Les alcaloïdes Daphniphyllum constituent une vaste famille de produits naturels isolés à partir de plantes à feuillage persistant couramment utilisés dans la médecine chinoise traditionnelle. Ils affichent une gamme impressionnante d'activités biologiques; antipyrétique, anti-inflammatoire, antioxydant et même anticancéreux. La calyciphylline B appartient à cette famille et possède un motif original comprenant sept stéréocentres adjacents, dont un stéréocentre quaternaire tout carbone, avec un échafaudage hexacyclique. Sa structure a été déterminée par données spectroscopiques, plus précisément par des techniques de RMN 2D. Malgré le peu d'information sur son activité biologique, sa synthèse représente sans le moindre doute un grand défi pour les chimistes organiciens. Le groupe de recherche du Prof. Hanessian a entrepris la synthèse totale de la calyciphylline B en 2010, laquelle est toujours en cours. Une nouvelle approche a été développée pour la préparation d'un intermédiaire azabicyclo[3.3.0]octane avancé. Ce mémoire résume les travaux de recherche de l'auteur sur les progrès réalisés pour la voie alternative élaborée par le groupe du prof. Hanessian. Le travail effectué comprend la formation d'un stéréocentre quaternaire, l'alkylation d'un énolate sur un triflate d'alkyle secondaire, une réduction diastéréosélective, une cyclisation réductrice ainsi qu'une oxydation de Wacker régiosélective. / The Daphniphyllum alkaloids constitute a broad class of natural products isolated from a genus of evergreen plants extensively used in traditional Chinese medicine. These alkaloids display an impressive range of biological activities, including antipyretic, anti-inflammatory, antioxidant, and even anticancer properties. Calyciphylline B is a structurally unique member of this family containing seven contiguous stereocenters including an all-carbon quaternary stereocenter with a fused-hexacyclic ring scaffold. Its structure was determined by spectroscopic methods, especially 2D NMR techniques. Despite the sparse availability of information on its biological activity, its synthesis is undoubtedly a great challenge for synthetic chemists. The research group of Prof. Hanessian embarked on the total synthesis of calyciphylline B in 2010 and the project is still ongoing. A new route was developed for the preparation of an advanced azabicyclo[3.3.0]octane intermediate. This thesis summarizes the research work of the author on the progress made for the synthetic route developed by the Hanessian group. The work done includes the formation of a quaternary stereocenter, alkylation of an enolate using a secondary alkyl triflate, diastereoselective reduction, reductive cyclization, and a regioselective Wacker oxidation.

Formaldehyde is a chemical used widely in the manufacture of building materials. A remarkable example is represented by the Lucite two-step Alpha technology for the large scale production of methyl methacrylate (MMA), the essential building block of all acrylic-based products. Esters and ketones are important intermediates in the manufacture of acrylate esters therefore α-hydroxymethylenation of carbonyl compounds using formaldehyde as a one carbon alkylating agent and subsequent dehydration to the corresponding methylenated derivatives has been explored in the current work. We report a novel catalytic approach for the synthesis of methyl methacrylate (MMA) via one-pot α-methylenation of methyl propanoate (a chemical intermediate of the ALPHA process) with formaldehyde, generated in situ by Ru-catalysed dehydrogenation of methanol. Elucidation of the mechanism involved in the catalytic dehydrogenation of methanol along with the collateral alcohol decarbonylation reaction was gained through a combined experimental and DFT study. The development of an alternative process where anhydrous formaldehyde is produced in situ would provide a simplification over the current second step of the ALPHA technology where the formaldehyde is initially produced as formalin, subsequently dehydrated to afford anhydrous formaldehyde in order to ensure high selectivity to MMA. As an alternative approach, ketones, in particular 3-pentanone and 2-butanone, were targeted as potential substrates in order to overcome some of the problems related to competing reactions that occur at the ester group. Hydroxymethylenation, followed by dehydration and Baeyer-Villager oxidation, possibly catalysed by enzymes to reverse the normal selectivity, leads to the formation of acrylate esters. The catalytic reaction is enabled by a gold carbene hydroxide complex in such a way that the substrate undergoes C-H activation and the nascent metal alkyl acts as a nucleophile towards the electrophilic formaldehyde, supplied in the form of alcoform* (solution of paraformaldehyde in methanol).

