Dissertations / Theses on the topic 'Hydrocarbon activation'

Lanthanum (La)-promoted hydrocarbon activation reactions were carried out in a laser vaporization metal cluster beam source. Reaction products were identified by time-of-flight mass spectrometry, and the approximate ionization thresholds of La-hydrocarbon complexes were located with photoionization efficiency spectroscopy. The accurate ionization energies and vibrational frequencies of the La complexes were measured using mass analyzed threshold ionization (MATI) spectroscopy. Their molecular structures and electronic states were investigated by combing the MATI spectroscopic measurements with quantum chemical and Franck-Condon factor calculations. In this dissertation, La-mediated C-H and C-C bond activation reactions were investigated for several small alkynes (acetylene, propyne) and alkenes (propene, 1,3-butadiene, 1-butene). The C-H bond activation was observed for both alkynes and alkenes and the C-C bond activation for alkenes. The metal-hydrocarbon intermediates formed by the C-H or C-C bond cleavage reacted further with one or more parent hydrocarbon molecules to produce larger species by C-C bond coupling reactions. Structural isomers of the intermediates and products were identified within an energy range of several kilocalories per mole. Reaction pathways for the intermediate and product formations were studied by theoretical calculations. The ground electron configuration of La atom is 4d16s2.Upon the hydrocarbon coordination, La atom is excited to a 4d26s1 configuration to facilitate the formation of two La-C bonds. After the metal-hydrocarbon complex formation, only one electron is left in the 6s orbital of the metal center. Therefore, the most stable electronic state of the La complexes studied in this work is in a doublet spin state. Ionization of the doublet state yields a preferred singlet ion state. Although La is in the formal oxidation state of +2, the ionization energies of the metal-complexes are significantly lower than that of the free atom. This observation suggests that the concept of the formal oxidation state widely used in chemistry textbooks is not useful in predicting the change of the ionization energy of a metal atom upon ligation. Moreover, ionization has a very small effect on the geometry of the hydrocarbon fragment in each complex but significantly reduces the La-C distances as a result of an additional charge interaction.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Dec. 18, 2007). " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry. On t.p., [prime] is the mathematical symbol.

The Aryl hydrocarbon Receptor (AhR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulting in the human specific toxicity, chloracne. To test whether the chloracnegenic potential of AhR-agonists depends upon binding affinity for the AhR, residency and/or down-regulation of the AhR, we investigated the effects of different AhR agonists in primary human keratinocytes and epidermal equivalents. The AhR agonists used were high-affinity, high-residency and high-potency TCDD, and two agonists not known to induce chloracne; low-affinity, low-residency and low-potency β-naphthoflavone (β-NF) and the low-affinity, low-residency and high-potency physiological agonist 2-(1‟H-indole-3‟-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). -NF, a partial agonist was used to test AhR dependency. The effects of these agonists on AhR activation, terminal differentiation, autophagy and expression of cathepsin D (CTSD) in primary human keratinocytes and epidermal equivalents were determined. All three agonists induced AhR activation by XRE-luciferase assay, which was inhibited by α-NF, demonstrating AhR dependence of the ligands. AhR degradation was induced by all ligands and CYP1A1 was induced strongly by TCDD but weakly by β-NF and ITE. CYP1A1 and XRE-luciferase induction correlated with ligand binding affinity; ranking levels of binding affinity as TCDD>β-NF>ITE. TCDD treatment induced a chloracne-like phenotype in epidermal equivalents, with a decrease in viable cell layer thickness and compacted stratum corneum. This was not induced by β-NF or ITE. To investigate the differential effects of AhR-ligands on epidermal equivalent phenotype, we studied differentiation markers filaggrin, involucrin and TGM-1. TGM-1 expression was induced specifically by TCDD while aberrant expression of involucrin and filaggrin were induced by TCDD, β-NF and ITE. AhR activation was not associated with increased apoptosis. Caspase-3 independent cell death has been implicated as a mechanism of decreased thickness of the viable cell layer, so we studied the effects of AhR-agonists on autophagy. Autophagy in keratinocytes and epidermal equivalents was characterised by induction of LC3 II, p62 degradation and transmission electron microscopy. TCDD robustly induced active autophagy, while ITE induced lower levels and β-NF blocked autophagy. TCDD- and ITE-induced autophagy in epidermal equivalents appeared to result in decreased numbers of lamellar bodies, which may account at least in part for the compacted stratum corneum phenotype shown by the TCDD-induced phenotype in epidermal equivalents and chloracne. As CTSD has been implicated in keratinocyte differentiation and an XRE domain has been identified upstream of CTSD, we studied the effects of ligand-dependent AhR activation on lysosomal aspartic protease CTSD expression. CTSD was increased by AhR activity in epidermal equivalents. Induction of CYP1A1 did not appear to be a specific biomarker of chloracnegenic potential of AhR agonists. The data presented have shown differential effects by TCDD, β-NF and ITE on autophagy that we hypothesise contributes to the chloracne phenotype. In this thesis, potential biomarkers specific to chloracne were identified in keratinocytes, TGM-1, CTSD, autophagy and decreased lamellar bodies, although further validation is required.

