Ce travail est centré sur la synthèse de complexes du rhodium contenant un ligand azoté et leur mise en œuvre dans la réaction catalytique de carbonylation du méthanol en acide acétique. Dans une première partie, nous nous intéressons à la préparation de complexes neutres de formule générale [RhI2(CO)(L)] (L = amines, imidazoles et pyrazoles) et à quelques homologues chlorés. Ces complexes plans carrés manifestent une réactivité directement liée à l’encombrement stérique du ligand azoté L dans la réaction d’addition oxydante de l’iodomethane suivie de la cis-migration du groupement méthyle pour former l’espèce acétyle. Dans une deuxième partie, les complexes précédents ont été engagés dans des essais catalytiques de carbonylation du méthanol dans les conditions du procédé industriel. Comme il s’est avéré que les complexes neutres se transforment en espèce [RhI2(CO)2]- pour laquelle les contre-cations associés sont constitués du ligand azoté protoné ou methylé, nous avons effectué la préparation et la caractérisation des complexes [HNR3][RhI2(CO)2] ou [MeNR3][RhI2(CO)2]. Par IR, RMN et électrochimie, nous nous sommes intéressés aux phénomènes d’appariement d’ions et nous montrons qu’il s’agit dans le meilleur des cas d’interactions hydrogènes. Celles-ci influent la vitesse de la réaction oxydante de CH3I. Dans la dernière partie, nous avons complété une étude, précédemment initiée au laboratoire, sur le mécanisme, qui dans la dernière étape du cycle catalytique permet de passer de l’espèce acétyle [RhI3(COCH3)(CO)2]- à l’espèce active [RhI2(CO)2]- avec production de l’iodure d’acyle. A l’inverse du concept admis d’élimination réductrice de CH3COI suivie de son hydrolyse immédiate en CH3COOH et HI, nous montrons, avec l’appui de calculs théoriques (DFT) qu’en fait un ligand I- est substitué par un ligand acetate pour conduire à l’espèce [RhI2(OAc)(COCH3)(CO)2]-. L’élimination réductrice produit alors l’anhydride acétique qui est hydrolysé en CH3COOH régénérant [RhI2(CO)2]-. Un tel mécanisme opère en présence d’ions acetate dans les milieux faiblement hydratés visés par l’industriel. / This study focuses on the synthesis and reactivity of rhodium complexes bearing N- containing ligands or counter-cations for the [Rh]-catalyzed methanol carbonylation reaction to produce acetic acid under the industrial Celanese Acid Optimization (AO) process conditions. In a first part, full synthesis and characterization of neutral Rh(I) square planar cis- [RhX(CO)2(L)] (X = Cl or I) complexes have been described, for which L is an N-ligand belonging to the amine, imidazole or pyrazole family. For the [RhI(CO)2(L)] complexes, variable-temperature 13C{1H} NMR spectroscopy has put in evidence a fluxional behavior for the different sized L ligands involved. The rate of this fluxional process reveals to be related to both electronic and steric contributions brought by L to the Rh center. These parameters (mainly steric), supported by single-crystal X-ray analyses in the solid state, also influence significantly the kinetics of the methyl iodide oxidative addition reaction followed by rapid CO migratory insertion, the overall being the rate determining step of the [Rh]-catalyzed methanol carbonylation cycle. In absence of CO, this reaction gives rise to the corresponding neutral Rh(III) acetyl complex, which immediately dimerizes to afford [Rh(μ- I)I(COMe)(CO)(L)]2 complex, for which several X-ray crystal structures have been obtained and studied. In addition, the surprising C-H activation in the case of a tBu-pyrazole ligand giving rise to a cyclometalated Rh dimer is reported. In a second part, the reactivity of the latter neutral Rh(I) [RhI(CO)2(L)] complexes as potential precursors has been investigated by batch experiments for the methanol carbonylation reaction. Mechanistic understanding via VT-HP-NMR experiments enabled to detect mainly anionic Rh(I) [RL][RhI2(CO)2] (R = H or CH3 according to the working conditions) complexes formed by decoordination followed by quaternization of the L ligand. Despite this result, the pyrazole family ligands showed better stability under the harsh process conditions. Thus, it cannot be ruled out that equilibrium between neutral and anionic species co-exist in the reaction medium at high temperatures and that [RL]I salt dissociation occurs, restoring the L ligand into the Rh coordination sphere. At this stage we focused on the anionic Rh(I) complex and prepared a series of [XNR3][RhI2(CO)2] (X = H or CH3) species, which have been fully characterized. Infrared, NMR, conductivity experiments and DFT model calculations together put in evidence ion interactions according to the nature of the ammonium counter-cation. Protonated cations significantly impact on the kinetics of the methyl iodide oxidative addition presumably due to H-interactions with the Rh square plane. The final part deals with the mechanism of the reductive elimination reaction, the last step of the [Rh]-catalyzed methanol carbonylation cycle, which from complex [RhI3(COCH3)(CO)2]-, regenerates [RhI2(CO)2]-. In contrast to the classically admitted mechanism of reductive elimination of CH3COI followed by subsequent hydrolysis to form AcOH and HI, we demonstrate from experimental DFT calculation that substitution of an iodo ligand by an acetate ion occurs to give rise to the [RhI2(OAc)(COCH3)(CO)2]- species. Thus, reductive elimination regenerates [RhI2(CO)2]- and produces acetic anhydride, which after hydrolysis affords two molecules of acetic acid. Such a mechanism operates under process conditions at low water content with a significant amount of acetate ions.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of new compounds alkyl 3-azolyl propanoate e alkyl 3-azolyl propanoic acid structurally analogues to gamma-aminobutiric acid (GABA) is reported. One more time using the acetal acylation method, now the acetal derivative of 4-oxopentanoic acid (levulinic acid), the methyl 4,4- dimethoxypentanoate, were obtained the precursors methyl 7,7,7-trifluoro[chloro]-4- methoxy-6-oxo-heptenoates, 1,3-dieletrophilic precursor with alcanoate substituent. Are presented efficient and regioespecific synthetic routes from reactions of cyclocondensation [3+2] among 1,3-dieletrofilic precursors with hydroxylamine and different hydrazines, until training isoxazoles and pyrazoles, functionalized with the side chain alkyl propanoate or propanoic acid. Simultaneously to the formation of heterocycles, were studied the hydrolysis reaction of trichloromethyl group and transesterification reaction of methyl propanoate, in the same reactional medium. All products are novel, presenting a good to excellent yields, high purity and the structures were assigned by 1H NMR, 13C NMR and mass spectrometry. / A síntese de novos compostos 3-azolil-propanoatos de alquila e 3-azolilácidos propanóicos, análogos estruturalmente ao ácido gama-aminobutírico (GABA) é relatada. Novamente aplicando o método de acilação de acetais, agora ao acetal derivado do ácido 4-oxopentanóico (ácido levulínico), o 4,4-dimetoxipentanoato de metila, foram obtidos os precursores 7,7,7-triflúor[cloro]-4-metoxi-6-oxo-heptenoatos de metila, precursores 1,3-dieletrofílicos com o substituinte alcanoato. São apresentadas rotas sintéticas eficientes e regioespecíficas a partir de reações de ciclocondensação [3+2] entre os precursores 1,3-dieletrofílicos, com hidroxilamina e hidrazinas diferentes, até a formação de isoxazóis e pirazóis, funcionalizados com a cadeia lateral propanoato de alquila ou ácido propanóico. Simultaneamente à formação dos heterociclos, foram estudadas as reações de hidrólise do grupamento triclorometila e hidrólise ou transesterificação do propanoato de metila, no mesmo meio de reação. Todos os produtos obtidos são inéditos, apresentando rendimentos de bons a excelentes e pureza alta e suas estruturas foram atribuídas por RMN1H e 13C e por espectrometria de massas.

