may be accelerated by the rapid screening of reactions for enantioselectivity. Chiral substrates are used in a novel fluorescence resonance energy transfer (FRET) assay. A fluorophore (donor), a fluorescence quencher (acceptor) and a recognition element are part of the assay substrates. The latter are prepared using different fluorescent donor/acceptor pairs for each enantiomer of the recognition element. Screening is performed using equimolar mixture of the two substrates. Weak fluorescence indicates no reaction. Strong fluorescence at both wavelengths indicates a non-selective reaction while an enantioselective coupling would display strong fluorescence at only one wavelength.* *Please refer to dissertation for diagrams.

This  thesis  is  divided  into  four  parts,  all  centered  around  Constitutional Dynamic  Chemistry  (CDC)  and  Dynamic  Kinetic  Resolution  (DKR)  using biocatalysts for selective transformations, and their applications in screening of bioactive compounds, organic synthesis, and enzyme classification.    In  part  one,  an  introduction  to  CDC  and  DKR  is  presented,  illustrating  the basic  concepts,  practical  considerations  and  potential  applications  of  such dynamic systems, thus providing the background information for the studies in the following chapters.   In part two, Dynamic Systemic Resolution (DSR), a concept based on CDC is exemplified.  With  enzyme-catalyzed  transformations  as  external  selection pressure,  optimal  structures  can  be  selected  and  amplified  from  the  system. This  concept  is  expanded  to  various  types  of  dynamic  systems  containing single, double cascade/parallel, and multiple reversible reactions. In addition, the  substrate  selectivity  and  catalytic  promiscuity  of  target  enzymes  are  also investigated.   In   part   three,   DKR   protocols   using   reversible   reactions   for   substrate racemizations  are  illustrated.  Biocatalysts  are  here  employed  for  asymmetric transformations,  resulting  in  efficient  synthetic  pathways  for  enantioenriched organic compounds.   Part  four  demonstrates  two  unique  applications  of  CDC:  one  resulting  in enzyme  classification  by  use  of  pattern  recognition  methodology;  the  other involving  enzyme  self-inhibition  through  in  situ  transformation  of  stealth inhibitors employing the catalytic activity of the target enzyme.<br><p>QC 20130614</p>

This thesis is divided into six parts, all centered around the development of dynamic (i.e., reversibly interacting) systems of molecules and their applications in dynamic combinatorial chemistry (DCC) and organic synthesis. Part one offers a general introduction, as well as a more detailed description of DCC, being the central concept of this thesis. Part two explores the potential of the nitroaldol reaction as a tool for constructing dynamic systems, employing benzaldehyde derivatives and nitroalkanes. This reaction is then applied in part three where a dynamic nitroaldol system is resolved by lipase-catalyzed transacylation, selecting two out of 16 components. In part four, reaction and crystallization driven DCC protocols are developed and demonstrated. The discovery of unexpected crystalline properties of certain pyridine β-nitroalcohols is used to resolve a dynamic system and further expanded into asynthetic procedure. Furthermore, a previously unexplored tandem nitroaldol-iminolactone rearrangement reaction between 2-cyanobenzaldehyde and primarynitroalkanes is used for the resolution of dynamic systems. It is also coupled with diastereoselective crystallization to demonstrate the possibility to combine several selection processes. The mechanism of this reaction is investigated and a synthetic protocol is developed for asymmetric synthesis of 3-substituted isoindolinones. Part five continues the exploration of tandem reactions by combining dynamic hemithioacetal or cyanohydrin formation with intramolecular cyclization to synthesize a wide range of 3-functionalized phthalides. Finally, part six deals with the construction of a laboratory experiment to facilitate the introduction of DCC in undergraduate chemistry education. The experiment is based on previous work in our group and features an acetylcholinesterase-catalyzed resolution of a dynamic transthioacylation system.<br>QC 20100628

La recherche de nouvelles réactions est un des enjeux fondamentaux de la chimie organique. En dehors de l’approche classique basée sur la conception d’une réaction en s’appuyant sur les propriétés chimiques des substrats, une nouvelle approche utilisant le criblage systématique de combinaisons aléatoires de fonctions réactives a été récemment adoptée par plusieurs groupes. Cette stratégie nécessite un outil analytique permettant de cribler un très grand nombre de réactions par jour et d’identifier les meilleures combinaisons conduisant à la formation de produits intéressants. Les travaux de thèse présentés dans ce mémoire s’inscrivent dans le contexte de l’utilisation des techniques de dosages immuno-enzymatiques (ELISA) comme outil de criblage pour la recherche de nouvelles réactions de couplage. Dans un premier temps le criblage de 2688 combinaisons de fonctions réactives et de catalyseurs choisies au hasard a été effectué. Ce criblage a permit de mettre en évidence deux nouveaux couplages en présence de sels de cuivre : une réaction entre les thiourées et les phénols conduisant à la formation des isourées et une réaction entre les N-hydroxythiourées et les alcynes conduisant à la formation des thiazole-2-imines. Dans un second temps le criblage de 2816 combinaisons de fonctions sélectionnées, cette fois-ci, de façon rationnelle a été effectué. Ce criblage a visé la découverte de nouvelles cycloadditions [3+2] répondant aux critères de la chimie « click ». Ainsi l’utilisation de dosage immuno-enzymatique a été étendue à l’optimisation des nouvelles réactions découvertes ainsi qu’à l’évaluation de leurs cinétique, chimiosélectivité et biocompatibilité. Près de 3000 tests complémentaires effectuées sur les « hits » issus du criblage primaire ont ainsi permit de mettre en évidence 4 nouvelles réactions de couplage dont une nouvelle réaction « click » : la cycloaddition sydnone-alcyne catalysée au cuivre (CuSAC). Dans la dernière partie de ce manuscrit les études plus détaillées sur la réaction CuSAC ont été effectuées, notamment l’identification de la structure du produit de couplage et l’étendue du champ d’application de cette réaction. Enfin, l’aspect « click » de la réaction CuSAC a été illustré par l’application de cette réaction au marquage d’une protéine<br>Discovery of new reactions is one of the fundamental goals in organic chemistry. In addition to the traditional approach to reaction discovery, consisting in designing a reaction on the basis of known chemical properties of reagents, new approaches based on the screening of random combinations of reactive functions and catalysts have been recently developed. The main prerequisite of this strategy is an analytical tool allowing screening of a big number of reactions per day and identifying combinations leading to the formation of unanticipated products. In the work presented herein a high-throughput immunoassay screening has been used for the discovery of new coupling reactions. In the first part of this work a screening of 2688 combinations of randomly chosen reactive functions and catalysts was carried out. This screening led to the discovery of two copper-promoted coupling reactions: a reaction between thioureas and phenols leading to the formation of isoureas through desulfurization; and a reaction between N-hydroxythioureas and alkynes leading to the formation of thiazole-2-imines. In the second part of the work a screening of 2816 combinations of rationally designed chemical functions and catalysts was carried out. This screening was focused on the discovery of catalytic [3+2] cycloadditions that comply with the standards of “click” chemistry. In this study, the use of immunoassay screening was extended to optimize new reactions and to evaluate their kinetics, chemoselectivity and biocompatibility. Therefore, around 3000 complementary tests were carried out on the hits, identified in the primary screening. This allowed the discovery of 3 new coupling reactions and one new “click” reaction: a copper-catalyzed sydnone-alkyne cycloaddition (CuSAC). The last part of the work was focused on detailed studies of the CuSAC reaction. Identification of the structure of the coupling product and substrate scope of this reaction was carried out. Finally, the applicability of the CuSAC reaction for bioconjugation was demonstrated by an example of protein labeling