En la presente tesis doctoral se han desarrollado dispositivos electroquímicos de estado sólido para la detección selectiva de hidrocarburos en los gases de escape de coches. Diversos materiales fueron empleados para ello. También se llevó a cabo la activación catalítica del electrodo de trabajo para mejorar la reacción electroquímica del analito objetivo. El etileno fue seleccionado como el analito objetivo para cuantificar la cantidad total de hidrocarburos ya que es uno de los hidrocarburos más abundantes en un gas de escape. Pero el dispositivo no solo debe proporcionar una respuesta selectiva al etileno, sino que también debe tener una baja sensibilidad cruzada a otros compuestos también abundantes en un gas de escape como monóxido de carbono, agua, dióxido de nitrógeno, etc. El dispositivo consiste en un sensor potenciométrico de estado sólido en el que óxido de zirconio estabilizado con 8% de óxido de itrio (8YSZ) es empleado como electrolito. Dos electrodos son impresos en la superficie de cada cara. Primero, diversos óxidos fueron empleados como electrodo de trabajo utilizando a su vez platino como electrodo de referencia a 550ºC. Muchos de los materiales fueron descartados por su falta de selectividad al etileno, su alta sensibilidad cruzada al monóxido de carbono o por su respuesta no estable. Finalmente, Fe0.7Cr1.3O3 mezclado con 8YSZ fue seleccionado como el material más prometedor dada su buena selectividad al etileno con baja sensibilidad cruzada al monóxido de carbono. Esta configuración fue expuesta a agua como a fenantreno y metilnaftaleno. Esto produjo un aumento de la sensibilidad cruzada del dispositivo al monóxido de carbono, motivo por el que el sensor no sea adecuado para los objetivos de esta tesis. La estrategia adoptada consistió en actuar sobre el electrodo de referencia. El Platino, empleado habitualmente en la bibliografía como electrodo de referencia, fue cambiado por un conductor mixto iónico-electrónico activo al oxigeno: La0.8Sr0.2MnO3 mezclado con 8YSZ (LSM/8YSZ). Desgraciadamente, esto provocó un aumento de la sensibilidad cruzada al monóxido de carbono. Diversas nanopartículas fueron añadidas en el electrodo de trabajo para mejorar la actividad catalítica y aumentar la reacción electroquímica al etileno. Níquel, titanio y aluminio (especialmente la combinación de los dos últimos con níquel) dieron la mejor respuesta: el sensor era selectivo al etileno con baja sensibilidad cruzada al monóxido de carbono, agua y fenantreno. El efecto del espesor del electrolito en la respuesta del sensor también fue evaluado en un rango de 0.1 a 1.2 mm. Aunque no había una gran diferencia en la respuesta, la sensibilidad cruzada al monóxido de carbono era menor en el caso del dispositivo más fino. Otras alternativas al 8YSZ como electrolito también fueron evaluadas para trabajar a menores temperaturas (400 a 550ºC): oxido de cerio dopado con gadolinio (CGO) y óxido de zirconio estabilizado con un 10% de óxido de escandio (ScSZ). El dispositivo basado en ScSZ mostró un buen comportamiento a etileno a bajas temperaturas y en condiciones secas pero la adición de agua provocaba un aumento de la sensibilidad cruzada al monóxido de carbono. Una vez infiltrado el electrodo de trabajo con níquel, ambos dispositivos mostraron un buen comportamiento a bajas temperaturas en condiciones secas para concentraciones de etileno inferiores a 100 ppm, aunque la mejor respuesta fue obtenida a 550ºC. Ambos dispositivos mostraron una respuesta selectiva al etileno con baja sensibilidad cruzada al monóxido de carbono, agua y fenantreno. Se estudió también el efecto de mezclar el electrodo de trabajo con un conductor iónico (8YSZ). Se mezcló La0.87Sr0.13CrO3 (LSC) con 8YSZ sin observarse un cambio en la respuesta comparado con el electrodo solo. Además la mejor configuración Fe0.7Cr1.3O3/8YSZ//8YSZ//LSM/8YSZ (infiltrado con níquel) fue expuesto a dioxide de nitr
The present thesis is focused on the development of solid-state electrochemical devices for the selective detection of hydrocarbons in car exhaust gases. For this purpose, several materials were tested as electrodes and electrolytes. Catalytic activation of the working electrode has also been taken into account to boost the electrochemical reaction of the target analyte. Ethylene is one of the most abundant hydrocarbons in an exhaust gas and was selected as the target analyte to quantify the total amount of hydrocarbons. Not only the device has to be selective to ethylene but it must also have a low cross-sensitivity toward other pollutants abundant in an exhaust gas such as carbon monoxide, water, other hydrocarbons, nitrogen dioxide, etc. Thus, a solid-state potentiometric sensor was selected based on 8% Ytria-stabilized Zirconia (8YSZ) as electrolyte. Two electrodes were screen-printed on top of each face. First, several metal oxides were tested as working electrode with platinum (Pt) as reference electrode at 550ºC. Most of the materials were discarded because of their lack of selectivity to ethylene, high cross-sensitivity toward carbon monoxide or problems regarding stability. Fe0.7Cr1.3O3 mixed with 8YSZ was finally selected as the most promising material because of its selective response to ethylene with relatively low cross-sensitivity toward carbon monoxide. This sensor configuration was then exposed to water and phenanthrene and methylnaphthalene. This led to an increase of the cross-sensitivity of the device toward carbon monoxide making the device not suitable for the purposes of the present thesis. The approach to improve the sensor performance was to modify the reference electrode. Platinum, usually employed in literature as reference electrode, was exchanged for a mixed ionic-electronic conductor active to oxygen: La0.8Sr0.2MnO3 mixed with 8YSZ (LSM/8YSZ). Unfortunately, this increases the device activity toward carbon monoxide increasing its cross-sensitivity. Several nanoparticles were added onto the working electrode to improve the catalytic activity and boost the electrochemical reaction of ethylene. Nickel, titanium and aluminum (the last two elements combined with nickel) provided the best performance: selectivity to ethylene with low cross-sensitivity toward carbon monoxide, water and phenanthrene. The effect of the electrolyte thickness was also checked in the range from 0.1 to 1.2 mm. Although there was not a huge difference between them, the cross-sensitivity toward carbon monoxide was slightly lower for the thinnest sensor. Other alternatives to 8YSZ electrolyte were tested at lower working temperatures (400 to 550ºC) with the same electrodes materials: gadolinium-doped cerium oxide (CGO) and 10% scandia-stabilized Zirconia (ScSZ). ScsZ-based device showed a good performance in dry conditions but the addition of water decreased its suitability. Once improved the catalytic activity of the working electrode, both devices showed a good performance at lower temperature in dry conditions for ethylene concentration above 100 ppm but the best response was achieved at 550ºC. Both devices were selective to ethylene with low cross-sensitivity toward carbon monoxide, water and phenanthrene. The effect of mixing the working electrode with an ionic conductor (8YSZ) was also tested by mixing La0.87Sr0.13CrO3 (LSC) with 8YSZ and no change in response was observed when compared to the bare electrode. Finally, the best sensor configuration Fe0.7Cr1.3O3/8YSZ//8YSZ//LSM/8YSZ (after infiltration with nickel) was exposed to nitrogen dioxide to check the cross-sensitivity. The response was still selective to ethylene even with the addition of nitrogen dioxide plus water.
En la present tesi doctoral s'han desenvolupat dispositius electroquímics d'estat sòlid per a la detecció selectiva d' hidrocarburs als gasos d'escapament dels automòbils. Diversos materials van ser empleats per a tal fi. També es va dur a terme l'activació catalítica de l'elèctrode de treball per a millorar la reacció electroquímica al anàlit objectiu. L' etilè va ser seleccionat com anàlit objectiu per a quantificar la quantitat total d' hidrocarburs, ja que és un dels hidrocarburs més abundants en un gas d'escapament. Però el dispositiu no ha de ser tan sols selectiu a l'etilè, sinó que també deu proporcionar una baixa sensibilitat creuada a altres elements força abundants en un gas d'escapament com són el monòxid de carboni, l'aigua, el diòxid de nitrogen, etc. Així, el dispositiu consisteix en un sensor potenciomètric d'estat sòlid en el que l'òxid de zirconi estabilitzat amb un 8% d'òxid d'itri (8YSZ) és empleat como a electròlit. Els elèctrodes van impresos a cadascuna de les superfícies del dispositiu. Primer, diversos òxids es van emprar com a elèctrode de treball fent servir platí com elèctrode de referència a 550ºC. Molts dels materials van ser descartats per motiu de la seva manca de selectivitat al etilè, la seva alta sensibilitat creuada al monòxid de carboni o perquè la resposta no era estable. Finalment, el Fe0.7Cr1.3O3 mesclat amb 8YSZ va ser seleccionat com el material més prometedor atès a la selectivitat a l'etilè i la baixa sensibilitat creuada al monòxid de carboni. Aquesta configuració és doncs exposada tant a l'aigua com al fenantrè i al metilnaftalè. Això va produir un increment de la sensibilitat creuada al monòxid de carboni, fent que el dispositiu no resulti idoni per als objectius de la present tesi. Es va adoptar com a estratègia modificar l'elèctrode de referència. Platí, empleat sovintment com a elèctrode de referència a la bibliografia, va ser canviat per un conductor mixt iònic-electrònic actiu a l'oxigen: La0.8Sr0.2MnO3 mesclat amb 8YSZ (LSM/8YSZ). Malauradament, això va provocar l'augment de la sensibilitat creuada al monòxid de carboni. Diverses nanopartícules van ser afegides al elèctrode de treball per tal de millorar la seva activitat catalítica i així augmentar la reacció electroquímica de l'etilè. Níquel, titani i alumini (especialment la combinació dels dos darrers amb níquel) van donar la millor resposta: el sensor era selectiu a l¿etilè amb una baixa sensibilitat creuada al monòxid de carboni, l'aigua i al fenantrè. L'efecte del espessor del electròlit a la resposta del sensor també va ser avaluada en un rang de 0.1 a 1.2 mm. Malgrat que no hi ha una gran diferència en la resposta, la sensibilitat creuada al monòxid de carboni és menor en el cas del dispositiu més prim. Altres alternatives al 8YSZ com a electròlit van ser també avaluades per tal de treballar a temperatures menors (400 a 550ºC): òxid de ceri dopat amb gadolini (CGO) i òxid de zirconi estabilitzat amb un 10% d'òxid d'escandi (ScSZ). El dispositiu basat en ScSZ va mostrar un bon comportament a l'etilè a baixes temperatures en condiciones seques, però la adició d'aigua provocava un augment de la sensibilitat creuada al monòxid de carboni. Una vegada que l'elèctrode de treball es infiltrat amb níquel, ambdós dispositius mostraren un bon comportament a baixes temperatures en condicions seques per a concentracions d'etilè menors de 100 ppm, encara que la millor resposta fou obtinguda a 550ºC. La resposta era selectiva a l'etilè amb una baixa sensibilitat creuada al monòxid de carboni, l'aigua i el fenantrè. Es va comprovar també l'efecte de mesclar l'elèctrode de treball amb un conductor iònic (8YSZ). Es va mesclar La0.87Sr0.13CrO3 (LSC) amb 8YSZ sense observa cap canví en la resposta comparada amb l'electrode sense 8YSZ. la millor configuració Fe0.7Cr1.3O3/8YSZ//8YSZ//LSM/8YSZ (infiltrado con níquel) fou exposada
Toldra Reig, F. (2018). Development of electrochemical devices for hydrocarbon sensing purposes in car exhaust gases [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/110968
TESIS

High-oxidation state main-group metal complexes are potential alternatives to transition metals for electrophilic C-H functionalization reactions. However, there is little known about how selection of the p-block, main-group metal and ligand impact C-H activation and functionalization thermodynamics and reactivity. Chapter 2 reports density functional theory (DFT) calculations used to determine qualitative and quantitative features of C-H activation and metal-methyl functionalization energy landscapes for reaction between high-oxidation state d10s0 InIII, TlIII, SnIV, and PbIV carboxylate complexes with methane. While the main-group metal influences the C-H activation barrier height in a periodic manner, the carboxylate ligand has a much larger quantitative impact on C-H activation with stabilized carboxylate anions inducing the lowest barriers. For metal-methyl reductive functionalization reactions, the barrier heights, are correlated to bond heterolysis energies as model two-electron reduction energies.In Chapter 3, DFT calculations reveal that arene C-H functionalization by the p-block main-group metal complex TlIII(TFA)3 (TFA = trifluoroacetate) occurs by a C-H activation mechanism akin to transition metal-mediated C-H activation. For benzene, toluene, and xylenes a one-step C-H activation is preferred over electron transfer or proton-coupled electron transfer. The proposed C-H activation mechanism is consistent with calculation and comparison to experiment, of arene thallation rates, regioselectivity, and H/D kinetic isotope effects. For trimethyl and tetramethyl substituted arenes, electron transfer becomes the preferred pathway and thermodynamic and kinetic calculations correctly predict the experimentally reported electron transfer crossover region.In Chapter 4, DFT calculations are used to understand the C-H oxidation reactions of methane and isobutane with SbVF5. SbVF5 is generally assumed to oxidize methane through a methanium-methyl cation mechanism. DFT calculations were used to examine methane oxidation by SbVF5 in the presence of CO leading to the acylium cation, [CH3CO]+. While there is a low barrier for methane protonation by [SbVF6]-[H]+ to give the [SbVF5]-[CH5]+ ion pair, H2 dissociation is a relatively higher energy process, even with CO assistance, and so this protonation pathway is reversible. The C-H activation/[]-bond metathesis mechanism with formation of an SbV-Me intermediate is the lowest energy pathway examined. This pathway leads to [CH3CO]+ by functionalization of the SbV-Me intermediate by CO, and is consistent with no observation of H2. In contrast to methane, due to the much lower carbocation hydride affinity, isobutane significantly favors hydride transfer to give tert-butyl carbocation with concomitant SbV to SbIII reduction. In this mechanism, the resulting highly acidic SbV-H intermediate provides a route to H2 through protonation of isobutane.

Lanthanum-mediated bond activation reactions of small hydrocarbon molecules, including alkenes, alkynes, and alkadienes, were carried out in a laser vaporization metal cluster beam source. Time-of-flight mass spectrometry and mass-analyzed threshold ionization (MATI) spectroscopy, in combination with quantum chemical and multi-dimensional Franck-Condon factor calculations, were utilized to identify the reaction products and investigate their geometries, electronic structures, and formation mechanisms. La-hydrocarbon association was only observed in the reaction of La with isoprene. C-H bond activation was observed in all reactions, hydrogen elimination was observed as the prominent reaction for the alkenes (2-butene, isobutene, 1-pentene, and 2-pentene), alkynes (1-butyne, 2-butyne, and 1-pentyne), and 1,4-pentadiene, and C-C bond activation was observed for the five-membered hydrocarbons (1-pentene, 2-pentene, 1-pentyne, isoprene, and 1,4-pentadiene). The La-hydrocarbon radicals formed in these reactions had lanthanacyclic structures in various sizes, and each of the La-hydrocarbon complexes had a doublet ground state with a 6s1 La-based electron configuration. Ionization removed the 6s electron, and the resultant ion was in a singlet state. Formations of dehydrogenated products were either through a concerted hydrogen elimination process or the dehydrogenation after ligand isomerization. The C-C bond activation proceeded through La-assisted hydrogen migration, followed by C-C bond cleavage, or vice versa.

Thesis (Ph. D.)--California Institute of Technology, 1987. UM #87-19,702.
Advisor names found in the Acknowledgements pages of the thesis. Title from home page. Viewed 01/15/2010. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Stockholms universitet, 2009.
Härtill 4 uppsatser. At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: In progress.

