Les travaux présentés portent sur l’étude du HNBR (Hydrogenated Nitrile Butadiene Rubber), un polymère à base d’acrylonitrile, pour son application en tant que liant d’électrodes dans les batteries lithium ions. Cette thèse repose sur un partenariat avec l’entreprise Hutchinson (spécialisée dans le domaine des polymères) qui a cherché à développer un nouveau procédé pour la fabrication des électrodes. Ce procédé par voie fondue a soulevé la problématique du polymère liant utilisé dans les électrodes puisque ce dernier doit être compatible avec le procédé tout en étant utilisable dans des batteries. C’est dans l’optique de trouver et valider un tel polymère que s’inscrit cette thèse sur le polymère HNBR. En premier lieu, nous nous sommes concentrés sur les répercussions du traitement thermique, étape importante du procédé par voie fondue, sur le HNBR. Il a été conclu que le traitement thermique conduit à une réticulation du polymère aidant ainsi à la stabilité chimique du HNBR dans les électrolytes organiques des batteries. Ensuite, le HNBR a été introduit comme liant d’électrodes et a été analysé, avec le procédé de fabrication classique puis avec le nouveau procédé. Nous avons remarqué que le HNBR est un bon candidat pour être utilisé dans un système électrochimique car il y est stable sur une large gamme de potentiels et permet d’obtenir des performances en cyclage et en puissance intéressantes. Face à ce constat, la dernière partie des travaux s’est concentrée sur une analyse approfondie du système en étudiant les interactions entre les fonctions polaires du HNBR, les nitriles, et les ions lithium présents dans l’électrolyte. La combinaison polymère-sel-solvant a été étudiée pour comprendre comment chacun de ces paramètres impacte les propriétés électrochimiques du système et en particulier la conductivité. Nous avons remarqué qu’un taux d’acrylonitrile élevé est favorable à une plus haute conductivité et que le solvant, de par son affinité avec le HNBR, est également à considérer. / In this thesis, we have investigated an acrylonitrile-based polymer, HNBR (Hydrogenated Nitrile Butadiene Rubber), for its application in lithium ion batteries. This work relies on a partnership with the company Hutchinson (specialized in polymers) who was interested in developing a new process for the fabrication of electrodes. This melt-based process revealed problems regarding the polymer that is used as a binder for the electrodes as it needs to be compatible with the process as well as with the application in batteries. The aim of the thesis was therefore to find and validate a polymer meeting these requirements. Hence, HNBR was investigated. At first, we focused on the thermal treatment of HNBR, a key step of the melt-process. It was concluded that the thermal treatment leads to the cross-linking of HNBR, which is an asset because it increases the chemical stability of HNBR in the presence of the organic electrolyte. The following step was to introduce HNBR into the electrode formulation and investigate the performances of electrodes, made with the classical process and then with the melt process. It was found that HNBR is a good candidate to be introduced in an electrochemical system because it is stable over wide potential ranges and it allows interesting cycling and power performance. Faced with these findings, the last part of the study was to focus on analyzing the system more deeply by investigating the interactions between the HNBR polar functions, nitriles, and the lithium ions from the electrolyte. The ternary system polymer-salt-solvent was analyzed to understand the impact of each of these parameters on electrochemical properties, especially the conductivity. We noticed a high acrylonitrile content was beneficial to have a higher conductivity and that the solvent, regarding its affinity with HNBR, needs also to be considered.