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Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.

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3-Chloro-4,4,5-trimethyl-3,5-diphenyl-4,5-dihydro-3H-pyrazole (3b) and 3-bromo-4,4,5-trimethyl-3,5-diphenyl-4,5-dihydro-3H-pyrazole (3c) were prepared for the thermolysis project. The thermal decompositions of 3b and 3c were monitored using 1H NMR spectroscopy. Plots of ln (% starting material) vs. time (sec) were linear for at least two half lives and the first order rate constants were determined over at least a 30o temperature range. The relative reactivity was found to be 3c > 3b. The activation parameters determined for the thermal decomposition of the pyrazoline at 150oC were found to be: for 3b &#;H‡ = 33 &#;1.0 kcal/mol, &#;S‡ = -2.4 &#; 0.07eu , k150 0 = 7.34 &#; 0.44 x 10 -5 s-1 ; for 3c &#;H‡ = 30&#;0.2 kcal/mol, &#;S‡ = -6.9 &#;0.03 eu, k150o = 42.3&#;0.7 x 10-5 s-1. Thermal decomposition of 3b both neat and in dibromobenzene (DBB) resulted in the formation of an intermediate 2,3-diphenyl-4-methyl-1,3-pentadiene (8) as a major product and minor isomers of 8. These intermediates then thermally decomposed to 1,1,3-trimethyl-2-phenyl-1H-indene (9) via an acid catalyzed process. In order to gain a mechanistic understanding (ionic vs. radical pathways) of the thermal decomposition of 3b, a product study was conducted in protic solvents. In methanol and ethanol, 3b underwent an ionic reaction (SN1-type) with the solvent to produce 3-methoxy/ethoxy-4,4,5-trimethyl-3,5-diphenyl-4,5-dihydro-3H-pyrazole (3/3d) in good yield. The reaction of 3b with refluxing protic solvents led to the development of new method for the synthesis of alkoxy-4,5-dihydro-3H-pyrazoles which is both safe and efficient.

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