Doctor of Philosophy
Department of Chemistry
Stefan Bossmann
My thesis is divided into two parts. The first part is focused on studies of N-heterocyclic carbene (NHC) palladium(IV) intermediates, which are involved in oxidative addition mediated C-C, and C-O bond formation processes as well as in C-Cl bond forming reactions via a reductive elimination process. Bis-NHC-Pd(II) complexes have been reported as effective catalysts to mediate direct conversion of methane into methanol. However, a H-D exchange study revealed that the bis-NHC-Pd(II) complexes are not the active species responsible for the C-H bond activation reaction. This unexpected result implies that the high oxidation state bis- NHC-Pd(IV) species may be the real catalyst! The oxidative addition of methyl iodide to the bis- NHC-Pd(II)-Me2 complex led to the successful observation of the formation of a transient trimethyl bis-NHC-Pd(IV) intermediate by both 1H-NMR and 13C-NMR spectroscopy. Different oxidants such as O2, PhI(OAc)2, PhI(OTFA)2 and Cl2 reacted with the bis-NHC-Pd(II)-Me2 complex, and competitive C-C and C-O bond formations, as well as C-C and C-Cl bond formations were observed. Dioxygen triggered C-C bond formation under dry condition and both C-C and C-O bond formation in the presence of H2O gave strong indications that the bis-NHCPd( II)-Me2 complex can be oxidized to a bis-NHC-Pd(IV) intermediate by dioxygen. The reaction between the hypervalent iodine regents PhI(OAc)2 and PhI(OTFA)2 and the bis-NHCPd( II)-Me2 complex gave only reductive elimination products. Therefore, this system can act as a model system, which is able to providing valuable information of the product forming (functionalization) step of the C-H bond activation system. The reaction between chlorine and the bis-NHC-Pd(II)-Me2 complex resulted in a relatively stable bis-NHC-Pd(IV)-Cl4 complex, which was characterized by 1H-NMR spectroscopy and mass spectroscopy. The structure of bis- NHC-Pd(IV)-Cl4 was unambiguously established by X-ray crystallography. The second part of this thesis describes the synthesis of functionalized bimagnetic core/shell iron/iron oxide nanoparticles for the treatment of cancer. Biocompatible dopamineoligoethylene glycol functionalized bimagnetic core/shell Fe/Fe3O4 nanoparticles were prepared via ligand exchange, and purified by repeated dispersion/magneto-precipitation cycles. A porphyrin (TCPP) has been tethered to the stealth nanoparticles to enhance their uptake by tumor cells and (neural) stem cells. The stealth nanoparticles have been delivered in a mouse model to tumor sites intravenously by using the EPR (enhanced permeation and retention) effect. Magnetic hyperthermia proved to be very effective against B16-F10 mouse melanomas in Charles River black mice. After hyperthermia, the nanoparticles have shown a significant effect on the growth of tumor (up to 78% growth inhibition).

Aquatic organisms in response to toxic insults from environmental pollutants activate defence systems including the aryl hydrocarbon receptor (AhR) in an attempt to metabolize and excrete these toxicants and their metabolites. These detoxification mechanisms however may come with certain energetic costs. I hypothesize that the activation of the AhR by β-Naphthoflavone (β-NF), a model AhR agonist, results in increased energetic costs requiring metabolic reorganization in rainbow trout hepatocytes. While the results obtained suggest that there are no significant energetic costs of AhR activation, analysis of enzyme activities suggests possible metabolic reorganization. This study also showed significant changes in cellular processes in hepatocytes over the incubation periods which previously were not reported. Furthermore, for the first time in fish hepatocytes, metabolic flux analysis (MFA) was used to examine intra-cellular metabolism, the applicability of which is discussed.

The aryl-hydrocarbon receptor (AhR) is an important receptor found in immune cells. It functions as a detector of environmental toxins, naturally occurring dietary products, and endogenous tryptophan derivatives for induction of gene transcription responses. Previous reports have implicated stimulation of AhR by various ligands in promoting T cell activation or regulatory function, with effects on autoimmune disease models. Also, effects of Ah toxins or natural products on increasing or suppressing inflammation and innate cytokine production, and dendritic cell function, have been reported. Different AhR-ligands could help in the development of either regulatory or pro-inflammatory T cells and consequently affect autoimmunity. In the present study, the effects of specific AhR-ligands on CD4 T cells, BMDC and CD8 T cells were investigated. Their effects were also tested for the first time on the induction of autoimmune diabetes using two different mouse models. Co-injection of the AhR-ligands curcumin, quercetin, or the ligand precursor tryptophan with sub-diabetogenic multiple low dose streptozotocin (MLD-STZ), increased the incidence of hyper-glycemia in C57Bl/6J mice. Furthermore, these ligands were able to significantly increase the development of Th17 and Th1 subsets and suppress Treg cells, in vivo and in vitro. In contrast, other ligands, including FICZ and I3C, decreased the incidence of diabetes in the MLD-STZ mouse model, in addition to their ability to increase the development of Th17, Th1 and Treg subsets, in vivo and in vitro. We found that injecting gp130fl/flCD4-Cre+ mice, which are characterized by enhanced production of Treg and reduced Th17 cell development, with MLD-STZ failed to cause hyper-glycemia, suggesting that the IL-6-receptor pathway controlling the Th17/Treg cell balance is important for diabetes induced by MLD-STZ. The effect of tryptophan, curcumin or quercetin was also tested for the first time using the RIP-LCMV-GP / P14 TCR transgenic diabetes model. We find that co-injection of these ligands together with immunisation with mature bone marrow-derived dendritic cells (BMDC) carrying self-antigen increased the incidence of diabetes in RIP-GP/P14 TCR transgenic mice. Also, these AhR-ligands were able to significantly increase Tc17 and Tc1 cell subsets, in vitro and in vivo. Furthermore, these ligands were able to increase the secretion of both pro-inflammatory, anti-inflammatory cytokines, and the expression of IDO by BMDC. FICZ and I3C, however, increased the expression of IDO and the anti-inflammatory cytokines TGF-β and IL-10. An immuno-suppressive function of FICZ and I3C was confirmed by co-injection of these AhR-ligands together with immunisation with mature BMDC carrying self-antigen, which resulted in a decrease in the incidence of diabetes in RIP-GP/P14 TCR transgenic mice. Suppression of diabetes was associated with increased development of IL-10+ CD8+ T cells, in vitro, while having no significant effect on either Tc1 or Tc17 subsets. It is concluded from this study that, the AhR-ligands FICZ and I3C could be attractive compounds to be used as therapeutics for diabetes and other autoimmune diseases, due to their ability to increase regulatory T cells (Treg and IL-10+ CD8+ ) subsets and enhance the secretion of anti-inflammatory cytokines and IDO expression by BMDC. However, activation of the AhR pathway by other AhR-ligands is associated with increased Th1/Tc1 and Th17/Tc17 responses, which could worsen autoimmunity.

Le chapitre 1 présente un résumé bibliographique des différentes façons de casser une liaison C-Hd'hydrocarbures, plus particulièrement du méthane, avec des complexes de métaux de transition tant de la gauche que de la droite du système périodique. Pour les métaux de transition de la gauche, notre attention a été principalement axée sur trois mécanismes: i) la métathèse de liaison sigma, ii) l’abstraction d’un hydrogène en position alpha couplée a l’addition-1,2 d’une liaison CH et iii) l’abstraction d’un hydrogène en position bêta couplée à l’addition-1,3 d’une liaison C-H.Le chapitre 2 aborde le problème de l'activation d'une liaison C-H du méthane par un complexe transitoire eta2-cyclopropène de niobium. Des études RMN à haute pression en solution, des études de marquage isotopiques ainsi que des analyses cinétiques sur l'échange dégénéré du méthane dans le complexe méthyle [TpMe2NbCH3(c-C3H5)(MeCCMe)] (1) sont décrits. L’activation stoechiométrique du méthane par le complexe mésitylène [TpMe2Nb(CH2-3,5-C6H3Me2)(c-C3H5)(MeCCMe)] (2) pour donner 1 est également réalisée. Les données montrent que ces réactions se déroulent via une abstraction intramoléculaire d'un hydrogène bêta du groupe cyclopropyle soit par un groupe méthyle soit par un groupe mésityle à partir du composé 1 ou 2, respectivement, ce qui donne l’intermédiaire réactif eta2-cyclopropène [TpMe2Nb(2-c-C3H4)(MeCCMe)] (A). Ceci est suivi par sa réaction inverse, l'addition-1,3 d’une liaison C-H du méthane pour donner le produit.Le chapitre 3 explore la réactivité du complexe 1 en vers des hétéroaromatiques, des hydrocarbures insaturés ainsi que le pentafluorobenzène et le ferrocène (FcH) via l’abstraction d’un hydrogène en position beta couplée à l’addition-1,3 d’une liaison C-H. Le compose 1 est en mesure d'activer de manière sélective la liaison C-H du furane, thiophène, 1-cyclopentène, phénylacétylène, pentafluorobenzène et ferrocène, donnant les produits correspondants [TpMe2NbX(c-C3H5)(MeCCMe)] (X = 2-C4H3O, 2-C4H3S, 1-C5H7, PhCC, C6F5, Fc) qui ont été isolés et caractérisés par spectroscopie RMN du 1H et 13C, des études électrochimiques ainsi que par des analyses de diffraction des rayons X
Chapter 1 reports a literature summary of the different ways of cleaving a hydrocarbon C-H bond, mostparticularly methane, with both early and late transition metal complexes. For early transition metals ourattention is focused on three mechanisms: i) the σ-bond metathesis, ii) the α-H abstraction/1,2-CH bond addition and iii) the β-H abstraction/1,3-CH bond addition.Chapter 2 challenges the problem of the activation of a CH bond of methane by a transient η2-cyclopropene complex of niobium. High pressure solution NMR, isotopic labelling studies and kinetic analyses of the degenerate exchange of methane in the methyl complex [TpMe2NbCH3(c-C3H5)(MeCCMe)] (1) are reported. Stoichiometric methane activation by the mesitylene complex [TpMe2Nb(CH2-3,5-C6H3Me2)(c-C3H5)(MeCCMe)] (2) giving 1 is also realized. Evidence is provided that these reactions proceed via an intramolecular abstraction of a β-H of the cyclopropyl group from either methane or mesitylene from 1 or 2, respectively, yielding the transient unsaturated η2-cyclopropene intermediate [TpMe2Nb(η2-c-C3H4)(MeCCMe)] (A). This is followed by itsmechanistic reverse 1,3-CH bond addition of methane yielding the product.Chapter 3 explores the reactivity of complex 1 towards heteroaromatics, unsaturated hydrocarbons, pentafluorobenzene and ferrocene (FcH) via the β-H abstraction/1,3-CH bond activation mechanism. Compound 1 is able to selectively activate the C-H bond of furan, thiophene, 1-cyclopentene, phenylacetylene, pentafluorobenzene and ferrocene, yielding the corresponding products [TpMe2NbX(c-C3H5)(MeCCMe)] (X = 2-C4H3O, 2-C4H3S, 1-C5H7, PhC≡C C6F5, Fc) which have been isolated and characterized by 1H, 13C NMR spectroscopy, electrochemical studies and X-ray diffraction analysis