Worldwide, malaria is one of the deadliest diseases. In 2016 it sickened 216 million people and caused 445,000 deaths. In order to control the spread of this deadly diseases to human, we can either target the mosquito vector (Anopheles gambiae) or the parasite (Plasmodium falciparum). Due to recent emergence of resistance to current insecticides and antimalarial drugs there is a pressing need to discover and develop new agents that engage new targets in these organisms. To circumvent the effect of resistance to pyrethroid insecticides on the efficacy of insecticide treated nets (ITNs), the use of acetylcholinesterase (AChE) inhibitors on ITNs has drawn attention. In the first project, we explored a small library of γ- substituted oxoisoxazole- 2(3H)-carboxamides and isoxazol-3-yl carbamates, and nitriles as AChE inhibitors targeting wild- type (G3) and resistant (Akron) An. gambiae mosquito. In total 23 compounds were synthesized and evaluated. Both carbamates and carboximides with a 2-cyclopropylethyl side chain (1-87a and 1-88a) were extremely toxic to Akron mosquitos, yet these compounds did not exhibit appreciable selectivity between human and An. gambiae AChE. Unfortunately, none of the nitriles showed appreciable toxicity to G3 strain of the mosquitoes, nor did they inhibit An. gambiae AChE. In the second project, conducted in collaboration with Professor Michael Klemba, we focused on the mode of action of an established antimalarial drug, Mefloquine (MQ). Dr. Klemba's recently developed amino acid efflux assay was used to determine the effect of MQ and its open-ring analogs on hemoglobin endocytosis and catabolism in P. falciparum-infected erythrocytes. In total 26 MQ analogs were synthesized and 18 were studied in depth to determine their potency to inhibit leucine (Leu) efflux and parasite growth (SYBR Green). An excellent correlation (R² = 0.98) over nearly 4 log units was seen for these 18 compounds in the two assays. These data are consistent with the hypothesis that the antimalarial action of these compounds principally derives from inhibition of hemoglobin endocytosis. After this observation, a number of photo-affinity probes were designed and synthesized in hopes of isolating the molecular target of MQ. These analogs are currently being used by Dr. Klemba in pull-down experiments. In the third project, conducted in collaboration with Professor Belen Cassera, we sought to optimize a new antimalarial drug lead that would circumvent current resistance mechanisms. In Plasmodium parasites, the methylerythritol phosphate (MEP) pathway is known to be essential for its growth. This pathway is absent in humans, presenting the opportunity to develop potentially safe and effective therapeutic candidates. Previous work in the Cassera and Carlier lab had established that MMV008138 was the only compound in the Malaria Box that targeted the MEP pathway and that it was (1R,3S)-configured. My research expanded previous efforts in the Carlier group and produced synthesis of 73 analogs of MMV008138 (3-21a'1) that were tested for growth inhibition. These analogs featured variation at the A-, B-, C- and D-ring. In the process, a novel Pictet-Spengler ring expansion reaction of ortho-substituted acetphenones was discovered. The ring-expanded products were identified by means of 1D and 2D NMR experiments, HRMS, and X-ray crystallography. Among the 73 analogs prepared, four compounds showed similar growth inhibition potency to the lead 3-21a'1. In particular, the methoxyamide 3-80a, and the fluorinated A-ring analogs 3-124a, 3-124c and 3-124d all showed excellent (500-700 nM) growth IC₅₀ values against P. falciparum. All four showed full rescue upon co-application of IPP (200 μM), confirming that they target the MEP pathway. ADME-Tox evaluation of these new analogs will soon be underway. / PHD / Malaria is a severe and potentially fatal mosquito-borne disease. The continuous emergence of insecticide-resistant mosquitoes and drug-resistant parasite strains necessitates the development of novel antimalarial agents, notably those that engage new targets in these organisms. Herein we present three projects in which the synthesis and characterization of new malaria insecticide and therapeutic candidates are described. Our aim in the first project was to synthesize acetylcholinesterase (AChE) inhibitors as potential mosquitocides to be deployed on insecticide-treated nets. Three different classes of compounds were synthesized and characterized. Their potency to inhibit the wild-type and insecticide-resistant mosquito AChE, and their corresponding mosquito toxicities were assessed. Mosquito-toxic compounds were identified, but they did not show appreciable selectivity between mosquito and human AChEs. The second project was directed toward finding the biological target of a known antimalarial drug; mefloquine (MQ). Numerous different MQ analogs were synthesized, and their potency was assessed in two biochemical assays. The results of this study strongly suggest that MQ kills malaria parasites by preventing them from ingesting the red blood cell hemoglobin. The third project was concerned with the optimization of a compound (MMV008138) that kills malaria parasites by preventing it from synthesizing a key biochemical building block (IPP). Several new compounds were prepared that had similar antimalarial activity to MMV008138, of which many have better potential to serve as antimalarial drugs. In addition, these studies provided valuable insights for the design of further improved analogs.