El creixent interès per a l’obtenció de compostos enantiomèricament purs, ha conduït a un important desenvolupament de la catàlisi asimètrica. En aquest context, aquesta tesis és centra en la síntesis de vàries famílies de lligands quirals altament modulars a partir de compostos de fàcil disponibilitat. Concretament, s'ha treballat en la síntesis de lligands fosfit-tioèter, fosfit-piridina, fosfit-triazola i lligands hidroaximida i tioamida. Tots ells tenen en comú que són sòlids, estables i per tant de fàcil manipulació. Aquests lligands s'han aplicat en la hidrogenació d’olefines funcionalitzades i no funcionalitzades catalitzada per Rh i Ir, en la reducció de cetones mitjançant transferència d’hidrogen catalitzada per Rh i Ru, en reaccions de substitució alílica catalitzada per Pd i en l'addició d'organoaluminats a aldehids catalitzada per Ni. A més a més, en alguns casos s'han realitzat estudis DFT per tal d'agilitzar el procés d'optimització dels lligands. Així doncs, s'ha aconseguit l'obtenció de diferents compostos químics quirals d'alt interès sintètic (alcohols, alcans funcionalitzats i no funcionalitzats, al·lils substituits) en grans enantioselectivitats i en el millor dels casos s'han aconseguit els productes en la seva forma enantiomèricament pura (>99% ee).<br>El creciente interés para la obtención de compuestos enantioméricamente puros para la obtención de compuestos enantioméricamente puros, ha conducido a un importante desarrollo de la catálisis asimétrica. En este contexto, esta tesis se centra en la síntesis de varias familias de ligandos quirales altamente modulares a partir de compuestos de fácil disponibilidad. Concretamente, se ha trabajado en la síntesis de ligandos fosfito-tioéter, fosfito-piridina, fosfito-triazoles y ligandos hidroaximida y tioamida. Todos ellos tienen en común que son sólidos, estables y por lo tanto de fácil manipulación. Estos ligandos se han aplicado en la hidrogenación de olefinas funcionalizadas y no funcionalizadas catalizada por Rh e Ir, en la reducción de cetonas mediante transferencia de hidrógeno catalizada por Rh y Ru, en reacciones de sustitución alílica catalizada por Pd y en el adición de organoaluminiatos a aldehídos catalizada por Ni. Además, en algunos casos se han realizado estudios DFT para agilizar el proceso de optimización de los ligandos. Así pues, se ha logrado la obtención de diferentes compuestos químicos quirales de alto interés sintético (ej. alcoholes, alcanos funcionalizados y no funcionalizados, alilos sustituidos) en grandes enantioselectividades y en el mejor de los casos se han conseguido los productos en su forma enantioméricamente pura (> 99% ee).<br>The growing interest in obtaining enantiomerically pure compounds in obtaining enantiomerically pure compounds has led to a significant development in the field of asymmetric catalysis. In this context, this thesis is focused on the synthesis of several families of highly modular chiral ligands from readily available compounds. Specifically, we worked on the synthesis of thioether-phosphite ligands, phosphite-pyridine, phosphite-triazole and hidroaximide and thioamide ligands. They all have in common that are solid, stable and therefore easy to handle. These ligands have been applied in the Rh- and Ir-catalyzed hydrogenation of functionalized and unfunctionalized olefins, in the Ru- and Rh-catalyzed asymmetric transfer hydrogenation of ketones, in Pd-catalyzed allylic substitution reactions and in the Ni-catalyzed addition of organoalumininum to aldehydes. Moreover, in some cases DFT studies have been performed to speed up the optimization of ligands. Hence, a variety of chiral chemical compounds of high synthetic interest (i. e. alcohols, functionalized and non-functionalized alkanes, substituted allyl) lhigh enantioselectivities were achieved and in some cases the products were obtained in their enantiomerically pure form(> 99% ee).