Etude de l'interaction entre les terres rares et les metaux de transition en jouant sur le mode d'impregnation, la nature des sels precurseurs des metaux de transition et des lanthanides et traitement thermique d'activation. Etude sur la dispersion et sur l'etat d'oxydation

This thesis describes both direct and indirect C-H activation borylation processes, catalysed by several Rh-based catalyst precursors. Chapter One presents an overview of the processes investigated, namely diboration, dehydrogenative borylation, and direct C-H activation of hydrocarbon substrates, which give borylated species that are of interest to synthetic chemists. The uses of such borylated species are also highlighted. Chapter Two highlights the synthetic procedure for the synthesis of the catalyst precursor [Rh(acac)(C0E)(_2)], which can be used to prepare bis-phosphine catalyst precursors of the form [Rh(acacXP(_2))]- Although a procedure appears in the literature, it is not well cited. Also, this new procedure replaces [Tl(acac)] with [Na(acac)] and hence avoids the use of thallium salts. Chapter Three investigates the reaction of two vinyl(boronate) esters (VBEs) with Bzcat], and a wide array of catalyst precursors, which yield, among other species, the tris(boronate) esters ArCH(_2)C(Bcat)(_3) and ArCH(Bcat)CH(Bcat)(_3); the former results from the addition of both borons of the B(_2) unit to the same carbon atom, and are of interest due to their wide synthetic versatility. Chapter Four investigates the dehydrogenative borylation of alkenes using both HBpin and B2pin2, and several catalyst precursors. Most significantly, this route allows the synthesis of 1,1-disubstituted vinyl(boronate) esters that cannot be made by alkyne hydroboration. Chapter Five investigates the direct C-H activation of benzylic and aromatic hydrogens using the catalyst precursor [Rh(Cl)(N(_2))(P(^i)Pr(_3))(_2)]. This allows the functionalisation of hydrocarbon substrates, which are ubiquitous. Chapter Six investigates the stability of B-chlorocatecholborane to phosphines with the view to a boron analogue of the Heck reaction. In such a reaction, phosphmes would likely be employed on the catalyst. An understanding of the stability of the boron reagent under typical reaction conditions is needed, therefore, in order to prevent degradation of B-chlorocatecholborane, a process that is known for catecholborane.

CO₂, without question, the most famous greenhouse gas, is known to have an increasing concentration in both the atmosphere and oceans. To slow down the pace not only of global warming but also the ocean acidification, several routes are proposed to effectively reduce the net emission of CO₂. Compared to Carbon Capture and Sequestration/Storage (CCS), Carbon Capture and Utilisation (CCU) has much more potential because of the lower costs of scale up and higher profitability to potentially attract capital investment. Different from the conventional CCU route which is to reduce CO₂ to fuels with hydrogen generated via renewable-energy-driving electricity, two processes are investigated in this thesis; that of Dry Methane Reforming (DMR) and the DeHydrogenation of Propane by CO₂ (DHP by CO₂). The projects on these two processes not only develop catalysts which would be suitable for the reaction performance, but also the ultimate aim is to link the processes with a renewable energy source (in the thesis we chose Solar Thermal Heating).Thermodynamic calculations and process simulations were also evaluated. The results of DMR unfortunately did not indicate a promising future to link with Solar Thermal Heating due to the very high temperature required during the process. However, the results of thermodynamic calculations and process simulations in DMR project illustrate a good opportunity to utilise flue gas in industry through the so-called Tri- Methane Reforming (TMR). In the DHP by CO₂ process, the catalysts developed were less promising than the ones in DMR due to the severe side-reactions occurred which significantly decreased the selectivity for the desired product. However - and importantly - through our thermodynamic calculations and process simulations, the DHP by CO₂ process has a bright future if the Solar Thermal Heating can be applied with the relative lower temperature requirement, making the CO₂ utilisation process much easier to be fulfilled than DMR.

The targets of this thesis were the selective oxidation of hydrocarbons under mild conditions, using cheap and environmentally friendly oxidants and initiators. Three projects are treated; the oxidation of an alkane using O2 and a co-oxidant, the oxidation of toluene using TBHP (tert-butyl hydroperoxide) and finally the oxidation of propane using hydrogen peroxide. C-H bond activation, O2 activation and high conversion with high selectivity were essential points to investigate. In the first project, alkane oxidation was studied in presence of a co-oxidant. The co-oxidant has for purpose to initiate the activation of the alkane and O2, as well as prevent the over-oxidation of the alkane. The co-oxidation of octane using benzaldehyde has been investigated using 1 wt. % AuPd/ C catalyst; the hypothesis is that benzaldehyde oxidation would use a radical mechanism able to activate octane to octanol. Also, the coupling of octanol with activated benzaldehyde would prevent the over-oxidation of octanol by the formation of an ester; octylbenzoate. The aim of the second study was to investigate the selective oxidation of toluene using TBHP at 80 °C with supported noble metal nanoparticle catalysts prepared by sol-immobilisation techniques. Au, Pd and Pt have been use to form mono, bi and trimetallic catalysts of different morphology supported on C and TiO2. These catalysts have been tested for toluene oxidation. The catalyst showing the best activity has been used for further investigation such as reuse test, using H2O2 as oxidant or O2 activation. The third project target was to oxidise propane using H2O2 in mild conditions. 2.5 wt. % Fe/ ZSM-5 (30) has been used to investigate reaction conditions in order to optimise the system. This catalyst has been acid treated; standard and treated catalysts were characterised and analysed to identify the structure and active sites. Role of supports and metals (mono and bimetallic) has been explored in order to improve this system.

Au cours de cette thèse, nous nous sommes intéressés à l'activation de liaisons sp² et sp³ C-H catalysée par le palladium pour la préparation d'(hétéro)aryl-aryles et de biaryles. Cette méthode est considérée comme attractive pour l'environnement par rapport aux méthodes classiques, tels que Suzuki, Heck, ou Negishi. Tout d'abord, nous avons décrit que la C2-arylation directe de benzothiophènes peut être effectuée par un catalyseur du palladium en l'absence de ligand phosphine avec une grande sélectivité. Nous avons également démontré qu'il est possible d'activer les positions C2 et C5 de pyrroles pour accéder en une seule étape a des 2,5-diarylpyrroles. Des 2,5-diarylpyrroles non-symétriques ont été formés par arylation séquentielle en C2 suivie par une arylation en C5. Nous avons également étudié la réactivité de polychlorobenzenes pour l'activation de liaisons C-H catalysé au palladium. Nous avons finalement étudié l'activation sp² et sp³ sélective catalysé au palladium de liaisons C-H du guaiazulene. La sélectivité de la réaction dépend du solvant et de la base : C2-arylation (KOAc en éthylbenzène), C3-arylation (KOAc dans le DMAc) et C4-Me arylation (CsOAc/K₂CO₃ dans le DMAc). Grâce à cette méthode, une liaison sp³ C-H peu réactive a été activée
During this thesis, we were interested in the sp² and sp³ C-H bond activation catalyzed by palladium catalysts for the preparation of (hetero)aryl-aryls and biaryls. This method is considered as cost effective and environmentally attractive compared to the classical couplings such as Suzuki, Heck, or Negishi. First we described the palladium-catalyzed direct C2-arylation of benzothiophene in the absence of phosphine ligand with high selectivity. We also demonstrated that it is possible to active both C2 and C5 C-H bonds for access to 2,5-diarylated compounds in one step, and also to non-symmetrically substituted 2,5-diarylpyrroles via sequential C2 arylation followed by C5 arylation. We also studied the reactivity of polychlorobenzenes via palladium-catalyzed C-H activation. We finally examined the palladium-catalysed selective sp² and sp³ C-H bond activation of guaiazulene. The selectivity depends on the solvent and base: sp² C2-arylation (KOAc in ethylbenzene), sp² C3-arylation (KOAc in DMAc) and sp³ C4-Me arylation (CsOAc/K₂CO₃ in DMAc). Through this method, a challenging sp³ C-H bond was activated

L'activation de la liaison Csp3-H peu réactive et sa fonctionnalisation en liaison carbone-hétéroatome constituent un défi pour les chimistes de synthèse. Un exemple d'intérêt industriel est la réaction d'oxydation du cyclohexane, dont les produits finaux (cétone et alcool) sont des intermédiaire clés pour la production de polyamides tels que les Nylon-6 et 6,6. Parmi les possibilités d'activation, la catalyse représente une méthode de choix. Dans le cadre de cette thèse des suspensions aqueuses à base de nanoparticules ont été évaluées en termes de stabilité et de performances catalytiques. Dans un premier temps, des colloïdes de ruthénium ont été synthétisés à partir de RuCl3,3H2O et caractérisés par des analyses physico-chimiques (MET, SPX, SAXS, UV-visible, etc.). Des espèces actives de Ru+3 dont la structure est de type Ru(OH)3-xClx ont été obtenues. Après optimisation des conditions de réaction, des conversions élevées, associées à des sélectivités pertinentes vis-à-vis de la cétone (jusqu'à 98%), ont été obtenues. Des études cinétiques et mécanistiques ont montré que la voie radicalaire est prépondérante. De plus, ces colloïdes de Ru aisément recyclables ont également été testés avec succès en oxydation d'autres hydrocarbures saturés et insaturés. Dans un second temps, un catalyseur à base de dioxyde de manganèse, métal moins coûteux et abondant, a été synthétisé par un procédé redox original, à partir de KMnO4 et en présence d'un ammonium quaternaire à tête polaire hydroxylée (HEA16Cl), qui joue simultanément le rôle de réducteur et d'agent stabilisant. Ce système s'est révélé être une alternative pertinente aux procédés à base de métaux nobles. Les nanobâtonnets de MnO2 se sont ainsi montrés actifs en oxydation du cyclooctane avec une sélectivité totale en cétone
The activation of the Csp3-H bond and its transformation into a carbon-heteroatom bond remains a great challenge for the organic chemistry. An example of industrial application is the oxidation reaction of cyclohexane, leading to the production of the corresponding ketone and alcohol, key intermediates of Nylon-6 and Nylon-6,6 polyamides. Among the strategies to activate this unreactive bond, catalysis affords a relevant and sustainable tool. In this work, aqueous suspensions of metal nanoparticles were evaluated in terms of their stability and catalytic performances. Firstly, ruthenium colloids were synthesized from RuCl3.3H2O and fully characterized by various physico-chemical analyses (TEM, XPS, SAXS, UV-visible, etc.). Ru+3 active species were obtained, with a Ru(OH)3-xClx structure. After optimization of the reaction conditions, high conversions, combined with pertinent selectivities towards the ketone (up to 98%), were achieved. The presence of radical species was proved through kinetic and mechanistic studies. Furthermore, these easily recyclable Ru colloids were also evaluated in the oxidation of several saturated and unsaturated hydrocarbons. Secondly, a catalyst based on manganese dioxide, a cheap and abundant metal, was synthesized by an original redox process, starting from KMnO4 and in the presence of a hydroxylated quaternary ammonium (HEA16Cl), which plays the role of a reducing and stabilizing agent. This system proved to be a relevant alternative to methodologies based on noble metals. The MnO2 nanorods showed a good activity in the cyclooctane oxidation with a 100% selectivity towards the ketone