Préalablement, une synthèse de l’aliskiren, un inhibiteur de la rénine développé pour le traitement de l’hypertension, a été réalisée auprès du groupe Hanessian. Durant cette synthèse, une réaction clé de cyclisation par métathèse, menant à la formation de lactone à neuf membres, a été réalisée. Durant cette réaction, nous avons observé une différence de réactivité entre les diastéréomères, menant à la formation de monolactones et de dilactones, générant ainsi de l’intérêt pour l’étude des facteurs en cause. Le présent mémoire rapporte et détaille les résultats de cette analyse quant à la formation de monomères versus celle de dimères par cyclisation à l’aide de catalyseurs de Grubbs et l’impact de différentes conditions réactionnelles et la diastéréochimie relative sur la réaction. Un intérêt pour la formation de liens benzyliques nous a incité à approfondir notre compréhension d’une méthodologie de substitution nucléophile diastéréosélective catalysée par des acides. Le rationnel mit de l’avant par les groupes Bach et Olah a procuré une compréhension du mécanisme réactionnel sur lequel nous avons basé nos observations subséquentes. Nous avons porté notre attention sur l’alkylation d’arènes, de phénols et de sulfonamides. Diverses régiosélectivités et diastéréosélectivités ont pu être observées en présence de substrats dérivés de la synthèse de l’aliskiren, de nitroalcools ainsi que de azidoalcools en utilisant plusieurs acides de Lewis et de Brønsted. / Previously, a synthesis of aliskiren, a renin inhibitor developed for the treatment of hypertension, was developed in the Hanessian group. As part of that synthesis, they used a ring-closing metathesis which led to the formation of a nine-membered lactone, a key intermediate of the synthesis. During the reaction, we observed a difference in reactivity between the various diastereoisomers leading to the formation of mono- and dilactones, inciting us to study the various factors involved. The present master’s thesis reports and details the results of the study of monomers versus dimers formation by cyclization using Grubbs’s catalysts and the effect of various reaction conditions and relative configuration on the reaction. An interest for the formation of benzylic bonds drove us to deepen our comprehension of a methodology of diastereselective nucleophilic substitution catalysed by acids. The rational brought forth by the Bach and Olah groups served as a basis for our understanding of the mechanism involved upon which we based our following observations. We focused our attention on the alkylation of arenes, phenols and sulfonamides. Various regioselectivities and diastereoselectivities were observed on substrates derived from the aliskiren’s synthesis, nitroaocohols and azidoalcohols while using various Lewis and Brønsted acids.

Une nouvelle approche pour la synthèse de l’aliskiren, un puissant inhibiteur de la rénine pour le traitement de l’hypertension chez l’homme, a été développée. De cette approche, des étapes clés tels qu’une allylation avec un des catalyseurs de MacMillan, une cyclisation par métathèse (RCM) pour la préparation d’une lactone à neuf membres et une séquence de réactions d’aziridination diastéréosélective/réarrangement de cycle par une catalyse acide donnant un produit aminohydroxylé ont permis de compléter la synthèse de l’aliskiren en 11 étapes. Durant l’élaboration de la séquence de réactions pour la préparation de l’aliksiren, il a été noté que la lactone à neuf membres avait une facilité à se réarranger via des intermédiaires quinonoïdaux et les produits issus de cette tendance ont été analysés. De plus, une étude sur la réaction de RCM, donnant la lactone à neuf membres, a montré une dépendance envers la nature diastéréomérique du substrat de départ. Une méthodologie d’alpha-allylation asymétrique de cétones catalysée au palladium, tirant avantage d’un ligand chiral PHOX, a été explorée et utilisée en vue de la synthèse de l’aliskiren. De cette méthode, une étude pour la synthèse de produits alpha-allylcétones acycliques a été démontrée et un effet d’additif sur la sélectivité et la vitesse de réaction a été découvert. De plus, la production d’un intermédiaire avancé d’un produit d’intérêts a été accomplie et la nature de la contribution de l’additif a été investiguée. Les produits obtenus depuis la méthodologie d’allylation catalysée au palladium et la formation d’intermédiaire cationique des certains dérivés de la synthèse de l’aliskiren ont inspirés une nouvelle approche faisant appel à des techniques d’alkylation en catalyse acide pour la formation de produits diaryliques. Il a été trouvé que le catalyseur de chlorure d’or(III) et de triflate de bismuth(III) étaient particulièrement efficaces, démontrant une différence de cinétique pour la réactivité d’un mélange diastéréoisomériques d’alcools alpha-substitués de départ. / A new synthetic route toward aliskiren, a potent renin inhibitor for the treatment of hypertension in man, was achieved. In this approach, the use of key steps such as an asymmetric allylation catalyzed by one of MacMillan’s catalysts, a ring closing metathesis for the formation of a 9-membered lactone and a catalytic aziridination/diastereoselective acid-catalyzed ring rearrangement reaction sequence leading to an aminohydroxylated product permitted us to achieve an 11-step synthesis of aliskiren. While elaborating the sequence towards the inhibitor, the tendency of the cyclic intermediate to rearrange through a quinonoid intermediate was observed. The products of the rearrangement were analyzed. Furthermore, studies exploring the formation of the nine-membered ring lactone demonstrated a dependency on the diastereomeric nature of the substrates. A new allylation methodology was explored for the preparation of aliskiren, in which a palladium catalyzed decarboxylative asymmetric alkylation took place in the presence of a chiral PHOX ligand. The scope of the reaction was studied varying substituents on acyclic alpha-allylketones and an additive effect was noticed with respect of the reaction rate and selectivity. In addition to the preparation of molecules with pharmaceutical interest, few experiments to elucidate the role of the additive in the allylation reaction were investigated. Inspired by our observation of quinonoid formation and our use of the palladium asymmetric allylation method to generate an alpha-stereogenic center, we anticipated that a diastereoselective synthesis of a key intermediate for the synthesis of aliskiren could be accomplished by introducing a nucleophile on a quinonoid intermediate from the least hindered face, under catalytic and acidic conditions. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric alpha-substituted benzyl alcohols.