En els últims anys, la creixent demanda de compostos enantiomèricament purs (fàrmacs, agroquímics...) ha impulsat el desenvolupament de la catàlisi asimètrica, sobretot emprant compostos organometàl·lics quirals com a catalitzadors. En aquest context, la síntesi de nous lligands quirals és essencial per descobrir bons sistemes catalítics en catàlisis asimètrica. Els sucres són una font important de lligands per l'elevada disponibilitat i baix preu. A més, són compostos altament funcionalitzats amb centres esterogènics. Això permet la síntesi de sèries sistemàtiques de lligands amb l'objectiu d'obtenir altes activitats i selectivitats per cada reacció en particular.<br/>Aquesta tesi s'ha centrat en la síntesi de compostos derivats de la D-(+)-glucosa, de la D-(+)-fructosa i la D-(+)-galactosa i l'aplicació com a lligands de catalitzadors homogenis quirals en quatre reaccions asimètriques: substitució al·lílica, Heck, addició 1,2 i addició conjugada 1,4. Per assolir aquest objectiu, s'ha plantejat la síntesi de tres famílies de compostos: fosfit-oxazolina (L1-L5), fosfit-fosforoamidit (L6) i monofosfit (L7-L11) (Figura 1). <br/>Després de la introducció (Capítol 1) i els objectius (Capítol 2), al capítol 3 es discuteix la síntesi i caracterització de les tres llibreries de compostos (L1-L11) i s'estudia l'aplicació de les tres llibreries a la reacció de substitució al·lílica asimètrica catalitzades per pal·ladi. <br/> La primera llibreria de compostos fosfit-oxazolina (L1-L5) ha mostrat altes enantioselectivitats (fins a un 99%) i bones activitats en un ampli ventall de substrats amb diferents propietats electròniques i estèriques. S'han observat importants efectes al variar els substituents de l'anell oxazolina, de la quiralitat axial i dels diferents substituents del biaril. L'estudi de diferents intermedis de reacció pal·ladi al·lil mitjançant espectroscòpia de ressonància magnètica nuclear ha permès entendre el comportament catalític d'aquests compostos. L'estudi també ha indicat que l'atac nuclèofil té lloc preferentment al carboni al·lílic terminal localitzat trans al fosfit.<br/><br/> <br/>Figura 1. Fosfit-oxazolina (L1-L5), fosfit-fosforamidit (L6) i monofosfit (L7-L11).<br/><br/>Les reaccions de substitució asimètrica utilitzant els compostos fosfit-fosforoamidit (L6) han mostrat que l'excés enantiomèric depèn preferentment dels substituents de les posicions en para dels bifenils. Aquests efectes han estat diferents segons el tipus de substrat. S'han obtingut excessos enantiomèrics fins a un 89% i altes activitats utilitzant el substrat rac-1,3-difenil-acetoxipropè, rac-(E)-etil-2,5-dimetil-3-hex-4-enilcarbonat i el rac-3-acetoxicicloheptè. Pel substrat lineal 1-(1-naftil)al·lil acetat, aquests lligands han mostrat no ser útils en termes de regioselectivitat però s'han obtingut bons excessos enantiomèrics de fins a un 72%.<br/>Si comparem aquests resultats amb els obtinguts amb els compostos fosfit-oxazolina (L1-L5) s'observa que el canvi de la funció oxazolina per la funció fosforoamidit té un efecte negatiu en la reacció de substitució al·lílica i en general decreixen les enantioselectivitats i la versalitat d'aquests compostos.<br/>L'aplicació de la llibreria de compostos monofosfit (L7-L11) en la reacció de substitució al·lílica asimètrica ha mostrat moderades enantioselectivitats (fins a un 46%). Els resultats en la catàlisi es veuen afectats en gran mesura per la diferència en la mida de l'anell carbohidrat, de les configuracions del carboni-3 i del carboni-4 de l'esquelet del lligand i pel tipus de substituents de l'anell biaril. <br/>El capítol 4 descriu l'aplicació dels compostos fosfit-oxazolina (L1-L5) com a lligands en la reacció de Heck asimètrica intermolecular. Una selecció correcta dels substituents en la funció oxazolina i del fosfit han permès obtenir excel·lents activitats (fins un 100% de conversió en 10 minuts), regioselectivitats i enantioselectivitats (fins un 99%) en un ampli rang de substrats utilitzant diferents fonts de triflat. <br/>El capítol 5 descriu l'aplicació de les tres llibreries de compostos (L1-L11) a les reaccions d'addició 1,2 a aldehids catalitzades per níquel. En primer lloc, s'ha estudiat l'aplicació dels compostos L1-L6. S'ha observat que la selectivitat del procés depèn principalment del grup funcional unit a l'esquelet del lligand, de les propietats estèriques del substituent en la funció oxazolina i de l'estructura del substrat. S'ha obtingut fins a un 59% d'excés enantiomèric utilitzant el precursor de catalitzador que conté el lligand L3a. En canvi, la utilització de la llibreria de compostos monofosfit (L7-L11) ha mostrat elevades enantioselectivitats (fins a 94%) i activitats en diferents tipus de substrat utilitzant baixes concentracions de catalitzador i sense excés de lligand.<br/>El capítol 6 descriu l'aplicació de les tres famílies de compostos (L1-L11) com a lligands en la reacció d'addició 1,4 catalitzada per coure de compostos organometàl·lics a diferents enones amb diferents propietats estèriques. <br/>L'ús de les llibreries de compostos fosfit-oxazolina (L1-L5) i fosfit-fosforamidit (L6) han proporcionat bones enantioselectivitats (fins a 78%) en l'addició de reactius de trialquilalumini a diferents enones. En canvi, la llibreria de compostos monofosfit (L7-L11) ha mostrat bones activitats però enantioselectivitats fins a 57%.<br>The growing demand for enantiomerically pure compounds for the development of pharmaceuticals, agrochemicals and flavors has captured the interest of the chemist in the last few decades. Of the various methods for producing enantiopure compounds, enantioselective homogeneous metal catalysis is an attractive one. In this context, carbohydrates have many advantages: they are readily available, are highly functionalized and have several stereogenic centers. This enables series of chiral ligands to be synthesized and screened in the search for high activities and selectivities for each particular reaction.<br/> In this context, this thesis focuses on the development of new chiral ligand libraries derived from carbohydrates, the synthesis of new catalyst precursors and their application in the Pd-catalyzed asymmetric allylic substitution, Pd-catalyzed asymmetric Heck reactions, Ni-catalyzed asymmetric addition of trialkylaluminium to aldehydes, and Cu-catalyzed asymmetric 1,4-conjugated addition of trialkylaluminium reagents to enones. <br/> For this porpose, we have designed and syntezied 3 new sugar based ligand libraries: phosphite-oxazoline (L1-L5), phosphite-phosphoroamidite (L6) i monophosphite (L7-L11) (Figure 1). <br/>After introduction (Chapter 1) and objectives (Chapter 2), in chapter 3 is discussed the synthesis and characterization of the ligand libraries (L1-L11) and and their application in the asymetric Pd-catalyzed allylic substituion reactions. <br/> Using phosphite-oxazoline ligands (L1-L5) we observed important effects of the oxazoline substituents and the axial chirality and the substituents of the biaryl moieties. However, the effects of these parameters depended on each substrate. High enantioselectivities (up to 99%) and good activities have been achieved in a wide range of substrates with different steric and electronic properties. <br/> The study of the Pd-1,3-diphenyl, 1,3-dimethyl and 1,3-cyclohexenyl allyl intermediates by NMR spectroscopy made it possible to understand the catalytic behaviour observed. This study also indicated that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphite moiety. <br/> <br/>Figura 1. Fosfit-oxazolina (L1-L5), fosfit-fosforamidit (L6) i monofosfit (L7-L11).<br/><br/> Asymmetric substitution reactions with catalyst precursors containing the phosphite-phosphoroamidite ligands showed that enantiomeric excesses depend strongly on the substituents at the para positions of the biphenyl moieties. However, these effects were different depending on the substrate in study. Enantiomeric excesses of up to 89% with high activities were obtained for rac-1,3-diphenyl-3-acetoxyprop-1-ene, rac-(E)-ethyl-2,5-dimethyl-3-hex-4-enylcarbonate and rac-3-acetoxycycloheptene. For the monosubstituted linear substrate 1-(1-naphthyl)allyl acetate, these ligands proved to be inadequate in terms of regioselectivities. However, we obtained good enantioselectivity by carefully selecting the substituents on the para position of the biphenyl moieties (ee's up to 72%). <br/> If we compare these results with those from the catalyst precursors containing the previous phosphite-oxazoline ligands (L1-L5), we found that the replacement of the oxazoline moiety by a phosphoroamidite group decreased enantioselectivities and versatibility. <br/> Asymmetric allylic alkylation with catalyst precursors containing the sugar-based monophosphite ligand library showed that the catalytic performance is highly affected by the size of the sugar backbone, the configurations at C-3 and C-4 of the ligand backbone and the type of substituents/configurations in the biaryl phosphite moiety. Low-to-moderate enantioselectivities (up to 46%) were obtained. <br/> In the asymmetric Pd-catalyzed Heck reactions (Chapter 4) with catalysts precursors based on phosphite-oxazoline ligands, we obtained excellent activities (up to 100% conversion in 10 minutes), regio- (up to >99%) and enantioselectivities (up to 99%) were obtained in a wide range of substrates and triflate sources. <br/> In the asymmetric Ni-catalyzed 1,2-addition of trialkylaluminium to aldehydes (Chpater 5) with catalysts precursors based on phosphite-oxazoline and phosphite-phosphoroamidite ligands, we found that the selectivity depends strongly on the type of functional group attached to the carbohydrate backbone, on the steric properties of the oxazoline substituents and on the substrate structure. Enantioselectivities up to 59% were obtained using the catalyst precursor containing the phosphite-oxazoline ligand L3a. In contrast to what we observed with the previous two ligand libraries, using sugar-based monophosphite ligands (L7-L11) provides high enantioselectivities (up to 94% ee) and activities in different substrate types, with low catalysts loadings and without excess of ligand. <br/> In Chapter 6, we described the phosphite-oxazoline and phosphite-phosphoroamidite ligands as chiral auxiliaries in the asymmetric Cu-catalyzed 1,4-conjugated addition of trialkylaluminium reagents to several enones provides good enantioselectivities (up to 80% ee). <br/> In the asymmetric Cu-catalyzed asymmetric 1,4-conjugated addition of trialkylaluminium reagents to several enones with catalysts precursors based on sugar monophosphite ligands, we found good activites and enantioselectivities up to 57% ee.