Ce travail est relatif a l'etude de deux reactions d'electrocatalyse. La premiere partie concerne la mise au point de cathodes moleculaires, realisees par l'inclusion de microparticules de metaux nobles dans des films de polypyrrole fonctionnalise et a leur application en hydrogenation electrocatalytique. L'etude de l'hydrogenation de deux substrats test, le limonene et la carvone, a montre qu'il est possible d'orienter la selectivite de ces electrodes modifiees selon la nature du metal incorpore (pt, pd ou rh). Le resultat le plus significatif est que l'incorporation dans le meme film de polymere de deux metaux d'activite catalytique differente (pt + pd ou rh + pd) conduit a des cathodes dont l'efficacite et la selectivite sont largement superieures a celle des cathodes basees sur un seul metal. La deuxieme partie de ce travail est consacree a l'etude de l'activation electrochimique de l'oxygene par des complexes mn (iii) - bases de schiff. Il apparait que le complexe mn (ii) - salen substitue en 5,5 par des atomes de chlore est le catalyseur le plus stable et le plus efficace pour la reaction test d'epoxydation du cyclooctene. D'autre part, la rigidification du complexe par l'utilisation d'un pont 1,2-cyclohexylidene ou 1,2-phenylene reliant les deux motifs salicylaldehyde du ligand, a la place du groupe ethylidene ligand salen, entraine une forte diminution de l'activite catalytique des complexes correspondants. Ce systeme electrocatalytique a egalement ete applique a l'oxydation de la tetraline et de la triphenylphosphine

Reactions du radical nh::(2) avec des alcanes, h::(2) et h::(2)o. Les reactions etudiees jouent un role important dans la modelisation des processus de combustion ou de post-combustion des hydrocarbure et dans la connaissance du mecanisme reactionnel gouvernant le traitement par injection d'ammoniac des oxydes d'azote contenus dans les gaz d'echappement des machines thermiques

Hydrocarbons are an abundant resource of carbon and hydrogen. For example, fossil can be used to produce useful organic compounds. However hydrocarbons seem to be inert. Thus, the activation of the C-H bond is a popular research area. Metals play the main role in most catalysts that convert hydrocarbons to starting materials in industry. The study of metals is important because the properties of the metal core greatly influences the reactivity of a catalyst.1 The study of the chemistry of metals in the gas phase provides valuable information about the properties of metals. This information can be expanded to the chemistry of metals in the condensed phase. Furthermore, it is often both more accurate and more manageable to study the profile of a reaction in the gas phase than in the condensed phase.2,3 There are many studies about metal cations in the gas phase due to ease of their production. However metals have low electronegativity, limiting the study of gas phase metal anions. Recently, a simple and efficient method to generate atomic metal anions was developed at the University of Ottawa in Dr. Mayer's research laboratory.4-6 Atomic metal anions of Fe-, Co-, Cu-, Ag-, Cs- and K- were generated in an electrospray ionization (ESI) source of a mass spectrometer (MS). In this thesis study generated metal anions were reacted with small hydrocarbons of pentane, 1-pentene, 2-pentene and 1-pentyne to investigate the role of different metal anions in the activation of the C-H bond. Also metal anions were reacted with small alcohols of 1-butanol, 2-butanol and 2-methyl-2-propanol to compare the results. Metal anions showed a variety of reactions with these hydrocarbons and alcohols. Fe- was the only metal anion to show the electron transfer reaction, indicating that alcohols are more electronegative than Fe- and less electronegative than other metal anions. Fe-, Co- and Ag- showed the complex formation reaction. All metal anions showed the deprotonation reaction. A deprotonation reaction follows the harpoon mechanism, the long range proton abstraction7, and depends on the gas phase acidity of fragments. The most informative reaction observed was the dehydrogenation reaction because a metal-containing fragment is observed as a product in the spectrum of this reaction. The observation of a metal-containing fragment in the spectrum is significant because it emphasizes the important role that metal anions play in this reaction. This suggests that a dehydrogenation reaction involves metal insertion into a C-H bond. Among the transition metal anions, it was observed that Fe- and Cu- are more reactive than Co- and Ag- with regards to the dehydrogenation reaction, probably because Fe- and Cu- have a greater hydrogen affinity than Co- and Ag- that facilitates the hydrogen abstraction reaction. Another reason could be that Fe- and Cu- have a greater gas phase acidity that leads to a more stable intermediate in the course of the reaction. The results of this thesis study revealed that Cs- and K- could not abstract H from these substrates, probably due to the absence of occupied d orbitals that would facilitate insertion into a C-H bond. Some metal anions not only can insert into a C-H bond of alcohols but also can insert into a C-O bond of alcohols to form metal hydroxide anions. Alcohols are more reactive than hydrocarbons with regards to reactions with metal anions because they contain a functional group. This thesis study shows that some atomic metal anions are able to activate the C-H bond and abstract two hydrogens to form a double bond in hydrocarbons. It is probable that the electronic configuration, gas phase acidity and hydrogen affinity of the metal anions governs their reactivity.

碩士
臺北醫學大學
醫學科學研究所
98
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates xenobiotic responses to a variety of aromatic hydrocarbons present in the environmental pollutant or in the internal organism. Recent, studies show that AhR negatively regulates the lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Microglia are the major resident immune cells of the CNS and survey the microenvironment for noxious agents or injurious processes. Therefore, we aim to investigate how AhR regulates the activation of microglia upon inflammatory and excitotoxic glutamate insults. We found that treatment with an AhR exogenous ligands 3-methylcholanthrene (3-MC) down-regulates LPS-induced, but not glutmate-induced inducible nitric oxide synthases (iNOS) mRNA expression, whereas the protein levels of LPS- and glutamate-induced iNOS were both suppressed by 3-MC. Furthermore, we found that the AhR mRNA expression was obviously decreased by both LPS and glutamate treatment, but the AhR protein levels were increased by LPS and glutamate treatment. Moreover, we found that LPS activates and accumulates AhR in the nucleus of microglia. These results not only suggest that AhR downregulates the LPS- and glutamate-induced over-activation of microglia, but also indicate that these insults could change the setting of the microglial AhR level for the regulation of subsequent inflammatory processes in the central nervous system.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are well-recognized for their immunosuppressive activity, which is mediated through an intracellular receptor and transcription factor, aryl hydrocarbon receptor (AhR). Laboratory animals exposed to TCDD are less resistant to infection and have severely impaired humoral and cell-mediated immune responses. This dissertation addressed the hypothesis that exposure to TCDD disrupts early events during the activation of CD4⁺ T cells, leading to their premature loss from the spleen. Initially, ovalbumin (OVA)-specific CD4⁺ T cells from transgenic DO11.10 mice were used to monitor the effects of TCDD on activated antigen-specific T cells. A graft-versus-host (GVH) model, in which T cells from C57B1/6 (B6) mice are injected into C57B1/6 x DBA/2 Fl (Fl) mice, was used to study the role of AhR specifically in the T cells in response to TCDD. B6 donor T cells (from AhR[superscript +/+] or AhR[superscript -/-] mice) respond to DBA/2 antigens in Fl mice and a CD4-dependent CTL response is generated. In both models, exposure to TCDD significantly decreased the number of responding CD4⁺ T cells in the spleen beginning on day 4 after initiation of the response. Exposure to TCDD altered the phenotype of OVA-specific CD4⁺ T cells beginning on day 2 after immunization with OVA. These studies also suggested that apoptosis was not the primary mechanism responsible for the loss of CD4⁺ T cells from the spleen in TCDD-treated mice. Exposure to TCDD induced AhR-dependent changes in the phenotype of B6 donor CD4⁺ T cells such that a subpopulation of CD25⁺ cells was increased in TCDD-treated Fl mice, and these cells had in vitro functional characteristics consistent with regulatory T (Treg) cells. Exposure to TCDD increased the frequency of donor CD4⁺ T cells producing interleukin (IL)-2. In addition, increased expression of CD25 in TCDD-treated mice was correlated with increased signaling through the IL-2 receptor. However, IL-2 alone was not sufficient to mimic the potent immunosuppressive effects of TCDD. These results suggest that TCDD suppresses T cell immunity in part by inducing and/or expanding a subpopulation of Treg cells by a mechanism that may involve IL-2.
Graduation date: 2006

The reactions of several gas-phase metal cations with small hydrocarbons have been studied using ion beam mass spectrometric techniques. We also present several theoretical studies into the sigma bonding between the first and second row transition metal ions and H and CH₃.

Chapter II discusses the three cations, europium, praseodymium, and gadolinium in an attempt to understand the role of f electrons in the reactivity of gas-phase lanthanide ions. Eu⁺ and Pr⁺ are found to be unreactive with alkanes while Gd⁺ readily activates both C—H and C—C bonds. The unreactive metals have only one non-4f valence electron. Oxidative addition of a C—H bond to these metals requires a strong bond to an f electron. Gd⁺, with two non-4f valence electrons need not use the 4f electrons and is seen to be very reactive. This reactivity behavior indicates that the 4f electrons of the lanthanides play little role in alkane activation due to the formation of weak sigma bonds.

In Chapter III and VI, we discuss the reasons for the unreactivity of gas-phase chromium ions. Molybdenum ions which have a very similar electrons structure are found to activate C—H bonds of alkanes. The metal ions are studied from the standpoint of gas-phase reactivity as well as the theoretical description of the bonding in the hydride and dihydride ions. The two metals are found to differ greatly in the strength of the sigma bonds that they form to hydrogen. The oxidative addition of C—H and C—C bonds to Cr⁺ is endothermic due to the extremely weak bonds formed to the metal ion.

Chapters IV and V report systematic, ab initio, generalized valence bond and configuration interaction calculations on the first and second row transition metal hydrides. The bonding in these systems is seen to depend on a number of factors including: (1) the electronic structure of the metal ions; (2) the sizes of the metal s and d orbitals and the effect on the intrinsic strength of the metal—hydrogen bond; and (3) the mediation of the intrinsic bond strengths by the loss of high spin exchange energy.