Les spectroscopies de photoémission, d'absorption X –assistées par des calculs DFT d'états de coeur excités – et la microscopie tunnel, ont permis de déterminer avec précision les géométries d'adsorption, sur la surface Si(001)-2×1, de quatre molécules possédant un groupe cyano, monofonctionnelle - comme l'acétonitrile - ou polyfonctionnelles - comme le benzonitrile, l'acrylonitrile et le cyanure de vinyle. La chimie organique fournit le cadre général des réactions possibles à la surface. Ce sont des considérations d'ordre cinétique qui sélectionnent les modes d'adsorption des molécules organiques. Un réglage fin des conditions expérimentales permettrait donc d'obtenir les modes d'adsorption désirés en vue d'application dans le domaine de l'électronique moléculaire.

The central role of Src in the development of several malignancies including breast cancer and the accumulating evidence of its interaction with receptor tyrosine kinases (RTK), integrins and steroid receptors have identified it as an attractive therapeutic target. In the current study we have evaluated the effect of a Src/Abl kinase inhibitor SKI-606, on breast cancer growth, migration, invasion and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion and migration by inhibiting MAPK and Akt phosphorylation. For in vivo studies MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP) [MDA-MB-231-GFP] were inoculated into mammary fat pad of female BALB/c nu/nu mice. Once tumor volume reached 30-50 mm3, animals were randomized and treated with vehicle alone or 150 mg/kg of SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45-54%) as compared to control animals receiving vehicle alone. Analysis of lungs, liver and spleen of these animals showed a significant decrease in GFP positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factors expression and inhibition of Src mediated signalling pathways in vivo. Together the results from these studies provide compelling evidence for the use of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.

No description available.

[ES] El panorama industrial actual se enfrenta a desafíos significativos mientras transita hacia la descarbonización y la sostenibilidad, impulsado por el imperativo de lograr emisiones netas cero para 2050. Se espera una importante contribución hacia este objetivo al conectar materias primas no convencionales y renovables, alternativas a los materiales fósiles convencionales como el petróleo, a las cadenas de valor existentes de la industria química. Actualmente, existe un creciente interés industrial en la producción de nitrilos de cadena corta como HCN y acetonitrilo, mientras que se espera que las tasas de demanda global disminuyan en los próximos años en el caso del acrilonitrilo. Como reemplazo para materias primas convencionales para la producción de nitrilos, como las olefinas ligeras C2-3 de origen fósil, el desarrollo de rutas de conversión selectivas a partir de bloques de construcción C1 renovables, como el bio/e-syngas o su derivado metanol, y precursores N1 renovables, como el amoníaco verde, proporciona rutas hacia los productos químicos nitrilos, prospectivamente con una huella de carbono más baja. La presente tesis desarrolla y estudia catalizadores sólidos capaces de dirigir simultáneamente reacciones de acoplamiento C-N y C-C para la producción de nitrilos alifáticos C2+, particularmente acetonitrilo. Se hace hincapié en desvelar la naturaleza y estructura del verdadero catalizador activo, que se desarrolla bajo las condiciones del proceso. Específicamente, la tesis estudia efectos promocionales provocados por la combinación de dos metales en compuestos intersticiales mixtos de metales, aleaciones y compuestos intermetálicos. En primer lugar, se realizan estudios catalíticos y teóricos complementarios de Teoría del Funcional de la Densidad (DFT) sobre la conversión de mezclas de amoníaco (N1) y gas de síntesis (C1, CO+H2) a acetonitrilo con un (pre)catalizador monometálico MoO3. Estos estudios demuestran que MoN1-x, que se desarrolla mediante