This thesis deals with method development in asymmetric catalysis and specifically syntheses of enantioenriched O-functionalized cyanohydrins. The first part describes the development of a method for the synthesis of O‑alkoxycarbonylated and O-acylated cyanohydrins. Ethyl cyanoformate and acyl cyanides were added to aldehydes in a reaction catalyzed by a chiral dimeric Ti-salen complex together with a tertiary amine. High yields and enantioselectivities were in most cases obtained. Mechanistic studies were performed and a reaction mechanism was proposed. ­ The second part describes a method in which the undesired minor enantiomer in a Lewis acid–Lewis base-catalyzed acylcyanation is continuously recycled into prochiral starting material. Close to enantiopure O‑acylated cyanohydrins were obtained in high yields. The third part deals with asymmetric acylcyanations of ketones. Acetyl cyanide was found to add to α‑ketoesters in a reaction catalyzed by a chiral Lewis base. Yields up to 77% and 82% ee were obtained. The final part describes an enzymatic method for high-throughput analysis of O‑acylated cyanohydrins. The enantiomeric excess and conversion were determined for products obtained from a number of aromatic and aliphatic aldehydes.<br>QC 20100818

Cette étude a porté sur l’analyse de l’énantiosélectivité de la lipase de Burkholderia cepacia (BCL) pour les acides 2-substitués, synthons chiraux d’intérêt pharmaceutique, avec pour objectif d’examiner le rôle de l’accès au site actif enfoui de BCL sur l’énantiosélectivité et de développer une procédure d’ingénierie permettant de créer des mutants d’énantiosélectivité améliorée. Pour traiter le problème, une nouvelle approche de calcul, basée sur des algorithmes de planification de mouvements issus de la robotique a été développée. Elle permet l’exploration conformationnelle des espaces multi-dimensionnels contraints et a été appliquée au calcul des trajectoires de plusieurs racémiques dans le site actif de BCL et à l’identification de résidus pouvant potentiellement gêner le déplacement du substrat le long du site actif. Les résultats obtenus in silico ont révélé une corrélation qualitative avec les valeurs d’énantiosélectivité et ont permis de proposer des cibles de mutagénèse. Sur cette base, l’ingénierie du site actif de BCL a été entreprise pour moduler sélectivement l’accès des énantiomères R et S à la triade catalytique. Un système d’expression hétérologue de BCL chez E. coli compatible avec une expression en microplaque, a été développé. Une librairie de 57 (3x19) mono-mutants sur les positions : Leu17, Val266 et Leu287 a été construite par iPCR puis criblée en utilisant une procédure à moyen débit pour identifier les variants actifs pour l’hydrolyse du pNPB. L’énantiosélectivité de ces mutants a ensuite été évaluée pour l’hydrolyse du racémique (R,S)-2 bromophényl acétate de 2-chloro-éthyle, par utilisation d’une nouvelle procédure de criblage en deep-wells. Ce crible a permis de mettre en évidence plusieurs mutants dont les plus prometteurs ont été caractérisés. Ainsi les mutants Leu17Ser et Leu17Met présentent une augmentation de l’énantiosélectivité d’un facteur 10 accompagnée d’une augmentation de leur activité d’un facteur 4 à 5. Le mutant Val266Gly présente, quant à lui, une inversion de l’énantiosélectivité pour le substrat d’intérêt. L’étude des trajectoires par les techniques de planification combinée à une représentation sous la forme de carte de voxels a été réalisée en parallèle. Pour les mutants sélectionnés, une bonne corrélation a été observée entre les résultats obtenus in silico et expérimentalement. De plus, cela a permis de proposer de nouvelles combinaisons de mutations ayant conduit à l’identification de deux double-mutants Leu17Met/Val266Met et Leu17Ser/Leu287Ile d’énantiosélectivité supérieure à 150 pour le substrat modèle, révélant ainsi l’intérêt de l’approche semi-rationnelle proposée<br>This work has been focused on the understanding of the Burkholderia cepacia lipase (BCL) enantioselectivity towards 2-substituted acids which are chiral building blocks of pharmaceutical interest. The main objective of this work was the investigation of the potential role of substrate accessibility toward the buried active site of BCL on enantioselectivity and the development of an engineering procedure for the design of enantioselective mutants. To study further this hypothesis, a novel computational approach, based on motion-planning algorithms, originally used in robotics, was developed. It allows the conformational exploration of constrained high-dimensional spaces and was applied to the computation of trajectories for a set of racemates within the catalytic site. This methodology also enables the identification of residues potentially hindering substrates displacement along the active site. Results obtained in silico were correlated qualitatively with experimental values of enantioselectivity. On the basis of these results, engineering of the narrow active site of BCL has been undertaken to modulate selectively the access of R and S enantiomers to the catalytic triade. An heterologous expression system of BCL in E. coli compatible with production at microplate scale was developed. A library of 57 (3x19) variants targeted at positions Leu17, Val266 and Leu287 was built by iPCR and subsequently screened using a medium-throughput procedure to identify active variants against pNPB hydrolysis. Next, the enantioselectivity of these mutants was evaluated towards a given racemate, the (R,S)-2-chloro ethyl 2-bromophenylacetate, using a novel screening procedure developed in deep wells. Such screening enabled the identification of several variants amongst which the most promising were characterized. Mutants Leu17Ser and Leu17Met showed a remarkable 10-fold increase of their enantioselectivity and a 4- and 5-fold improvement of their specific activity. Compared to the wild-type enzyme, mutant Val266Gly displayed a reversed enantioselectivity for the substrate of interest. Investigation of the trajectories using motion-planning techniques combined to a voxel map representation was carried out. For selected variants, a fair correlation was observed between in silico and experimental results. Moreover, this enabled us to suggest novel combinations of mutations that led to the identification of two double-mutants Leu17Met/Val266Met and Leu17Ser/Leu287Ile showing an enantioselectivity value higher than 150 for the racemic substrate, revealing thus the effiency of the semi-rational strategy