Chapter VII presents a theoretical comparison between the metal hydride ions and metal methyl ions. The present theoretical study indicates that for a variety of metal systems, the metal—hydrogen and metal—carbon bonds are very similar, both from the standpoint of metal orbital hybridization as well as bond dissociation energy.

There is a strong association between estrogen exposure and breast cancer risk. Estrogen can activate estrogen receptor alpha (ERalpha) to increase cell proliferation. Estrogen can also be metabolized into genotoxic compounds to induce DNA damage and mutations. Activation of the aryl hydrocarbon receptor (AHR) and nuclear factor erythroid-2 like 2 (NFE2L2; NRF2) can alter the production of genotoxic estrogen. The present thesis investigated the signalling mechanisms of ERalpha, AHR, and NRF2 and how their interaction might modulate breast cancer risk. In Chapter 2, genome-wide, but promoter-focused analysis of ERalpha binding sites in T-47D breast cancer cells identified potential cell line specific differences in estrogen signalling between T-47D and the commonly used MCF-7 breast cancer cells. CYP2B6 was identified to be an ERalpha target gene in T-47D cells but not MCF-7 cells, supporting cell line dependent effect in estrogen signalling. In Chapter 3 and 4, genome-wide analyses of AHR binding sites were performed to investigate the molecular criteria governing genomic AHR transactivation in vivo in mouse and in vitro in MCF-7 breast cancer cells. Our analysis identified 1) the previously established aryl hydrocarbon response element to be an important, but not an absolute requirement in AHR transactivation and 2) key epigenetic modifications that modulate AHR-dependent gene regulation. Lastly, in Chapter 5, interaction among ERalpha, AHR, and NRF2 was presented at the regulatory region of two NRF2 target genes, NADPH Quinone Oxidoreductase 1 (NQO1) and Heme Oxygenase 1 (HMOX1). ERalpha repressed, whereas AHR enhanced NRF2-dependent NQO1 and HMOX1 mRNA expression through altered p300 recruitment and Histone H3 Lysine 9 acetylation. Collectively, this thesis examined novel molecular mechanisms that might alter breast cancer development/progression by modulating ER, AHR, and NRF2 activity.

博士
臺北醫學大學
醫學科學研究所
101
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels, and it plays an important role in formation and integrity of blood brain barrier in early developmental processes. Since endothelial cell migration is one of the major events essential for angiogenesis, the finding of the anti-migration effect of aryl-hydrocarbon receptor (AhR) activation in endothelial cells suggests to that activating AhR might also exert an anti-angiogenic activity. Recent studies suggested that the vascular endothelium in central nervous system (CNS) might be a potential target of dioxin neurotoxicity. Dr. Juan’s lab previously demonstrated the anti-proliferative and anti-angiogenic effects of 3-methylcholanthrene (3MC), an AhR agonist, in human umbilical vascular endothelial cells (HUVECs). These findings showed that activated AhR might induce anti-migration, disruption of cell-cell and cell-matrix interactions, which led to increases in impediment of angiogenesis and BBB integrity, but the underlying mechanism is unclear. The aim of this study was to investigate the molecular mechanisms underlying ligand-bound AhR on angiogenesis and on the maintenance of endothelial barrier integrity. In the first part of this study, the research was aimed to investigate the molecular mechanisms underlying AhR-mediated inhibition of motility in HUVEC through alterations of RhoA/FAK expressions. FAK was downregulated whereas RhoA was up-regulated upon AhR agonist 3MC treatment. Consequently, novel functional XRE binding sites containing the core sequence 5’-GCGTG-3’in the promoter regions of RhoA and FAK were identified by electrophoretic mobility shift and chromatin immunoprecipitation assays. These results suggested the alterations of the binding activities of AhR in HUVECs treated with 3MC. Moreover, 3MC increased membrane-bound RhoA levels via suppression of a negative feedback pathway of FAK/p190RhoGAP. Subsequently, the formations of actin stress fiber and focal adhesion complex were observed with an increase in activated form of RhoA in 3MC-treated cells, and these dynamic changes of cytoskeleton were prevented by a RhoA inhibitor and AhR antagonists. Apparently, in vitro by a transwell approach showed that these compounds significantly prevented 3MC-induced inhibition of migration in HUVECs. The in vitro findings were further confirmed using an animal model of Matrigel formation in Balb/c mice. Collectively, AhR-mediated changes in genomic regulation of FAK/RhoA, triggering RhoA activation, cause the anti-migratiory and anti-angiogenic effects in HUVECs by 3MC administration. In the second part of this study, the signaling cascade of AhR-mediated up-regulation of RhoA expression was further studied to investigate the molecular mechanisms of the disruption of BBB upon 3MC treatment in MCVECs. The AhR/RhoA-mediated molecular mechanisms of PTEN/PKCδ/pGSK3β/β-catenin signaling pathway, which might implicate in alterations to blood-brain barrier integrity, were verified. PTEN phosphorylation, which was increased by 3MC-mediated AhR/RhoA activation, facilitated the proteasomal degradation of β-catenin through PKCδ/pGSK3β-mediated β-catenin phosphorylation. The decrease in β-catenin causes down-regulation of fibronectin and α5β1 integrin. In addition, the interactions of focal adhesion proteins and junctional proteins among FAK, VE-cadherin, vinculin, and β-actin were simultaneously decreased, suggesting adherens junction instability. Novel functional TCF/LEF1 binding sites in the promoter regions of fibronectin and α5/β1 integrins were identified by electrophoretic mobility shift and chromatin immunoprecipitation assays, resulting in the decreases in the binding activities of β-catenin in 3-MC-treated MCVECs. Furthermore, 3MC-mediated alterations in MCVECs were prevented by simvastatin and pravastatin treatment through inhibiting RhoA activation, and the in vitro findings were substantiated by an in vivo blood-brain barrier assay. Therefore, endothelial barrier dysfunction due to 3MC occurs through AhR/RhoA-mediated β-catenin down-regulation, which is prevented by simvastatin treatment in vivo. These results suggest that 3MC-induced up-regulation of RhoA contributed to the expressions of PTEN/PKCδ/GSK3β/β-catenin signaling pathway, which in turn decreased vascular endothelial cell’s ECM “fibronection” and its integrins “α5β1”, and the 3-MC-mediated disruption of endothelial barrier was prevented by RhoA inhibitors intervention. Taken together, the findings from the present study suggest that 3-MC/AhR-mediated alterations in vascular endothelial cells increase inhibition of angiogenesis and disruption of endothelial barrier integrity through regulating activation of RhoA and its downstream effectors.

碩士
國立陽明大學
生理學研究所
102
Chronic ethanol exposure-associated oxidative stress causes various degrees of brain damage among individuals depending on their exposure to other environmental factors, such as organic environmental pollutants that activate aryl hydrocarbon receptors (AhR). This study was to investigate how the combination of subchronic ethanol ingestion and AhR ligand exposure regulates mitochondrial enzymes, the oxidative stress-associated cytochrome P450 2E1 (CYP2E1) and CYP1A1, and the anti-oxidative Cu/Zn-superoxide dismutase (SOD1) in cerebral cortical neurons. In this study, primary cultured cortical neurons were prepared from embryonic day 17 Sprague Dawley fetal rats, and cultured neurons at 9 days in vitro (9 DIV) were used in our study. The cultured neurons were subjected to subchronic ethanol treatment, i.e. 80mM ethanol for 3 days, followed by incubating with or without AhR agonists, a natural ligand tryptophan photoproduct 6-formylindolo [3,2-b] carbazole (FICZ, 20nM) or the environmental ligand 2,3,7,8-tetrachlorodibenzodioxin (TCDD, 20nM) for 24hr. Immunofluorescent staining and WST-1 assay indicated that subchronic ethanol and AhR ligand induced neuronal loss. Subchronic ethanol increased CYP2E1 protein expression as examined by Western blotting in cortical neurons, and the effect was suppressed by the AhR agonist application. The induction of CYP1A1, an AhR target gene, was enhanced when AhR agonists were applied under subchronic ethanol treatment. In contrast, subchronic ethanol does not affect the AhR ligand-induced AhR protein and mRNA downregulation. The anti-oxidative enzyme SOD1 was reduced under subchronic ethanol exposure with or without AhR ligands, whereas AhR ligands can induce SOD1 mRNA but the effect was diminished under subchronic ethanol treatment. Reciprocally, we found that subchronic ethanol - AhR agonist exposure can increase oxidative stress as determined by NADPH oxidase activity assay. Next, we used AhR antagonist TMF to block AhR activation, and found that TMF suppressed SOD1 expression and increased oxidative stress in the ethanol-free condition, but can enhance SOD1 expression without inducing oxidative stress in neurons under subchronic ethanol exposure. Finally, we established a subchronic binge ethanol animal model, and found that SOD1 and CYP1A1 mRNA expressions were both increased in the rat cerebral cortex and hippocampus, whereas the SOD1 mRNA in the cerebellum was decreased. Together, our data tend to suggest a cross-talk between the subchronic ethanol ingestion and AhR activation reciprocally enhances or attenuates their own primary effects on the expression of CYP2E1, CYP1A1, and SOD1, which may subsequently regulate oxidative stress in cortical neurons and alcoholic brains. Information obtained from this preliminary study may provide clues for the impact and mechanism of environmental confounding factors on the alcoholism-associated neurological deficits.