6 Title: Sythesis and catalytic properties of ferrocenophane phosphines Author: Karel Škoch Institution: Faculty of Science, Charles University in Prague, Department of Inorganic Chemistry Supervisor: prof. RNDr. Petr Štěpnička, Ph.D. Keywords: ferrocene, ferrocenophane, phosphine ligands, palladium, asymetric catalysis, aza- Morita-Baylis-Hillman reaction, asymetric allylic alkylation Abstract: This Thesis describes the preparation of five sterically and electronically different ferrocene phosphines, (R)-1,1'-[1-(diarylphosphino)propan-1,3-diyl]ferrocenes (R)-1a-e, and a study into their coordination and catalytic properties. The key precursor of the phosphine synthesis, chiral alcohol (R)-2, was prepared according to the procedure described in the literature. Alcohol (R)-2 was converted with retention of configuration to diarylphosphines (R)-1a-e in one-step reaction with trimethylsilylchloride and sodium iodide and then with the corresponding diarylphosphine. Phosphines 1a-e were characterized by NMR and MS methods. For the basic representative 1a the following palladium(II) complexes were prepared: [PdCl(LNC )(1a)] (10, LNC = 2-[(dimethylamino)methyl]phenyl-C1 ,N) and trans- [PdCl2(1a)2] (9a). In addition, the isomeric complex cis-[PdCl2(1a)2] (9b) was isolated from the reaction mixture after catalytic...

A presente tese trata de α-sulfonil carbânions, trazendo uma contribuição para a compreensão da sua estabilidade conformacional e reatividade frente a reagentes eletrofílicos. As reações investigadas foram as alquilações e sulfenilações de α-sulfonil tioésteres e as descarboxilações alquilativas dos ácidos α-fenilsulfonil-α-fenilpropanóicos racêmico e opticamente ativo. A apresentação e discussão dos resultados das reações de alquilação e sulfenilação é precedida por uma revisão bibliográfica que apresenta os trabalhos mais relevantes da literatura sobre as reações de α-sulfonil carbânions com diversos eletrófilos, envolvendo reações tais como: halogenação, alquilação, acilação, condensação e sulfenilação. Os estudos das reações de alquilação, por nós efetuados com dois diferentes α-sulfonil tioésteres, empregando o método em fase homogênea, indicaram que, no caso dos haletos de metila, etila e alila, foram obtidas misturas dos produtos mono- e di- alquilados, enquanto que no caso do brometo de benzila houve formação exclusiva de produtos monoalquilados (ver arquivo). Entretanto, a alquilação pelo emprego do método de catálise de transferência de fase (CTF), efetuada com o α-fenilsulfonil tioacetato de metila, conduziu exclusivamente aos produtos monoalquilados correspondentes, independentemente do reagente alquilante empregado (ver arquivo). Estes resultados mostraram a superioridade do método em transferência de fase sobre o em fase homogênea. Os estudos das reações de sulfenilação, efetuados com o α-fenilsulfonil tioacetato de metila e os seus derivados α-alquilsubstituídos, empregando o método CTF, conduziram exclusivamente aos produtos monossulfenilados (ver arquivo). Neste caso, o método em transferência de fase também se mostrou superior ao em fase homogênea, sendo os produtos monossulfenilados obtidos em maior rendimento. É sugerido um mecanismo para as reações de alquilação e sulfenilação de α-sulfonil tioésteres em CTF, empregando sistema sólido / líquido, o qual explica a ausência, nestas condições reacionais, dos produtos dialquilado e dissulfenilado. A apresentação e discussão dos resultados das reações de descarboxilação alquilativas dos ácidos α-fenilsulfonil-α-fenilpropanóicos racêmico e opticamente ativo é precedida por uma introdução que apresenta os estudos mais relevantes da literatura sobre as reações de descarboxilação de ácidos α-sulfonil carboxílicos na presença de eletrófilos, tais como hidrogênio, halogênio, carbono e enxofre. São de especial interesse os estudos envolvendo o curso estereoquímico da reação de descarboxilação protonativa de ácidos α-sulfonil carboxílicos opticamente ativos em meio alcalino, demonstrando a grande estabilidade do α-sulfonil carbânion, que retém a sua configuração original, sendo esta mantida mesmo após a protonação. Estas investigações se relacionam com os nossos estudos de descarboxilação alquilativa dos ácidos α-fenilsulfonil-α-fenilpropanóicos racêmico e opticamente ativo, efetuados em continuação aos estudos anteriores de descarboxilações alquilativas dos ácidos α-fenilsulfonil-α-fenil carboxílicos realizados no nosso laboratório. Os nossos resultados mostraram que é possível obter a sulfona tetrassubstituída pela reação do ácido α-fenilsulfonil-α-fenilpropanóico com iodeto de etila na presença