碩士<br>國立臺灣科技大學<br>化學工程系<br>101<br>The objective of this study was to examine the effects of preparation variables on the catalytic properties of CuAlPO4 molecular sieve, and to know the conditions required to synthesize a CuAlPO4 of high activity in the synthesis of phenol. The study began with the comparison of two synthesis methods, the hydrothermal and one-step methods, for the molecular sieves. Two templates, TPA and F127 and their mixture were used in the hydrothermal method. But the one-step method used only F127. The results showed that the molecular sieves prepared using TPA as a template were not very active. Of the molecular sieves prepared using F127, the one from one-step method exhibited superior activity. Next, attempts were made on optimizing the one-step method. The factors examined were the quantity of F127 and copper used and the calcination temperature. The results showed that for each mole of AlPO4, the most appropriate amounts of F127 and copper were 1g and 0.1 mole respectively and with the optimal calcination temperature being 450℃. The catalysts prepared in this study were characterized by XRD, BET, FESEM, NH3-TPD, TGA, and TEM. The activities of the catalysts were examined by phenol syntheses. Syntheses were carried in liquid phase using a batch reactor. The reactants were benzene and hydrogen peroxide with acetonitrile as the solvent. The product selectivity was extremely high with no other organic product being detected except phenol. The activation energy determined based on the data taken from 50-70℃ was 73.2 kJ/mol. The active center was found on AlPO4 surface. Copper played a role as a catalyst promoter. Serious catalyst deactivation was detected due mainly to coking and copper leaching. Deactivated catalyst could be regenerated by washing and burning off the carbon deposit. However, the activity of the regenerated catalyst was less than the original fresh one. The rate of deactivation was related to the concentration of hydrogen peroxide. Using low concentration of hydrogen peroxide in the reaction could prevent the deactivation.

M. Tech. (Department of Chemical Engineering, Faculty of Engineering and Technology): Vaal University of Technology<br>The arylation and alkenylation of alkenes under the influence of a palladium catalyst, commonly referred to as the Heck reaction, has been extensively exploited by synthetic chemists since its debut in the late 1960’s. A traditional Heck coupling is based on an aryl iodide or bromide as the electrophilic partner and a terminal alkene as the nucleophilic partner. Academic and industrial interest in this reaction has increased in recent years, fueled by the development of more active catalyst systems, the discovery of waste-free versions, and the desire to put the vast empirical data on a sound mechanistic basis. In this study, we wish to report the use of commercially available substituted pyrazolones (1-(4-Sulfophenyl)-3-methyl-5-pyrazolone (L1), 1-(2,5-Dicloro-4-sulfophenyl)-3-methyl-5-pyrazolone (L2) and 5-oxo-1-phenyl-2-pyrazolin-3-carboxylic acid (L3)) and pyrazoles (α-[(2-Ethoxy-2-oxoethoxy)imino]-3-pyrazole acetic acid (L4) and 3.5 dimethyl pyrazole (L5)) as auxiliary ligands in the Heck coupling reaction. These ligands were used either with PdCl2 or Pd(OAc)2 to catalyze the Heck reaction of iodobenzene with ethyl acrylate or butyl acrylate. GC-MS was used to monitor the reaction, percentage (%) conversions were determined based on the consumption of iodobenzene. Different reaction parameters such as ligands, temperature, base, solvent and influence of time were investigated. It was observed that the lower conversion was obtained for ethyl acrylate and conversions above 80% were obtained for butyl acrylate. Ligand effect proved to be very crucial during the Heck coupling reactions of iodobenzene with butyl acrylate and ethyl acrylate. For instance in the absence of ligands with PdCl2, the conversions were 29 % and 44 % for butyl acrylate and ethyl acrylate, respectively. When Pd(OAc)2 was used in the absence of ligands the conversions were 25 % and 36 % for butyl acrylate and ethyl acrylate, respectively. In the study for the effect of temperature, 80 ◦C was observed as the best temperature since promising conversions were obtained with little or no sign of deactivation of the catalysts. On the other hand, increasing the temperature to 120 ◦C and above high percent conversions are observed; however deactivation of the catalysts occurs as observed from the precipitation of palladium black at the bottom of the vial. From the results obtained it is clear that pyrazolone and pyrazole ligands/palladium systems are important at very low catalyst loadings and mild temperatures. Based on the employed reaction conditions the influence of base suggested that the organic base triethylamine was the reagent of choice since better conversions were obtained compared to inorganic bases. The inhomogeneity of the inorganic base proved to be a disadvantage in the reaction of iodobenzene with butyl acrylate at employed reaction conditions. It was also found that parameters such as solvents and time effects were important in the Heck reaction. Polar aprotic solvents proved to be solvents of choice rather than non-polar solvents, from the investigated solvents DMF gave better conversions under the used reaction conditions giving average conversions of 78 % and 75 % for all the ligands in the presence of PdCl2 and Pd(OAc)2, respectively. During the investigation of time effect, it was noteworthy to observe that L4 had a slow initiation rate, for instance after 0.5 h conversions of 2 % and 10 % were obtained for catalytic systems, PdCl2 and Pd(OAc)2 respectively. Also it was observed that under the investigated parameters there was no need to run the reaction for 24 h because after 4 h not much of a difference in conversions was observed. In comparing the influence of these two different auxiliary ligands, pyrazolone based ligands were more efficient than pyrazole based ligands under the investigated parameters. The fully detailed information supporting this has been discussed in Chapter 4.

