A convenient, economical, large scale synthesis of N-acetyldehydro-alanine (a-acetamidoacrylic acid) and its methyl ester was developed via a sequence of N-chlorination-dehydrochlorination. The method was extended to the synthesis of the corresponding N-benzoyl, N-phenylacetyl and N-benzyloxycarbonyl derivatives. The conversion of a-methoxy-N-acetyl alanine derivatives to the corresponding a-mercapto alanine derivatives, using zinc chloride and an appropriate mercaptan, was investigated. Methyl a-methoxy-N-acetyl-D, L-alaninate was successfully converted to the a-acetylthio derivative, in 24% yield; however, a 90% yield could be obtained by treatment of the dehydroalanine derivative with hydrogen chloride gas in neat thiolacetic acid. A facile conversion of the a-acetylthio derivative to the a-methoxy derivative, using sodium methoxide in methanol, was observed to occur. The normally facile conversion of an acetylthio group to a mercapto group, using sodium borohydride, gave mixtures of the a-mercapto derivative and alanine derivative. The reactions at the a position of a-hetero-N-acetyl-D,L-alanines and a,B-disubstituted N-acetyl-D,L-alanine derivatives seemed consistent with the formation of an acylimine intermediate under basic conditions and a carbonium ion intermediate under acidic conditions. From these studies, a facile, clean synthesis of a-halo-a-mercapto-and a-alkoxy-N-acetyl-D,L-alanine derivatives was accomplished. All attempts to synthesize a,B-dimercapto derivatives failed because the B-halogen could not be replaced with a mercapto group when the a position was a mercapto or methoxy derivative. Attempts to generate a B-mercapto-a-halo derivative also failed. A facile synthesis of the E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate was developed. The ratio of Z to E isomers was found to vary with the base used for the elimination. The E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate were converted to the B-mercapto derivatives by reaction with mercaptan. The reaction proceeded with retention of stereochemistry. The formation of B-substituted N-acetyldehydroalanine derivatives seemed consistent with an acylimine intermediate followed by a sequence of Michael-type addition and dehydrochlorination. A study of the conversion of the B-mercapto-N-acetyldehydroalanine derivatives to mixed dithioacetals, which would be useful in the synthesis of natural antibiotics, was undertaken. This approach to the synthesis of mixed dithioacetals was unsuccessful because an exchange of mercapto groups was observed, the addition of a second, different mercaptan failed or the yield was too low to be synthetically useful. A synthesis of B,B-dimercapto-N-aeetyldehydroalanine (mixed, unsaturated dithioacetals) derivatives was accomplished. However, because of low yields, a reduction to B,B- dimercapto-N- acetyl-D,L-alanine derivatives (mixed dithloacetals) was not investigated.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In this study, acute effects of mercury on mouse blood, kidneys and liver were evaluated. Mice received a single dose of mercuric chloride (HgCl2 - 4.6 mg/kg, subcutaneously) for three consecutive days. We investigated the possible beneficial effects of antioxidant therapy (N-acetylcysteine (NAC) and diphenyl diselenide (PhSe)2) comparing to sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), an effective chelating agent on mercury exposure in mice. We also verified if metallothionein (MT) induction would be involved in a possible mechanism of protection against mercury poisoning and if different therapies would modify MT levels and other toxicological parameters. The results demonstrated that animals treated with mercuric chloride presented a reduction in the body weight gain and therapies did not were effective in reverting this damage. HgCl2 exposure inhibited δ-aminolevulinic dehydratase (δ-ALA-D) activity in liver and only DMPS treatment prevented the inhibitory effect. Animals treated with mercury presented an increase in renal NPSH and therapies did not modify these levels. Urea concentration was increased after mercury exposure. NAC plus (PhSe)2 was partially effective in protecting against this effect of mercury . DMPS and (PhSe)2 were effective in restoring the increment in urea concentration caused by mercury. Thiobarbituric acid-reactive substances (TBARS), ascorbic acid levels, aspartate (AST) and alanine (ALT) aminotransferases were not modified after mercury exposure. Moreover, mercury poisoning caused an increase in hepatic and renal MT levels and antioxidant therapies did not modify this parameter. Our data pointed out the lack of the therapeutic effect of antioxidants tested. / Neste trabalho foram avaliados os efeitos da intoxicação aguda induzida por cloreto de mercúrio (HgCl2) em sangue, rim e fígado de camundongos. Os animais receberam uma única dose de HgCl2 (4,6 mg/Kg de peso), via sub-cutânea, por três dias consecutivos. Investigou-se o possível efeito protetor da terapia com antioxidantes (N-acetilcisteína-NAC e disseleneto de difenila-(PhSe)2) comparando ao ácido 2,3-dimercapto-1-propanosulfônico (DMPS), um agente quelante efetivo contra intoxicações por mercúrio. Além disto, foi verificado se a indução de metalotioneínas (MT) poderia estar envolvida em um possível mecanismo de proteção contra a intoxicação pelo mercúrio e se as diferentes terapias poderiam modificar os níveis de MT e outros parâmetros toxicológicos. Os resultados demonstraram que os animais tratados com cloreto de mercúrio apresentaram uma redução no ganho de peso corporal e as terapias não foram efetivas em reverter este dano. A exposição ao HgCl2 causou inibição na atividade da enzima δ-aminolevulinato desidratase (δ-ALA-D) em fígado de camundongos e somente a terapia com DMPS foi efetiva em reverter esta inibição. Os animais tratados com mercúrio apresentaram um aumento nos níveis de NPSH renal e as terapias não modificaram estes níveis. A concentração de uréia foi aumentada nos animais expostos ao cloreto de mercúrio. A terapia com NAC + (PhSe)2 foi parcialmente efetiva em proteger contra este efeito do mercúrio. Já as terapias com DMPS e (PhSe)2 foram efetivas em proteger contra o aumento nos níveis de uréia induzido pelo mercúrio. As substâncias reativas ao ácido tiobarbitúrico (TBARS), os níveis de ácido ascórbico e as transaminases (aspartato-AST e alanina-ALT) não foram alteradas após a exposição ao HgCl2. Além disso, os resultados demonstraram que a exposição ao mercúrio causou um aumento nos níveis de metalotioneínas hepático e renal e as terapias com antioxidantes não modificaram este parâmetro. Nossos dados apontam para a falta de efeito terapêutico dos antioxidantes testados.

The polymerization of methyl methacrylate (MMA) was investigated in this dissertation. Selected kinetic models from the literature were reviewed, and two new, generalized models of diffusion-limited effects (gel- and glass effects), derived from the current models were proposed and tested for bulk and solution polymerization of MMA in batch and semi-batch reactors, under isothermal and non-isothermal conditions. The newly proposed models include the capability of modeling termination by combination, radical transfer to monomer and depropagation reaction. The new and previous models were compared with experimental data of bulk and solution polymerizations of MMA, under a selection of non-steady state processes conditions (initiator and monomer feed, step changes in temperature) and compositions (initiator and chain transfer agents, regarding both type and dosages). The particular case of a non-isothermal bulk polymerization was also investigated. A simulation program (Reactormodel) was developed in Matlab, and its algorithm is provided. / Sem resumo.