de NaH / DMSO, desde que se expulse o CO2 formado na reação (ver arquivo). É apresentada a síntese do ácido α-fenilsulfonil-α-fenilpropanóico opticamente ativo, o qual foi obtido por vários passos reacionais, através da resolução do ácido α-fenilsulfenil-α-fenilpropanóico e a sua posterior oxidação. A configuração de ambos os compostos foi determinada pela análise de raios X, mostrando ser o isômero S. As sínteses destes ácidos foram efetuadas por dois métodos distintos, constituídos de 3 e 5 passos reacionais. Entretanto, não foi possível obter a sulfona tetrassubstituída opticamente ativa pela reação do ácido α-fenilsulfonil-α-fenilpropanóico opticamente ativo com iodeto de etila nas mesmas condições empregadas no caso do composto racêmico correspondente. Foi obtido um esclarecimento do processo da descarboxilação de ácidos α-sulfonil carboxílicos a partir de cálculos semi-empíricos que mostraram a existência de duas etapas intermediárias na descarboxilação dos respectivos carboxilatos, ou seja, uma em que o CO2 se liga ao carbânion (I) e outra, de mais baixa energia, em que ele se liga ao oxigênio sulfonílico (II) (ver arquivo). Foram fornecidas provas, através de experiências comparativas de alquilação e protonação, que para que o α-sulfonil carbânion mantenha a sua configuração, é necessário que o eletrófilo reaja com o carbânion antes da expulsão total de CO2, isto é, na fase em que ele se encontra ligado ao oxigênio sulfonílico (II). Este é o caso da descarboxilação protonativa, que mostrou ocorrer com retenção da configuração na experiência por nós realizada. A racemização que ocorre no caso da descarboxilação alquilativa foi atribuída à pequena janela de reação, que impede a aproximação do reagente alquilante. Foi por nós sugerido que a ligação do CO2 ao oxigênio sulfonílico seria responsável pela barreira rotacional que mantém a assimetria do α-sulfonil carbânion, tornando-o conformacionalmente estável. No decorrer do presente estudo foram sintetizados 11 compostos ainda não descritos na literatura, entre eles: três α-bromo tioésteres, cinco α-sulfonil tioésteres, quatro α-sulfonil tioésteres α-sulfenilados e uma sulfona tetrassubstituída. / This thesis gives a contribution to the chemistry of α-sulfonyl carbanions, such as the comprehension of its conformational stability and reactivity towards electrophilic reagents. The investigated reactions were alkylation and sulfenylation of α-sulfonyl thioesters and the decarboxylative alkylation of racemic and optically active α-phenylsulfonyl-α-phenylpropanoic acids. The presentation of the results and the discussion of the alkylation and sulfenylation reactions are preceded by a bibliographic revision describing the most important reports in the literature concerning the reactions of α-sulfonyl carbanions with different electrophiles, such as: protonation, halogenation, alkylation, acylation, condensation and sulfenylation. Our studies of the alkylation reaction, carried out with two different α-sulfonyl thioesters, employing homogeneous media, indicated that in the case of methyl, ethyl and allyl halides, mixtures of mono- and dialkylated products were obtained. However, in the case of benzyl bromide, the corresponding monoalkylated compound was obtained as the only reaction product (see file). On the other hand, the alkylation of methyl α-phenylsulfonyl thioacetate by PTC method afforded, exclusively, the corresponding monoalkylated products. These results show the superiority of the PTC method over the homogeneous one (see file). The sulfenylation reactions carried out with methyl α-phenylsulfonyl thioacetate and their α-alkylsubstituted derivatives employing PTC conditions, afforded only monosulfenylated α-sulfonyl thioesters as the only reaction products. Also in this case, the PTC method showed to be superior to give the monosulfenylated products in higher yields (see file). A mechanism for the alkylation and sulfenylation reactions in solid / liquid PTC system, which explains the absence of the dialkylated and disulfenylated products is suggested. The presentation and discussion of the results for the alkylative decarboxylation reactions of racemic and optically active α-phenylsulfonyl-α-phenylpropanoic acids is preceded by a bibliographic introduction reporting the most important works in the literature concerning the decarboxylation of α-sulfonyl carboxylic acids in the presence of electrophiles such as hydrogen, halogens and sulfur. Specially important are the studies on the stereochemical course of the base-catalyzed protonative decarboxylation of optically active α-sulfonyl carboxylic acids, showing