nitridación superficial, es el catalizador activo real y sugieren que la activación disociativa de HCN, asistida por oxígeno, es el paso controlante de la cinética de formación de acetonitrilo. A continuación, se estudian efectos promocionales de metales de transición divalentes de primera fila en catalizadores basados en molibdeno, utilizando un conjunto de compuestos de molibdato mixto cristalino, estructuralmente análogos, como precursores de catalizador. El dopado con Mn (Mn:Mo ~1) proporciona un catalizador particularmente selectivo y estable para la síntesis de acetonitrilo a partir de mezclas de NH3/gas de síntesis, logrando una tasa de formación de acetonitrilo de 50·10-3 mmol gcat-1 min-1 a 723K. Un conjunto de métodos in situ y operando con sensibilidad bulk y superficial, proporcionan evidencias de que un oxinitruro mixto MnM, con una simetría Fm-3m, y rico en defectos estructurales, representa el catalizador activo. Se sugiere que la mayor oxofilia del oxinitruro mixto MnMo, junto con el papel clave del oxígeno superficial para la activación disociativa de HCN, subyacen al efecto sinérgico de ambos metales. Finalmente, se estudió la conversión de mezclas en fase vapor de metanol (C1) y amoníaco (N1) a compuestos nitrogenados sobre nanocristales bimetálicos GaNi soportados en SiO2. Las aleaciones desordenadas de GaNi (Ga/(Ga+Ni)< 20%) son particularmente selectivas hacia la síntesis de nitrilos, mientras que los compuestos intermetálicos GaNi (Ga/(Ga+Ni)> 40%) catalizan principalmente la aminación de metanol a metilaminas. La difracción de rayos X y espectroscopía de absorción de rayos X, in situ y operando, revelan que el galio es un promotor necesario, el cual contribuye a la estabilización de fases expandidas de fcc Ni(C,N) así como Ni3C, a temperaturas relevantes para la catálisis (673-773K), cuyo desarrollo en la superficie del catalizador corresponde al inicio de la producción de nitrilos C2+ mediante la integración de reacciones de acoplamiento C-N y C-C. / [CA] El panorama industrial actual s'enfronta a desafiaments significatius mentres transita cap a la descarbonització i la sostenibilitat, impulsat per l'imperatiu d'aconseguir emissions netes zero per a 2050. S'espera una important contribució cap a este objectiu en connectar matèries primeres no convencionals i renovables, alternatives als materials fòssils convencionals com el petroli, a les cadenes de valor existents de la indústria química. Actualment, existix un creixent interés industrial en la producció de nitrils de cadena curta com HCN i acetonitril, mentres que s'espera que les taxes de demanda global disminuïsquen en els pròxims anys en el cas del acrilonitrilo. Com a reemplaçament per a matèries primeres convencionals per a la producció de nitrils, com les olefines lleugeres C2-3 d'origen fòssil, el desenvolupament de rutes de conversió selectives a partir de blocs de construcció C1 renovables, com el bio/e-syngas o el seu derivat metanol, i precursors N1 renovables, com l'amoníac verd, proporciona rutes cap als productes químics nitrils, prospectivament amb una petjada de carboni més baixa. La present tesi desenvolupa i estudia catalitzadors sòlids capaços de dirigir simultàniament reaccions d'acoblament C-N i C-C per a la producció de nitrils alifàtics C2+, particularment acetonitril. Es posa l'accent a revelar la naturalesa i estructura del verdader catalitzador actiu, que es desenvolupa sota les condicions del procés. Específicament, la tesi estudia efectes promocionals provocats per la combinació de dos metalls en compostos intersticials mixtos de metalls, aliatges i compostos intermetàl·lics. En primer lloc, es realitzen estudis catalítics i teòrics complementaris de Teoria del Funcional de la Densitat (DFT) sobre la conversió de mescles d'amoníac (N1) i gas de síntesi (C1, CO + H2) a acetonitril amb un (pre)catalitzador monometálico MoO3. Estos estudis demostren que MoN1-x, que es desenvolupa mitjançant nitridació superficial, és el catalitzador actiu real i suggerixen que l'activació dissociativa