碩士<br>國立勤益科技大學<br>化工與材料工程系<br>100<br>This Study hopes to simulate the industrial process by used the high-pressure plug-flow fixed-bed reactor from lab self-assembly, and carried out the production of PX while provide the relevant parameters to the manufacturers production required.We bought different Silicon to Aluminum ratio and different particle size of ZSM-5 catalyst, which to examined the activity of toluene disproportionation, and modified the catalyst by Si-CVD/Base molecule poison in order to promote the selectivity of PX. The result of experimental show that unmodified ZSM-5 catalyst with the highest convert activity is 46.6% from CBV2314, and the lowest convert activity only 1.28% from GPPC01. The lower conversion of toluene disproportionation over the Silicon to Aluminum ratio increases of ZSM-5 catalyst, according to the results of the screening test of 14 kinds of catalyst, Silicon to Aluminum ratio about 30 could get a better conversion.We used Si-CVD modify ZSM-5 catalyst in four modified condition : which can be obtained the PX selectivity 97.0% on modified CBV2314, and toluene conversion of 14.4%. The modified after Si-CVD CBV2314 further tuning modified the catalyst of used base molecular, could be once again raise the PX selectivity to 98.6%, while the conversion of toluene was 4.6%.

Enantioselective indicator displacement assays (eIDAs), was transitioned to a high-throughput screening protocols, for the rapid determination of concentration and enantioselectivity (ee) of chiral diols and α-hydroxycarboxylic acid. To improve the design of our previously established receptor based on o-(N,N-dialkylaminomethyl)arylboronate scaffolds for eIDAs. The rigidity of the receptor, which pertinent from the formation of an intramolecular N-B dative bond was investigated. o-(Pyrrolidinylmethyl)phenylboronic acid its complexes with bifunctional substrates such as catechol, [alpha]-hydroxyisobutyric acid, and hydrobenzoin was studied in detail by x-ray crystallography and ¹¹B NMR. Our structural study predicts that the formation of an N-B dative bond, and/or solvolysis to afford a tetrahedral boronate anion, depends on the solvent and the complexing substrate present. To simplify the operation of eIDAs, we introduced an analytical method, which utilize a dual-chamber quartz cuvette, which reduces the number of spectroscopic measurements from two to one and introduced artificial neural networks (ANNs) which simplifies data analysis. In a second example a high-throughtput screening protocol for hydrobenzoin was developed. The method involves the sequential utilization of what we define herein as screening, training, and analysis plates. Several enantioselective boronic-acid based receptors were screened using 96-well plates, both for their ability to discriminate the enantiomers of hydrobenzoin and to find their optimal pairing with indicators resulting in the largest optical responses. The best receptor/indicator combination was then used to train an ANN to determine concentration and ee. To prove the practicality of the developed protocol, analysis plates were created containing true unknown samples of hydrobenzoin generated by established Sharpless asymmetric dihydroxylation reactions, and the best ligand was correctly identified. The system was extended to pattern recognition for the rapid determination of identity, concentration, and ee of chiral vicinal diols. A diverse enantioselective sensor array was generated with three chiral boronic acid receptors and pH indicators. The optical response produced by the sensor array, was analyzed by two pattern recognition algorithms: principal component analysis (PCA) and ANNs. The PCA plot demonstrated good chemoselective and enantioselective separation of the analytes, and ANNs was used to accurately determine the concentration and ee of five unknown samples.<br>text

Thesis (Ph. D.)--University of Notre Dame, 2007.<br>Thesis directed by Paul McGinn for the Department of Chemical and Biomolecular Engineering. "April 2007." Includes bibliographical references (leaves 213-229).

<p>It is well-known that f-block elements can exhibit coordination modes which surpass those of the transition metals. With uranyl and uranium bis(imido) complexes a strong preference is shown for the oxo or imido ligands in the <i>trans-</i> position; a phenomenon which is known as the inverse trans- influence which is unique to high valent actinides. However, when a third imido is added to the complex, a decrease in bond order occurs and this preference is diminished. Through the synthesis of several novel coordination complexes of tris(2,6-diisopropylphenyl)imido uranium [U(NDipp)₃] with a variety of ligands, we were able to analyze the energy differentials between bonding modes in both the solution and solid state. Furthermore, density functional theory calculations were employed to model the energetic preferences between these geometries. The combination of analyses gives rise to the observation that the orientation of the imido substituents is fluxional depending on the rigidity of the supporting ligands, and oftentimes exhibits low energetic barriers for the formation of different conformers.</p> <p> Uranium tris(imido) species bearing <i>trans</i>-imidos are desirable synthons as they can be used to mimic reactivity of more complicated uranium oxide polymeric systems. Such systems are advantageous as they are easily soluble in organic solvents, making them amenable to standard characterization methods and ligand substitution strategies. Our group has previously shown that uranium tris(imidos), easily synthesized from [(^MesPDI^Me)U(THF)]₂ and various azides, feature axial imido substituents exhibiting differing bond characteristics than the adjacent equatorial imido substituent. The aim of this work is to show that multiple analogues of mixed imido products can be formed from either the aforementioned dimer or stable tris(imido) synthons by exploiting reactivity differences between the axial and equatorial positions. </p> Presented herein are novel copper-​catalyzed ring opening reactions of cyclopropanols and various electrophiles to synthesize a variety of beta-​functionalized ketones. The reactions feature mild conditions and tolerates a wide selection of functional groups leading to complex products which can be used in the synthesis of bioactive molecules.