the high stability of the a-sulfonyl cabanion, which retains its original configuration even after protonation. There is a link between these investigations and our studies of the alkylative decarboxylation of racemic and optically active α-phenylsulfonyl-α-phenylpropanoic acids, which are undertook in continuation to our investigations on the alkylative decarboxylation of α-phenylsulfonyl-α- phenyl carboxylic acids. Our results showed that it is possible to obtain the tetrasubstituted sulfone from the reaction of α-phenylsulfonyl-α-phenylpropanoic acid with ethyl iodide, in the presence of NaH / DMSO as base, provided that the CO2, which is formed during the reaction, is expelled (see file). The synthesis of the optically active α-phenylsulfonyl-α-phenylpropanoic acid containing several reaction steps is presented, through the resolution of the α-phenylsulfenyl-α-phenylpropanoic acid, followed by its oxidation. The configurations of both acids were determined through X-rays analyses, and showed to be S. However, it was not possible to obtain the optically active tetrasubstituted sulfone from the reaction of optically active α-phenylsulfonyl-α-phenylpropanoic acid with ethyl iodide in the experimental conditions employed for the corresponding racemic acid. The insight for the decarboxylation process of the α-sulfonyl carboxylic acids was obtained from semi-empiric calculations that showed the existence of two intermediate steps in the decarboxylation of the corresponding carboxylates, one of which with CO2 bonded to the carbanion and another one, of lower energy, in which the CO2 is linked to the sulfonyl oxygen (see file). Proofs were provided, through the comparative experiments of alkylation and protonation for the optically active α-sulfonyl acid, that for retention of configuration of the α-sulfonyl carbanion it is necessary that the reaction of the carbanion with the electrophile takes place before the total expulsion of CO2, i.e., when it is linked to SO2. It was suggested that the CO2-OSO linkage could be responsible for the rotational barrier, which maintains the symmetry of the a-sulfonyl carbanion, which becomes conformationaly stable. Finally, eleven new compounds were prepared in the course of the present study such as: three α-bromo thioesters, five α-sulfonyl thioesters, four α-sulfenylated α-sulfonyl thioesters and one α-tetrasubstituted sulfone.

Made available in DSpace on 2014-12-17T15:41:41Z (GMT). No. of bitstreams: 1 KeilaSA.pdf: 2159921 bytes, checksum: eaf4fb1bec7305fa007222908f6259ac (MD5) Previous issue date: 2008-02-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Chitosan derivatives were prepared by reductive alkylation using glutaraldehyde and 3-amino-1-propanol. The reducing agent used was the sodium borohydride. Tests of solubility, stability and viscosity were performed in order to evaluate these parameters effects in the reaction conditions (molar ratio of the reactants and presence of nitrogen in the reaction system). The molecular structure of commercial chitosan was determined by infrared (IR) and hydrogen nuclear magnetic resonance spectroscopy (1H NMR). The intrinsic viscosity and average molecular weight of the chitosan were determined by viscosimetry in 0.3 M acetic acid aqueous solution 0.2 M sodium acetate at 25 ?C. The derivatives of chitosan soluble in aqueous acidic medium were characterized by 1H NMR. The rheological behavior of the chitosan and of the derivative of chitosan (sample QV), which presented the largest viscosity, were studied as a function of polymer concentration, temperature and ionic strength of the medium. The results of characterization of the commercial chitosan (the degree of deacetylation obtained equal 78.45 %) used in this work confirmed a sample of low molar weight (Mv = 3.57 x 104 g/mol) and low viscosity (intrinsic viscosity = 213.56 mL/g). The chemical modification of the chitosan resulted in derivatives with thickening action. The spectra of 1H NMR of the soluble derivatives in acid aqueous medium suggested the presence of hydrophobic groups grafted into chitosan in function of the chemical modification. The solubility of the derivatives of chitosan in 0.25 M acetic acid aqueous solution decreased with increase of the molar ratio of the glutaraldehyde and 3-amino-1-propanol in relation to the chitosan. The presence of nitrogen and larger amount of reducing agent in reaction system contributed to the increase of the solubility, the stability and the viscosity of the systems. The viscosity of the polymeric suspensions in function of the shear rate increased significantly with