series of tungsten alkyls of stoichiometry Cp'W(NO)(R)(R') [Cp' = Cp, Cp*; R = CH₂CMe₃ , CHȈ2CMe₂Ph, CH₂SiMe₃ ; R' = CH₂CMe₃ , CH₂CMe₂Et, CH₂CMe₂Ph, CH₂SiMe₃, CH₃, Ph, C l , CH₂Ph, OCH₃, NME₂ ] is shown by NMR and, in some cases, IR spectroscopies to adopt an a-agostic structure when secondary interactions such as lone pair or 7i-electron donation are not possible. This was confirmed by X-ray diffraction studies of several of these compounds and by a neutron diffraction study of Cp*W(NO)( CH₂CMe₃)₂ . In each, the agostic interaction is best described as a closed, 3-center, 2-electron bond and serves to give the electron-deficient tungsten center an 18-electron configuration. The complexes in which R and R' are neopentyl-like display fluxional behavior in solution, exhibiting averaged NMR spectra as a result of a competition between R and R' for formation of an a-agostic bond with the metal. This competition is manifested in terms of unusual NMR chemical shifts and coupling constants for the α-CH2 groups. These data establish that the strength of the C-H—W interaction is dependent on the nature of C p ' , R, and R ' . For complexes with R = R ' , it varies in the order Cp* > Cp and R = R ' = CH₂CMe₃ ~ CH₂CMe₂Ph > CH₂SiMe₃ . For complexes with R ± R ' , two trends are observed: First, among all the alkyl ligands studied, the relative a-agostic donor ability is CH₂CMe₃ > CH₂CMe₂Et > CH₂CMe₂Ph > CH₂SiMe₃ » CH₃ (CH₂Ph is nonagostic). Second, when R = CH₂CMe₃ and R ' = CH₂CMe₃ , CH₂CMe₂ E t , CH₂CMe ₂Ph, CH₂SiMe₃ , CH₃, Ph, Cl , or CH₂Ph, the α-agostic donor ability of R decreases as R' is changed from Ph to CH₃ to Cl to CH₂SiMe₃ to CH₂CMe₂Ph to CH₂CMe₂Et to CH₂CMe₃ to CH₂Ph. The neopentyl complexes, Cp'W(NO)(CH₂CMe₃)₂ [Cp' = Cp, Cp*] and Cp*W(NO)(CH₂CMe₃)(CH₂Ph), undergo facile a-abstraction of neopentane at 60-70 °C to give transiently the 16-electron alkylidene complexes, [Cp'W(NO)(=CHCMe₃ ) ] and [Cp*W(NO)(=CHPh)], respectively. Both [Cp'W(NO)(=CHCMe₃ ) ] and [Cp*W(NO)(=CHPh)] can be trapped with tertiary phosphines in THF solvent to yield the corresponding phosphine adducts as the anti rotamer. In the case of [Cp*W(NO)(=CHCMe₃)], the trapping can also be effected in neat pyridine or Me2NEt. Cp*W(NO)(=CHCMe₃)(PMe₃ ) undergoes associative addition reactions with Me₂NH, MeOH, and PhC0₂H to give Cp*W(NO)(CH₂CMe₃)(ER) [ER = NMe2, OMe, 02CPh] and free PMe3. The amido complex is also formed smoothly when [Cp*W(NO)(= CHCMe₃)j is generated in THF in the presence of Me₂NH. When [Cp*W(NO)(= CHCMe₃)] is generated in alkene solvents, it undergoes [2+2] cycloaddition and/or C - H activation reactions depending on the alkene structure. Cycloaddition is observed for acyclic alkenes which lack allylic C - H bonds and for cyclic alkenes with strained C=C bonds. In the case where the acyclic alkenes contain accessible allylic hydrogens, complicated C - H activation product mixtures are formed. Alkanes and arenes also react readily with [Cp*W(NO)(=CHCMe3)] at 70 °C by C -H activation. Reactions with alkanes proceed with moderate steric selectivity and produce mixed bis(alkyl), metallacyclobutane, alkene, or allyl complexes depending on the alkane structure. Cp*W(NO)( CH₂CMe₃)(CH₂SiMe₃) is produced in high yield in the reaction with Me₄Si . The major product of the reaction with 1,1,2,2-tetramethylcyclopropane is a metallacycle formed by intermolecular C - H activation followed by y-cyclometalation. Neohexane and cyclohexane, which are capable of P-elimination, react to give alkene complexes which can be trapped by PMe₃ or Me₂NH. In contrast, alkanes such as pentane and methylcyclohexane react to give Cp*W(NO)(73-allyl)(H) complexes in both the presence and absence of PMe₃. Reactions with arenes are similarly sensitive to steric effects and involve competitive aryl vs benzyl C - H activation. The benzyl-activated products are unstable at 70 °C, decomposing to give benzylidene complexes that also readily cleave aryl and benzyl C - H bonds. Mechanistic studies, including isotopic labeling, isotope effect, and kinetic studies, strongly implicate that the thermal decompositions of Cp'W(NO)( CH₂CMe₃)₂ proceed by a reversible, rate-determining a-abstraction process to form the neopentane complex, [Cp'W(NO)(= CHCMe₃)(772-H- CH₂CMe₃)], in which the metal can coordinate interchangeably to the neopentane a- and y - C - H bonds. Concurrently, the coordinated neopentane dissociates irreversibly from the metal center to yield [Cp'W(NO)(= CHCMe₃) ] , which can rapidly form adducts with dative ligands or coordinate another hydrocarbon and undergo addition reactions. The thermal decompositions of the mixed bis(alkyl) complexes, Cp*W(NO)( CH₂CMe₃)(R), where R = CH₂CMe₂ E t , CH₂CMe₂Ph, CH₂SiMe₃ , CH₃ , and Ph, are also reported. These studies show that the pathway by which these compounds decompose is governed primarily by the strengths of the M - C bond broken and formed, and that the presence of α-agostic interactions in the ground state has little, i f any, effect on the mechanism of decomposition.

Gentle thermolysis of the 18e alkyl-allyl complex, Cp*W(NO)(CH₂CMe₃)(η³-1,1-Me₂C₃H₃) (1.1), generates a reactive 16e allene intermediate, Cp*W(NO)(η²-H₂C=C=CMe₂) (A), by a first-order process with concomitant evolution of neopentane via hydrogen abstraction from the dimethylallyl ligand. Intermediate A has been structurally characterized as its PMe₃ adduct, and is capable of effecting both single and multiple intermolecular C-H bond activations of hydrocarbon solvents to form alkyl-allyl and allyl-hydrido complexes. The products of reactions of A with methyl-substituted arenes (i.e. sp² C-H vs sp³ C-H) indicate an inherent preference for the activation of stronger arene C-H bonds, however steric effects are also relevant as indicated by the exclusive formation of benzylic C-H activation products in mesitylene. Thermolyses of 1.1 in alkane solvents generate products resulting from three successive C-H bond-activation reactions. Preliminary studies suggest that allyl-hydrido complexes are formed along with an organic product; for example, in cyclohexane, 1,1- dimethylpropylcyclohexane results from coupling of a solvent molecule and a fragment derived from the precursor dimethylallyl ligand. The allyl-hydrido complexes have potential synthetic utility, since studies conducted on structurally and electronically related CpMo complexes show that they may be capable of ultimately producing homoallylic alcohols.

Thermolysis of Cp*W(NO)(CH₂C₆H₅)(CH₂CMe₃) (2) in various solvents generates neopentane and benzylidene Cp*W(NO)(=CHC₆H₅) (B) in situ. Complex B activates the C-H bonds of alkane solvents to yield alkene or allyl hydride complexes, and activates arene solvents to yield aryl or benzyl derivatives. The basic mechanistic features of the formation and reactivity of B, and the scope of B's activation chemistry are very similar to those of the previously-studied neopentylidene Cp*W(NO)(=CHCMe₃) (A) derived from Cp*W(NO)(CH₂CMe₃)₂ (1). However, the product distributions derived from the activation of substituted arenes by B are more abundant in the aryl products over the benzyl products than those obtained from A (toluene, p>xylene). Likewise, the aryl regioisomer distributions obtained from B favour the meta isomer over other isomers, more so than those obtained from A (α,α,α-trifluorotoluene, toluene). The mechanism of the thermal chemistry of 1 and 2 is re-examined for the possible involvement of hydrocarbon intermediates in the formation of the activation products. The observation of H/D scrambling in Cp*W(NO)(CD₂CMe₃)₂ (1-d₄) prior to neopentane elimination indicates that hydrocarbon intermediates do exist on the reaction coordinate. The near-unity values of the KIEs measured for benzene, tetramethylsilane and mesitylene indicate that the key step in the C-H activation of these substrates is coordination to the metal center, rather than substrate C-H bond scission. An in-depth experimental and theoretical investigation of the activation of toluene reveals that the aryl vs benzyl product distributions are controlled by the relative energetics of substrate coordination in two different fashions to the metal center. In contrast, the aryl regioselectivity is controlled by the relative energies of the aryl products. The product distributions obtained from the activation of other substituted arenes are controlled by these same factors, but with variations that depend on the substrate and the alkylidene complex utilized. The alkylidene systems can potentially be used to convert alkanes into homoallylic alcohols, via the allyl hydride products of C-H activation. Strategies for developing related Cp'M(NO)-based systems (Cp' = Cp or Cp*; M = Mo, W) are also described, along with preliminary investigations into the activation chemistry derived from CpMo(NO)(CD₂CMe₃)₂ and Cp*W(NO)(CH₂CMe₃)(η³-l,l-Me₂-C₃H₃).

The reaction of previously characterized ruthenium oxo complex, [L_OEtRu^V(O)(µ-O)]₂ with alcohol substrates was undertaken to elucidate the mechanism of the oxidation reaction. Unfortunately, an autocatalytic reaction between the organometallic product, [L_OEtRu^IV(OH)(µ-O)]₂ and the reactant alcohol, as well as catalyst decomposition made exact determinations of rate constants impossible. During the course of this investigation, the free acid form of the ligand, L_OEtH, was isolated as a viscous oil. Subsequent investigation of the reactions of [L_OEtRu^V(O)(µ-O)]₂ with other species such as acids, salts and bases demonstrated the inherent instability of the complex. In several cases, initial products were spectroscopically characterized, but isolation of pure compounds was not achieved.

Given the problems with the decomposition of ruthenium complexes which utilized the Klaui ligand, trimetaphosphate was studied as a potentially oxidation-resistant alternative for the development of oxidation catalysts. Attempts were made to prepare salts of the trimetaphosphate ligand which are soluble in nonpolar media and free of water of hydration. Coordination complexes of the trimetaphosphate anion and transition elements were synthesized. The mode of coordination and stability of the ligand was examined by infrared and visible spectroscopy. In all cases, the very weakly coordinating trimetaphosphate anion failed to displace other weakly associated ligands from the metal, failed to adopt the proper coordination geometry or was easily removed from the metal center by water.

Hexabenzyloxycyclotriphosphatriene was synthesized and thermally rearranged to 1,3,5 - tribenzyl - 2,4,6 tribenzyloxy - 2,4,6 trioxocyclotriphosphazane as per published procedures. Characterization of the rearranged product by NMR techniques revealed the previously undetermined stereochemistry of the product. This ligand precursor has been shown to react with trialkyl silyl chlorides, although the products have not been characterized.

Cp*₂Ta(=N^tBu)(THF)[B(C₆F₅)₄] (1) was synthesized according to the method developed previously in our group. A cationic analog to Bergman's Cp₂Zr(=N^tBu), the reactivity of this complex to hydrocarbon substrates was studied. Contrary to previous reports, this complex does not react with methane, but C-H activation reactions were observed for propyne and phenyl acetylene. In the propyne case, an initial mixture of the [2+2] and C-H activation products was driven to exclusively the C-H activation product thermally. An interesting intramolecular activation of a Cp* methyl group precludes much of the desired C-H activation chemistry. The steric demands of the active site was demonstrated by the observed reaction with ethylene, but the lack of reactivity towards propene. A very interesting dealkylation of the imido group was observed upon reaction with carbon dioxide, which is proposed to involve the intermediacy of a coordinated isocyanate. Cp*₂Ta(=N^tBu)(THF)[B(C₆F₅)₄] reacts as expected with water, HCl and dihydrogen, and reacts cleanly with methylene chloride to give Cp*₂Ta(NH^tBu)Cl[B(C₆F₅)₄]. Many of the new compounds have been crystallographically and spectroscopically characterized. The reactivity of this complex can be rationalized in terms of the presence of both electrophilic and nucleophilic sites in the same molecule.