de HCN, assistida per oxigen, és el pas controlante de la cinètica de formació d'acetonitril. A continuació, s'estudien efectes promocionals de metalls de transició divalentes de primera fila en catalitzadors basats en molibdé, utilitzant un conjunt de compostos de molibdat mixt cristal·lí, estructuralment anàlegs, com a precursors de catalitzador. El dopat amb Mn (Mn:Mo ~1) proporciona un catalitzador particularment selectiu i estable per a la síntesi d'acetonitril a partir de mescles de NH3/gas de síntesi, aconseguint una taxa de formació d'acetonitril de 50·10-3 mmol gcat-1 min-1 a 723 K. Un conjunt de mètodes in situ i operant amb sensibilitat bulk i superficial, proporcionen evidències que un oxinitrur mixt MnM, amb una simetria Fm-3m, i ric en defectes estructurals, representa el catalitzador actiu. Se suggerix que la major oxofilia del oxinitrur mixt MnMo, juntament amb el paper clau de l'oxigen superficial per a l'activació dissociativa de HCN, subjauen a este efecte sinèrgic de tots dos metalls. Finalment, es va estudiar la conversió de mescles en fase vapor de metanol (C1) i amoníac (N1) a compostos nitrogenats sobre nanocristalls bimetàl·lics GaNi suportats en SiO2. Els aliatges desordenats de GaNi (Ga/(Ga+Ni)< 20 %) són particularment selectives cap a la síntesi de nitrils, mentres que els compostos intermetàl·lics GaNi (Ga/(Ga+Ni)> 40 %) catalitzen principalment l'aminació de metanol a metilamines. La difracció de raigs X i espectroscòpia d'absorció de raigs X, in situ i operant, revelen que el gal·li és un promotor necessari, el qual contribuïx a l'estabilització de fases expandides de fcc Ni(C,N) així com Ni3C, a temperatures rellevants per a la catàlisi (673-773 K), el desenvolupament de la qual en la superfície del catalitzador correspon a l'inici de la producció de nitrils C2+ mitjançant la integració de reaccions d'acoblament C-N i C-C. / [EN] The current industrial landscape is facing significant challenges as it transitions towards decarbonization and sustainability, driven by the imperative of achieving net-zero emissions by 2050. An important contribution towards this goal is expected from connecting unconventional and renewable feedstocks, alternative to conventional fossil raw materials such as crude oil, to existing value chains of the chemical industry. There is currently growing industrial interest in the production of short-chain nitriles such as acid cyanide and acetonitrile, while lower global demand rates are expected in the next years for acrylonitrile. Departing from conventional raw materials for nitrile production, such as C2-3 light olefin petrochemicals, the development of selective conversion routes from renewable C1 building blocks, such as bio/e-syngas or its derivative methanol, and renewable N1 precursors, like green ammonia, provides prospectively lower carbon footprint routes towards nitrile commodity chemicals. The present thesis develops and studies solid catalysts able to concomitantly steer C-N and C-C coupling reactions for the production of C2+ aliphatic nitrile N-chemicals, precisely acetonitrile. Emphasis is placed on unveiling the nature and structure or the true working catalyst, which develops under relevant process conditions. Specifically, the thesis studies promotional effects brought about by the combination of two metals in mixed-metal interstitial compounds, alloys and intermetallic compounds. First, complementary catalytic and theoretical Density Functional Theory studies on the conversion of mixtures of ammonia (N1) and syngas (C1, CO and H2) to acetonitrile with a monometallic MoO3 (pre)catalyst show MoN1-x, which develops upon near-surface nitridation, as the actual working catalyst and suggest O-assisted dissociative activation of HCN as a kinetically controlling step towards acetonitrile and higher nitriles. Next, promotional effects by first-row divalent transition metals on molybdenum-based catalysts are studied, using a set of structurally analogous crystalline ammonium mixed-metal molybdate compounds as catalyst precursors. Doping