polymer concentration, suggesting the formation of strong intermolecular associations. The chitosan presented pseudoplastic behavior with the increase in polymer concentration at a low shear rate. The derivative QV presented pseudoplastic behavior at all concentrations used and in a large range of shear rate. The viscosity of chitosan in solution decreased with an increase of the temperature and with the presence of salt. However, there was an increase of the viscosity of the chitosan solution at higher temperature (65 ?C) and ionic strength of the medium which were promoted by hydrophobic associating of the acetamide groups. The solutions of the chitosan derivatives (sample QV) were significantly more viscous than chitosan solution and showed higher thermal stability in the presence of salt as a function of the hydrophobic groups grafted into chitosan backbone / Derivados de quitosana foram preparados atrav?s de alquila??o redutiva usando glutaralde?do e 3-amino-1-propanol. O agente redutor utilizado foi o boro hidreto de s?dio. Os efeitos das vari?veis reacionais (propor??es molares dos reagentes e nitrog?nio no meio reacional) nas caracter?sticas dos pol?meros em fun??o das mudan?as estruturais foram avaliados atrav?s de testes de solubilidade, estabilidade e viscosidade. A estrutura molecular da quitosana comercial foi determinada por espectroscopia de infravermelho (IV) e de resson?ncia magn?tica nuclear de hidrog?nio (RMN 1H). A viscosidade intr?nseca e a massa molar m?dia da quitosana foram determinadas por viscosimetria, em ?cido ac?tico 0,3 M acetato de s?dio 0,2 M, a 25 ?C. Os derivados de quitosana sol?veis em meio aquoso ?cido foram caracterizados por RMN 1H. O comportamento reol?gico da quitosana e do seu derivado (amostra QV), que apresentou maior viscosidade, foram estudados em fun??o da concentra??o de pol?mero, da temperatura e da for?a i?nica do meio. Os resultados da caracteriza??o da quitosana comercial utilizada neste trabalho demonstraram uma amostra de baixa massa molar (Mv = 3,57 x 104 g/mol) e de baixa viscosidade (viscosidade intr?nseca = 213,56 mL/g). O grau m?dio de desacetila??o foi 78,45 %. A modifica??o qu?mica da quitosana resultou em derivados com caracter?sticas viscosificantes. Os espectros de RMN 1H dos derivados sol?veis em meio aquoso ?cido mostraram a inser??o de grupos hidrof?bicos na estrutura da quitosana em fun??o da modifica??o qu?mica realizada. A solubilidade dos derivados de quitosana em solu??o aquosa de ?cido ac?tico 0,25 M diminuiu com o aumento da propor??o molar do glutaralde?do e 3-amino-1-propanol em rela??o ? quitosana. A presen?a de nitrog?nio e maior quantidade de agente redutor no meio reacional contribu?ram para o aumento da solubilidade, estabilidade e viscosidade dos sistemas polim?ricos. A viscosidade das dispers?es polim?ricas em fun??o da taxa de cisalhamento aumentou significativamente com a concentra??o de pol?mero, sugerindo a forma??o de fortes associa??es intermoleculares. A quitosana apresentou comportamento pseudopl?stico com o aumento da concentra??o de pol?mero em solu??o e a baixas taxas de cisalhamento, enquanto que o seu derivado, QV, apresentou comportamento pseudopl?stico em todas as concentra??es utilizadas e em uma larga faixa de taxa de cisalhamento. A viscosidade da solu??o de quitosana diminuiu com o aumento da temperatura e com a presen?a de sal. No entanto, houve um aumento da viscosidade da solu??o de quitosana ? temperatura mais alta (65 ?C) e em maior for?a i?nica, promovido por associa??es hidrof?bicas dos grupos acetamido. As solu??es do derivado QV foram significativamente mais viscosas do que as solu??es de quitosana e obtiveram maior estabilidade t?rmica em solu??o na presen?a de sal em fun??o dos grupos hidrof?bicos inseridos na estrutura da quitosana

Made available in DSpace on 2014-12-17T15:42:30Z (GMT). No. of bitstreams: 1 KeilaSA_TESE.pdf: 6694216 bytes, checksum: df1754b48618e11f2ae95e003ae20c2c (MD5) Previous issue date: 2013-12-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Chitosan is a biopolymer derived from the shells of crustaceans, biodegradable, inexpensive and renewable with important physical and chemical properties. Moreover, the different modifications possible in its chemical structure generate new properties, making it an attractive polysaccharide owing to its range of potential applications. Polymers have been used in oil production operations. However, growing concern over environmental constraints has prompted oil industry to search for environmentally sustainable materials. As such, this study sought to obtain chitosan derivatives grafted