碩士<br>逢甲大學<br>化學工程學系<br>101<br>In this study, hydrogen oxidation catalyst and hydrogen revolution catalyst were rapidly screened by scanning electrochemical microscopy (SECM). These arrays were prepared based on the concept of the combinational method. Primarily and dopes the multi-component alloy catalyst array by the platinum which other metal Co, Cu, Ir, Ni, Pb, Fe, Zn, Cr, Sn and Mo manufacture. The surface morphology, elemental composition and structure of electrocatalysts were characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDX) and High Resolution X-ray Diffraction （HRXRD）, respectively. Hydrogen oxidation catalyst arrays were screened with a TG-SC mode by SECM. Tip/substrate voltammetry and approach curve measurements were used to examine the kinetics of the potential electrocatalysts toward hydrogen oxidation. Results show that, Pt1Co3Cu1、Pt1Ir2Ni2和Pt1Zn4 showed better catalytic activity toward hydrogen oxidation. The kinetic parameters for hydrogen oxidation were obtained by fitting approach curves. The rate constant of the Pt-based electrocatalysts were about in the range from 0.29 to 0.32 cm/s. Hydrogen revolution catalyst arrays were screened with a SG-TC mode by SECM. Finally, there is the use of cyclic voltammetry, tafel and polarization curves to analyze the stability and kinetic parameters. In the acidic environment, Pt1Co2Cu2/C, Pt1Ir2Ni2/C, Pt1Pb1Fe3/C and Pt1Zn1Cr3/C,catalysts , and in the alkaline environment, Pt1Zn1Cr3/C and Pt2Sn1Mo2/C show better catalytic acivity.

碩士<br>逢甲大學<br>化學工程學系<br>107<br>The aim of this study is to discovery the optimum composition of NiO2-based binary and ternary metal oxide catalysts for oxygen evolution reaction (OER) by scanning electrochemical microscopy. A metal oxide mainly composed of nickel and added with other metals such as cobalt, iron, lanthanum, gallium, vanadium, gold, silver, lanthanum, manganese, lanthanum, tin, zinc, copper, tungsten by the combinatorial methods. The ratio of the catalyst with higher activity after screening is prepared into a large electrode. The Tafel slope, electron transfer coefficient, standard rate constant, onset potential and amount of oxygen evolution of the catalysts were determinded by Tafel plots, linear sweep voltammetry and polarization curve . The surface morphology and elemental compositon of catalysts were characterized by sanning electron microscope and energy dispersive spectrometer while the crystalline and chemical state of the catalysts were characterized by high resolution X-ray diffractometer and X-ray photoelectron spectroscope. The results show that the Ni0.4Ir0.2Co0.4Ox catalysts have the best activity for OER. The catalytic current value, overpotential and standard rate constant of the Ni0.4Co0.4Ir2Ox catalysts are 9.44 nA/cm2, 0.492V and 2.4110-12 cm/s at 0.55 V vs. Ag/AgCl. Key word：metal oxide catalysts, nickel oxide, oxygen evolution reaction (OER), scanning electrochemical microscopy (SECM)

The demand for novel and robust microbial biocatalysts for industrial and pharmaceutical applications continue to grow at a fast pace.This warrants a continuous need for advanced tools and technologies to exploit the vast metabolic potential of microorganisms in different environments. Unlike culture-based studies that can only reveal the metabolic potential of cultivable microorganisms, functional metagenomics charts the enzymatic potential of the entire microbial communities in a given environment. This method has substantially contributed to the effective discovery of unique microbial genes for industrial and medical applications. Functional metagenomics involves the extraction of microbial DNA directly from environmental samples,construction of an expression library containing the entire microbial genome, and screening the libraries for the presence of desired phenotypes. Therefore, development of a pipeline for analyzing and screening metagenomic libraries is essential for rapid detection of the desired features from thousands of clones of a single library. Here, we developed a pipeline for high-throughput screening of the lipolytic genes from the Red Sea.Further, a high-throughput single cell microfluidics platform combined with a laser-based fluorescent screening bioassay was deployed to discover new lipolytic genes. Our analysis led to the identification of 24 microbial genes for lipases and esterase from a metagenomic library of the Red Sea water. The results further showed that the constructed pipeline is robust in conducting functional metagenomics and for the discovery of new genes. It also implies that the Red Sea is a rich under- investigated source of natural resources of new genes and gene products.

碩士<br>逢甲大學<br>化學工程學所<br>100<br>In this study, multi-component electrocatalyst arrays (Pd-M, M=Co, Ni, Fe) were rapidly screened for hydrogen oxidation reaction (HOR) by scanning electrochemical microscopy (SECM). These arrays were prepared based on the concept of the combinational method. The surface morphology, elemental composition and structure of electrocatalysts were characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDX) and High Resolution X-ray Diffraction （XRD）, respectively. All electrocatalyst arrays were screened with a TG-SC mode by SECM.Tip/substrate voltammetry and approach curve measurements were used to examine the kinetics of the potential electrocatalysts toward hydrogen oxidation. Results show that, among bimetallic electrocatalysts, Pd8Co2, Pd7Ni3, Pd9Fe1 showed better catalytic activity toward hydrogen oxidation than others. The Pd7Ni3 was the best electrocatalyst for hydrogen oxidation . The ternary electrocatalysts have poorer catalytic activity than the bimetallic electrocatalysts. According to the tip/substrate voltammetry analysis, hydroxide and oxides coverd bimetallic electrocatalyst surface become inactive at hight potential of 0.4 V. The kinetic parameters for hydrogen oxidation were obtained by fitting approach curves. The rate constant (k0) of the Pd-based electrocatalysts were about in the range from 0.004 to 0.009 cm/s.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2007.<br>Title from title screen (site viewed Feb. 17, 2009). PDF text: viii, 383 p. : ill. (chiefly col.) ; 49.9 Mb. UMI publication number: AAT 3294904. Includes bibliographical references. Also available in microfilm and microfiche formats.