碩士
國立成功大學
化學系碩博士班
96
Recently we found several highly substituted naphthalenes 37 have been synthesized in one pot by treatment of arenes 38 with alkynes 35 in the presence of palladium acetate and silver acetate. In this Pd-catalyzed protocol, an arene provides a "benzo" unit to construct a naphthalene core via a two-fold aryl C�{H bond activation. To the best of our knowledge, this is the first example of preparation of naphthalenes from two-fold of aryl C�{H bond activations. We have optimized the reaction conditions and tested various arenes from the preparation of such molecules. This synthetic method provides three advantages: simple, clean and atomic economic. Crystal structures of cycloadducts 5-n-butyl-8-methyl-1,2,3,4-tetraphenylnapht- halene (37ea), 5,8-diisopropyl-1,2,3,4-tetraphenyl-naphthalene (37ga) and 5,8-dimethyl-1,2,3,4-tetra(4-tolyl)naphthalene (37ac) have been analyzed by X-ray diffractions. The twisted structure of naphthalenes arises not only from the over-crowded substituents but also from the contribution of the CH3�{π interaction.

碩士
國立臺灣大學
生物化學暨分子生物學研究所
105
Hepatocellular carcinoma (HCC), the main type of primary liver cancer, is a serious healthcare problem worldwide. Tumor immune escape is involved in the initiation and progression of HCC, which may result from indoleamine 2,3-dioxygenase (IDO)-mediated metabolism of tryptophan to kynurenine (KYN). Activation of the aryl hydrocarbon receptor (AhR) by KYN, which is an endogenous ligand for AhR, has been implicated in liver carcinogenesis. Recently, it has been demonstrated that IDO was overexpressed in 35.5% of HCC resection samples and resulted in significantly poor prognosis, whereas the precise role of IDO remain to be elucidated. Here we showed that IFN-γ induced IDO expression and activity in Huh7 shCtrl but not in shIDO cells. Since KYN is capable of activating AhR signaling pathway, we examined the function of IDO activity in HCC cells. We found that KYN can rescue the proliferation rate which had been suppressed by loss of IDO activity. IDO activity can coordinately activate both AhR and β-catenin signaling pathway, which is directly responsible for the increased proliferation. Moreover, immunoblotting analysis confirmed that IDO enhanced the nuclear translocation and signaling activation of both AhR and β-catenin. We thus tested the hypothesis that constitutive AhR signaling may drive EMT-related molecules, which result in loss of E-cadherin and spoil the down-regulation of β-catenin. As hypothesized, IDO activity enhanced snail and SLUG proteins dose-dependently, which is highly correlated to the inhibition of E-cadherin. We then investigated the Akt signaling in the presence of IDO activity and found that level of p-Akt and p-GSK-3β was significantly increased, which abolished the inhibition of free cytosolic β-catenin. In conclusion, we found that IDO enzymatic activity coordinately activated both AhR and β-catenin signaling that is responsible for increased proliferation. Furthermore, IDO activity-derived KYN promoted β-catenin signaling through induction of EMT-related molecules via AhR activation. In addition, IDO activity-mediated activation of Akt signaling resulted in constitutive activation of β-catenin signaling. These results provide evidence for previously unknown tumor-promoting function of IDO and indicates its potential as a therapeutic target.

Significant developments have been made in the field of C–H activation. However, various disadvantages, mainly low reactivity and selectivity, limit their usage in large-scale synthesis. It is crucial to understand the mechanisms and the nature of the transient species involved in the C–H activation paths to develop effective catalytic routes for homogeneous C–H functionalization reactions. Computational techniques are employed in this study to throw light on these processes. Chapter 1 briefly introduces C–H activation and functionalization reactions. After classifying the reactions on the basis of mechanisms, computational studies on the mechanisms of C–H activation reactions are described. The challenges involved in the discovery of efficient homogeneous C–H functionalization catalysts and progress made in the field are discussed. The insights provided to overcome the problems associated with the catalytic C–H functionalization reactions in a few examples are highlighted. In Chapter 2, DFT model studies are carried out to estimate the affinity and selectivity of 16-electron half-sandwich d6-metal fragments (η5–C5H5)Re(CO)2 and (η6–C6H6)W(CO)2 for binding with alkane C–H bonds. Different C–H binding sites of pentane, at the M06 level of theory have been evaluated. The effects of ancillary ligand variations on the metal–pentane binding strength are studied by substituting different ligands such as N-heterocyclic carbene (NHC), PF3 and NO+ for one of the carbonyl ligands. Isomers of the metal-pentane C–H σ-complexes studied in this chapter are shown in Scheme 1. Binding energies of the terminal methyl C–H bonds (C1 and C5) are significantly lower than those of the methylene C–H bonds (C2, C3 and C4) in all the cases. The metal–pentane binding interactions of the rhenium complexes are significantly stronger than those of the corresponding tungsten analogs. The PF3 complexes have slightly greater binding energies compared to the CO complexes, in both Re(I) and W(0) analogs. These results are in conformity with the experimental results. The electron-deficient nitrosyl complexes have the highest binding energies. These results illustrate that by proper tuning of the electronic factors of the transition-metal fragments with different ancillary ligands, the alkane C–H binding affinity can be controlled. Energy decomposition analyses (EDA) are carried out to determine the nature of the interaction between the metal fragments and pentane C–H bonds. Scheme 1. Formation of pentane C–H σ-complexes Chapter 3 addresses the energetics of various intramolecular site-exchange (chain walking) processes and C–H oxidative addition reactions (Scheme 2) of the pentane C–H σ-complexes studied in Chapter 2. Four possible site-exchange processes such as 1,2-, 1,3-, 1,4- and 1,5-migration processes are studied using DFT/M06 level of theory. η2-(H,H)···M type transition states are located for these migrations (Scheme 2). The 1,3-migration is the most favorable process. Two different pentyl hydride isomers, as shown in Scheme 2, are obtained for oxidative addition of methyl and methylene C–H bonds of pentane for all systems, at same level of theory. Oxidative insertion of metal into the methyl C–H bonds is more favorable than insertion into the methylene C–H bonds for all complexes. The activation energies of all site-exchange and C–H oxidative addition processes of the Re(I) complexes are significantly greater than those of the corresponding W(0) complexes. For all these processes, the activation barriers of the electron-deficient NO+ complexes are the greatest among all ligand systems studied, in both Re(I) and W(0) systems. These results are consistent with the experimental results and suggest that the experimentally observed pentyl hydride isomer [(η5–C5H5)Re(CO)(PF3)H(C5H11)] might be Isomer B and not Isomer A (Scheme 2). The C–H oxidative addition reactions are less favorable than dynamic site-exchange processes in all complexes. These results imply that the metal fragments migrate along the pentane chain more easily than insert into the pentane C–H bonds. Scheme 2. Alkane chain walking and C–H oxidative addition reactions Chapter 4 deals with the mechanisms and energetics of a unique metal migration process of an olefin complex that proceeds via olefinic (C–H)···Metal interaction. Migration of the Re(I) fragment from one π face of the olefin to the opposite π face in [(η5–C5H5)Re(NO)(PPh3)(PhCH═CH2)]+ has been documented experimentally by Gladysz and coworkers. The experimental results provide evidences for an intramolecular mechanism for this process (i.e., without styrene dissociation from Re(I)) and based on kinetic isotope effects (KIE), the involvement of a trans C–H bond is indicated. Either oxidative addition or a vinylic (C–H)···Re interaction could account for the experimentally observed kinetic isotope effect. In this study, the free energy of activation for the migration of Re from one enantioface of the olefin to the other through various pathways is computed using DFT calculations at the B3LYP and M06 levels. Two pathways, one that involves migration of Re through a trans (C–H)···Re interaction and another that involves oxidative addition of Re into the trans C–H bond, are identified as possible paths (Scheme 3) at the B3LYP level. Surprisingly, at the M06 level, DFT computes a lower energy path for the conducted tour mechanism that is not consistent with the experimental KIE. But the computed energy profiles for the reaction are consistent with the experiment when computations are carried out at the B3LYP level. Scheme 3. Mechanisms of olefin π face exchange reaction In Chapter 5, the mechanistic studies of C–H metathesis of d6 half-sandwich complex [(η5–C5Me5)Ru(CH3)(CO)(C6H6)] are discussed. A 1-step mechanism that proceeds via a four-center transition state and a 2-step Oxidative Addition and Reductive Coupling mechanism (OA/RC) are identified as possible mechanisms (Scheme 4) using DFT/M06 level of theory. The 1-step mechanism is more favorable than the 2-step mechanism. As in the oxidative addition intermediate, metal–hydrogen bond is observed in the four-center transition state of the 1-step mechanism. This mechanism is referred to as Oxidative Hydrogen Migration (OHM) rather than σ-Bond Metathesis (σ-BM) which proceeds via a transition state without M−H bonding. The effects of metal (M = Fe(II), Ru(II) or Os(II)) and ancillary ligand (L = H–, NHC, CO or NO+) variations on the mechanisms and energetics of the model Cp complex [(η5–C5H5)M(CH3)(L)(C6H6)] are also studied (Scheme 4). Scheme 4. Oxidative hydrogen migration vs Oxidative addition/reductive coupling Increase in the electron-density on the metal center, using electron-donating ligands such as H−, favors the formation of the oxidative species (intermediate or transition state) and reduces the activation barriers of the C–H metathesis reaction. Similarly, the electron-withdrawing NO+ ligand, which reduces the electron density on the metal center, increases the activation energies of the C–H metathesis reaction or disfavors the formation of the oxidative species. Factor affecting the choice of the mechanism of the C–H metathesis reaction is found to be the net charge transfer between the two fragments [(η5–C5H5)M(CH3)(L)] and benzene in [(η5–C5H5)M(CH3)(L)(C6H6)]. The computational studies reported in this thesis provide valuable insight into the mechanisms and energetics of C–H binding, activation and fluxional processes of the (C–H)···Metal σ alkane and alkene complexes. These studies will be helpful in solving problems associated with the C–H activation reactions. Reference Thenraj, M.; Samuelson, A. G. Organometallics 2013, 32, 7141. (For structural formula and figures pl see the abstract pdf file.)