with Mn (Mn:Mo ~1) affords a particularly selective and stable catalyst for acetonitrile synthesis from NH3/syngas mixtures, achieving an acetonitrile formation rate of 50·10-3 mmol gcat-1 min-1 at 723 K. A battery of in situ and operando bulk and near-surface sensitive methods provide evidence that a defective MnMo mixed-metal oxynitride, with a Fm-3m symmetry, best represents the working catalyst. The higher oxophilicity of the mixed-metal MnMo oxynitride, alongside the key role of surface oxygen for HCN dissociative activation, is suggested to underlie the Mn-Mo bimetallic synergistic effect. Finally, the conversion of vapor mixtures of methanol (C1) and ammonia (N1) to N-compounds was studied on SiO2-supported GaNi bimetallic nanocrystals. Disordered GaNi alloys (Ga/(Ga+Ni)< 20 %) show to be particularly selective towards nitrile synthesis, whereas GaNi intermetallic compounds (Ga/(Ga+Ni)> 40 %) catalyzed primarily methanol amination to methylamines. In situ and operando X-ray diffraction and X-ray absorption spectroscopy reveal that Ga is a necessary promoter in nickel-based nanocrystals, contributing to the stabilization of expanded fcc Ni(C,N) and Ni3C phases at catalysis relevant temperatures (673-773 K), whose development on the catalyst surface corresponds to the onset of C2+ nitrile production by integration of C-N and C-C coupling reactions. / Martínez Monje, ME. (2024). Catalytic co-valorization of C1 and N1 compounds towards nitrile chemicals [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/207107

Gegenstand dieser Arbeit sind Versuche zur Synthese neuer binärer Kohlenstoffnitride im Allgemeinen und von C3N4-Vorläuferverbindungen im Speziellen. Hierbei werden v. a. die Herstellung und die Eigenschaften organischer Polyazide beschrieben, die aufgrund ihrer Gefährlichkeit durch zahlreiche Folgereaktionen in weniger brisante Moleküle überführt werden mussten. Als Derivatisierungsreaktionen kamen hierbei beispielsweise die 1,3-dipolare Cycloaddition mit Norbornen und Cyclooctin, die STAUDINGER-Reaktion mit verschiedenen Phosphinen sowie die Aza-WITTIG-Reaktion zum Einsatz. Es konnten dabei u. a. zehn Röntgeneinkristallstrukturen erhalten und als Strukturbeweis aufgeführt werden. Zahlreiche hochaufgelöste Massenspektren sowie Elementaranalysen und NMR-Daten bestätigten außerdem alle neu erhaltenen Strukturen. Einen weiteren Schwerpunkt dieser Arbeit stellen Versuche zur Synthese von monomerem C3N4 dar, dessen Herstellung zwar nicht gelang, für dessen Bildung allerdings neue Möglichkeiten ausgehend von verschiedenen Edukten beschrieben werden. Darüber hinaus wurden bereits bekannte Moleküle auf ihre Eignung als C3N4-Vorläufer untersucht, wobei z. B. durch Azid-Addition an Nitrilgruppen unerwartete neue Produkte erhalten werden konnten.

Gegenstand dieser Arbeit sind Versuche zur Synthese neuer binärer Kohlenstoffnitride im Allgemeinen und von C3N4-Vorläuferverbindungen im Speziellen. Hierbei werden v. a. die Herstellung und die Eigenschaften organischer Polyazide beschrieben, die aufgrund ihrer Gefährlichkeit durch zahlreiche Folgereaktionen in weniger brisante Moleküle überführt werden mussten. Als Derivatisierungsreaktionen kamen hierbei beispielsweise die 1,3-dipolare Cycloaddition mit Norbornen und Cyclooctin, die STAUDINGER-Reaktion mit verschiedenen Phosphinen sowie die Aza-WITTIG-Reaktion zum Einsatz. Es konnten dabei u. a. zehn Röntgeneinkristallstrukturen erhalten und als Strukturbeweis aufgeführt werden. Zahlreiche hochaufgelöste Massenspektren sowie Elementaranalysen und NMR-Daten bestätigten außerdem alle neu erhaltenen Strukturen. Einen weiteren Schwerpunkt dieser Arbeit stellen Versuche zur Synthese von monomerem C3N4 dar, dessen Herstellung zwar nicht gelang, für dessen Bildung allerdings neue Möglichkeiten ausgehend von verschiedenen Edukten beschrieben werden. Darüber hinaus wurden bereits bekannte Moleküle auf ihre Eignung als C3N4-Vorläufer untersucht, wobei z. B. durch Azid-Addition an Nitrilgruppen unerwartete neue Produkte erhalten werden konnten.