<p>The recent surge in shale gas production led to increases in alkane resources across the United States. One promising approach to convert the alkanes to higher value products is through dehydrogenation and oligomerization processes. This conversion to alkenes, if done in small modular units near the shale wells further aids in the ease of transportation and distribution of the final products. However, having highly selective processes is a major hindrance to improve the economic feasibility of the modular processes. Theoretical studies are of great significance to analyze detailed reaction mechanisms and identify the reaction pathways that leads to unselective product formations. These studies further enable the search for selective catalysts for any given chemistry based on descriptor analysis. Therefore, in this work Density Function Theory and Ab-initio Molecular Dynamics methods are used in conjunction with microkinetic modeling analyses to investigate the complex reaction networks involved in the shale gas conversion. Specifically, the work focuses on propane dehydrogenation (PDH) on alloy surfaces along with ethylene oligomerization on zeolite catalysts.</p><p> A major part of thesis is focused on finding selective and stable alloy catalysts for PDH chemistry. The initial work focused on understanding the selectivity, activity, and stability differences between 1:1 intermetallic alloys (PdIn) and the pure metal surfaces. This combined experimental and computational study shed light on the important role of step surfaces in understanding the activity trends across alloys. Through a detailed microkinetic analysis and simplified rate expression analysis, a novel selectivity descriptor in terms of effective barriers for propane C-H bond breaking and propyne C-C bond breaking was derived for propylene formation. This newly proposed descriptor showed greater fidelity for predicting the trends in experimental selectivities for a small set of Pd alloys than the previously proposed selectivity descriptors. Building upon these insights, a high throughput screening framework using graph-theory algorithms and python-based databasing has been developed to identify trends across a larger set of alloy combinations. The framework helped us identify a novel set of alloys that have not been explored until now for this chemistry. These alloy combinations were then experimentally tested and shown to have high selectivities for propylene formation and along with stabilities close to benchmark Pt-Sn catalysts. Detailed transition state analysis on terraces shows that the undesired C-C bond breaking pathways involves larger surface atom ensembles (4-5 atoms) while the C-H bond breaking involves smaller surface atom ensembles (1-2 atoms). This led to the conclusion that the site-isolation of active metal atoms is important to increase the selectivities for propylene formation. More importantly the combination of detailed mechanistic and screening studies using graph-theory methods shows a generalized framework towards finding new catalysts spaces for complex chemistries.</p><p>The work on ethylene oligomerization on the other hand is focused on understanding the role of mobility of active Ni species in the zeolites towards isomerization and deactivation reaction mechanisms. For this specific project, we have used state-of-the-art AIMD methods, including potential of mean force calculations, for accurate estimation of free energies for the reaction intermediates and transition states. The thermodynamic and kinetic analyses show that the reaction pathways involving mobile intermediates have the highest rates towards butene formations even under pressures lower than 1 bar. Further the isomerization step is found to be feasible on Ni-ethyl complex in agreement with experiments. Finally, the mobile complexes were shown to dimerize through alkyl bridged complexes and the generated complex has higher barriers for C-C bond formation than the isolated complex indicating that these are likely pathways for catalyst deactivation. This mechanistic understanding paves the way for fine-tuning the reaction conditions as well as ways in which the active site can be speciated inside the zeolitic frameworks to increase the selectivity towards 1-butene and reduce deactivation.</p>

<p>Various organic reactions, including important synthetic reactions involving C–C, C–N, and C–O bond formation as well as reactions of biomolecules, are known to be accelerated when the reagents are present in confined volumes such as sprayed or levitated microdroplets or thin films. This phenomenon of reaction acceleration and the key role of interfaces played in it are of intrinsic interest and potentially of practical value as a simple, rapid method of performing small-scale synthesis. This dissertation has three focusing subtopics in the field of reaction acceleration: (1) application of reaction acceleration in levitated droplets and mass spectrometry to accelerate the reaction-analysis workflow of forced degradation of pharmaceuticals at small scale; (2) fundamental understanding of mechanisms of accelerated reactions at air/solution interfaces; (3) discovery the use of glass particles as a `green' heterogeneous catalysts in solutions and systematical study of solid(glass)/solution interfacial reaction acceleration as a superbase for synthesis and degradation using high-throughput screening.</p><p><br></p><p>Reaction acceleration in confined volumes could enhance analytical methods in industrial chemistry. Forced degradation is critical to probe the stabilities and chemical reactivities of therapeutics. Typically performed in bulk followed by LC-MS analysis, this traditional workflow of reaction/analysis sequence usually requires several days to form and measure desirable amount of degradants. I developed a new method to study chemical degradation in a shorter time frame in order to speed up both drug discovery and the drug development process. Using the Leidenfrost effect, I was able to study, over the course of seconds, degradation in levitated microdroplets over a metal dice. This two-minute reaction/analysis workflow allows major degradation pathways of both small molecules and therapeutic peptides to be studied. The reactions studied include deamidation, disulfide bond cleavage, ether cleavage, dehydration, hydrolysis, and oxidation. The method uses microdroplets as nano-reactors and only require a minimal amount of therapeutics per stress condition and the desirable amount of degradant can be readily generated in seconds by adjusting the droplet levitation time, which is highly advantageous both in the discovery and development phase. Built on my research, microdroplets can potentially be applied in therapeutics discovery and development to rapidly screen stability of therapeutics and to screen the effects of excipients in enhancing formulation stabilities.</p><p><br></p><p>My research also advanced the fundamental understanding of reaction acceleration by disentangles the factors controlling reaction rates in microdroplet reactions using constant-volume levitated droplets and Katritzky transamination as a model. The large surface-to-volume ratios of these systems results in a major contribution from reactions at the air/solution interface where reaction rates are increased. Systems with higher surface-active reactants are subject to greater acceleration, particularly at lower concentrations and higher surface-to-volume ratios. These results highlight the key role that air/solution air/solution interfaces play in Katritzky reaction acceleration. They are also consistent with the view that reaction increased rate constant is at least in part due to limited solvation of reagents at the interface.</p><p><br></p><p><br></p><p>While reaction acceleration at air/solution interfaces has been well known in microdroplets, reaction acceleration at solid/solution interfaces appears to be a new phenomenon. The Katritzky reaction in bulk solution at room temperature is accelerated significantly by the surface of a glass container compared to a plastic container. Remarkably, the reaction rate is increased by more than two orders of magnitude upon the addition of glass particles with the rate increasing linearly with increasing amounts of glass. A similar phenomenon is observed when glass particles are added to levitated droplets, where large acceleration factors are seen. Evidence shows that glass acts as a ‘green’ heterogeneous catalyst: it participates as a base in the deprotonation step and is recovered unchanged from the reaction mixture. </p><p><br></p><p>Subsequent to this study, we have systematically explored the solid/solution interfacial acceleration phenomena using our latest generation of a high-throughput screening system which is capable of screening thousands of organic reactions in a single day. Using desorption electrospray ionization mass spectrometry (DESI-MS) for automated analysis, we have found that glass promotes not only organic reactions without organic catalysts but also reactions of biomolecules without enzymes. Such reactions include Knoevenagel condensation, imine formation, elimination of hydrogen halide, ester hydrolysis and/or transesterification of acetylcholine and phospholipids, as well as oxidation of glutathione. Glass has been used as a general `green' and powerful heterogeneous catalyst.</p>