with hydrophilic (poly(ethylene glycol), mPEG) and/or hydrophobic groups (n-dodecyl) via a simple (one-pot) method and evaluate their physicochemical properties as a function of varying pH using rheology, small-angle Xray scattering (SAXS), dynamic light scattering (DLS) and zeta potential. The chitosan derivatives were prepared using reductive alkylation under mild reaction conditions and the chemical structure of the polymers was characterized by nuclear magnetic resonance (1H NMR) and CHN elemental analysis. Considering a constant mPEG/Chitosan molar ratio on modification of chitosan, the solubility of the polymer across a wide pH range (acidic, neutral and basic) could only be improved when some of the amino groups were submitted to reacetylation using the one-pot method. Under these conditions, solubility is maintained even with the simultaneous insertion of n-dodecyl. On the other hand, the solubility of derivatives obtained only through mPEG incorporation using the traditional methodology, or with the ndodecyl group, was similar to that of its precursor. The hydrophilic group promoted decreased viscosity of the polymer solutions at 10 g/L in acid medium. However, at basic pH, both viscosity and thermal stability increased, as well as exhibited a pronounced pseudoplastic behavior, suggesting strong intermolecular associations in the alkaline medium. The SAXS results showed a polyelectrolyte behavior with the decrease in pH for the polymer systems. DLS analyses revealed that although the dilute polymer solutions at 1 g/L and pH 3 exhibited a high density of protonated amino groups along the polymer chain, the high degree of charge contributed significantly to aggregation, promoting increased particle size with the decrease in pH. Furthermore, the hydrophobic group also contributed to increasing the size of aggregates in solution at pH 3, whereas the hydrophilic group helped reduce their size across the entire pH range. Nevertheless, the nature of aggregation was dependent on the pH of the medium. Zeta potential results indicated that its values do not depend solely on the surface charge of the particle, but are also dependent on the net charge of the medium. In this study, water soluble associative polymers exhibit properties that can be of great interest in the petroleum industry / A quitosana ? um biopol?mero derivado de carapa?as de crust?ceos, de baixo custo, biodegrad?vel, renov?vel, que apresenta propriedades f?sico-qu?micas importantes e, ainda, proporciona diferentes possibilidades de modifica??es em sua estrutura qu?mica, gerando novas propriedades, o que torna esse polissacar?deo muito atraente do ponto de vista de aplica??o. Os pol?meros s?o utilizados em v?rias opera??es na produ??o do petr?leo. Entretanto, a crescente preocupa??o com as restri??es ambientais t?m promovido a busca por materiais ambientalmente sustent?veis pela ind?stria do petr?leo. Dessa forma, esse estudo prop?s a obten??o de quitosana graftizada com grupos hidrof?lico (poli(etileno glicol), mPEG) e/ou hidrof?bico (n-dodecila) por uma metodologia mais simples (one-pot) e a avalia??o de suas propriedades f?sico-qu?micas em fun??o da varia??o de pH, atrav?s das an?lises de reologia, espalhamento de raios-X a baixos ?ngulos (SAXS), espalhamento de luz din?mico (DLS) e potencial zeta. Os derivados de quitosana foram preparados utilizando a rea??o de alquila??o redutiva em condi??es reacionais brandas e a estrutura qu?mica dos pol?meros foi caracterizada por resson?ncia magn?tica nuclear de hidrog?nio (RMN 1H) e an?lise elementar CHN. Considerando constante a raz?o molar mPEG/Quitosana na modifica??o qu?mica da quitosana em diferentes metodologias, foi poss?vel melhorar a solubilidade da quitosana em uma ampla faixa de pH (?cido, neutro e b?sico) usando a metodologia one-pot, em que uma parte dos grupos amino foi reacetilada. Nesta condi??o, at? mesmo com a inser??o simult?nea do n-dodecila, a solubilidade se manteve. Por outro lado, a solubilidade dos derivados obtidos apenas com a incorpora??o de mPEG atrav?s de metodologia tradicional, ou com o grupo ndodecila, foi similar ao seu precursor. O grupo hidrof?lico promoveu a diminui??o da viscosidade das solu??es polim?ricas a 10 g/L em meio ?cido. Entretanto, em pH b?sico, esse grupo contribuiu para o aumento da viscosidade e da estabilidade t?rmica das solu??es, assim como, favoreceu um comportamento pseudopl?stico mais acentuado, sugerindo fortes associa??es intermoleculares no meio alcalino. Os resultados de SAXS apresentaram um comportamento de polieletr?lito com a diminui??o do pH para os sistemas polim?ricos. As an?lises de DLS revelaram que as solu??es dilu?das dos pol?meros a 1 g/L em pH 3, embora apresentem uma alta densidade de grupos amino protonados ao longo da cadeia polim?rica, o alto grau de cargas contribuiu significativamente para a agrega??o, promovendo o aumento do tamanho das part?culas com a diminui??o do pH. Al?m disso, o grupo hidrof?bico tamb?m contribuiu para aumentar o tamanho dos agregados em solu??o no pH 3 e o grupo hidrof?lico favoreceu para reduzi-los em toda faixa de pH. Entretanto, a natureza de agrega??o foi dependente do pH do meio. Os resultados do potencial zeta indicaram que seus valores n?o dependem apenas da carga da superf?cie da part?cula, mas ? resultante da carga l?quida do meio. Os sistemas polim?ricos associativos em solu??o aquosa obtidos neste estudo apresentam propriedades que podem ser atraentes em v?rias aplica??es na ind?stria do petr?leo

The topic of this thesis is the design and synthesis of biaryl-based self adaptableligands for asymmetric metal catalysis. The results discussed in papers I-III are covered, together with some unpublished results concerning substrate-adaptable catalysts. A general survey of self-adaptable catalysts is presented first. The second chapter of this thesis starts with a survey of inversion barriers in biphenyl-based ligands and catalysts. Thereafter, the determination of barriers to conformational adaptation in dibenzoazepines and dibenzophosphepines is described. Palladium complexes with a diphosphine ligand or a diamine ligand, as well as the free diamine ligand, were studied. Entropies and enthalpies of activation were determined with variable temperature NMR spectroscopy. The mechanism of conformational change in the metal complexes was elucidated. The third chapter describes the synthesis of semiflexible and rigid phosphinite ligands, as well as their application in rhodium-catalysed asymmetric hydrogenation. Modest enantioselectivities (up to 63% ee) were obtained. The semiflexible ligand was found to behave like the most active rigid diastereomer. The fourth chapter describes the behaviour of amine and phosphoramidite ligands in model complexes relevant to the palladium-catalysed asymmetricallylic alkylation of benchmark substrates. Diphosphoramidite and aminephosphoramiditeligands were designed and synthesised. Pd(olefin) complexesof diamine and diphosphoramidite ligands were studied, and their symmetry determined. It was found that both types of ligands are able to adapt their conformation to the substrate. / QC20100630

This thesis deals with the design and synthesis of ligands for asymmetric catalysis: palladium catalyzed allylic alkylations, and rho-dium and iridium catalyzed hydrogenations of olefins. Chirally flexible phosphepine ligands based on biphenyl were synthesized and their properties were studied. The rotation barrier for configurationally flexible phosphepines was determined by NMR spectroscopy. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the metal center were observed upon complexation with Rh(I). It was shown that one diastereomer of the flexible ligand exhibits higher activity but lower selectivity than its diastereomer in the rhodium catalyzed hydrogenation of methyl alfa-acetamidocinnamate. These ligands were also tested in nickel catalyzed silabora-tions. Chiral P,N-ligands with pseudo-C2 and pseudo-CS symmetry based on pyrrolidines-phospholanes or azepines-phosphepines were synthesized and studied in palladium catalyzed allylic alkylations. Semi-flexible azepine-phosphepine based ligands were prepared and their ability to adopt pseudo-C2 or pseudo-CS symmetry depending on the substrate in allylic alkylations was studied. It was shown on model allyl systems with flexible N,N-ligands that the ligand prefers CS-symmetry in compexes with anti-anti as well as syn-syn allyl moieties, but that for the latter type of complexes, according to computations, the configuration of the ligand is R*,R* in the olefin complexes formed after addition of a nucleophile to the allylic group. A preliminary investigation of the possibilities to use a su-pramolecular approach for the preparation of P,N-ligands with pseudo-C2 and pseudo-S symmetry was made. An N,N-ligand with C2 symmetry was prepared and its activity in palladium catalyzed ally-lic alkylation was studied. Pyridine-based P,N-ligands were tested in iridium catalyzed hy-drogenations of unfunctionalized olefins with good activities and se-lectivities. In order to attempt to improve the selectivity, ligands with a chirally flexible phosphepine fragment were prepared and applied in catalysis with promising results. / QC 20100929