Ressonância Paramagnética Eletrônica (RPE) e Absorção Ótica Eletrônica foram utilizadas para estudar-se os complexos de Cobre (II) com tris-hidroximetil aminometano em solução. A análise dos parâmetros de RPE e óticos medidos na solução a diversos pHs foi feita tendo-se à mão as curvas de formação dos complexos. Estas curvas foram construídas em função do pH da solução, usando os dados de equilíbrio químico publicado por K. S. Bai e Martell (J. Inorg. Nucl. Chem. 31 (1969) 1697-1707), numa faixa de concentração de tris na qual este reagente é usando como tampão em estudos biológicos e químicos. Determinou-se cinco conjunto de parâmetros de RPE (go, ao, a11 e A11, correspondentes a diferentes complexos de íon metálico. Cada um desses espectros é encontrado em determinados intervalos de pH, sendo possível associá-los aos complexos previstos nas curvas de formação. A maior estabilidade dos complexos que se formam a pHs mais altos segundo as constantes de equilíbrio é evidenciada pelos valores e go isotrópico (RPE) menores pelos desdobramentos hiperfino isotrópico ao (RPE) e de campo cristalino (ótica) maiores do que os encontrados nas soluções menos alcalinas. A formação do complexo quelato neutro a pH alcalino foi observada, e obteve-se seu tensor g, das medidas do cristal simples. Este tensor encontra-se em bom acordo com o valor de g isotrópico determinado em solução (go=1/3(gxx+gyy+gzz)). Existe evidência de que este complexo seja pentacoordenado). Observou-se similaridade entre os parâmetros para os complexos coordenados por: 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. Isto leva à conclusão de que do ponto de vista energético a coordenação de nitrogênio Cu2+ e a coordenação do oxigênio negativo ao Cu2+ nestes complexos são equivalentes, pelo menos dentro de nossa resolução experimental. / Electron Paramagnetic Ressonance (EPR) and optical visible spectroscopies were used to study the complexes of Cu (II) íon with tris-hydroxymethylamino methane (tris) in solution. Analyses of EPR and optical parameters measured in solution were made using the calculated formation curvesof the complexes. These formation curves were calculated as function of the solution pH, on the basis of the equilibrium constants published by K.S. Bai and Martell (J. Inorg.Nucl. Chem. 31 (1969)-1967-1707), for a concentration of this normally employed in a buffer in biochemical studies. Five sets of EPR parameters ((go, ao, a11 e A11) were determined corresponding to different metal complexes. Each det is found in a characteristic pH range and it was possible to make a correlation of these complexes with the appear in the formation curve plot. The greater stability of the complexes in the high pH range is indicated by the values of go, wich are smaller and the values of the hyperfine splittings ao and the crystal field splittings (from optical measurements) which are greater tahn at the less alcaline solutions. The formation of the neural chelate complexa t alcaline pH was observed, and its g-factors were obtained from measurements with the single crystal. These g-factors agree very well with the solution value (go=1/3(gxx+gyy+gzz)) and the orthorombic symmetriy is obtained. Evidence is present that this complex is penta-coordinated. It was observed a similarity between the EPR parameters for the complexes coordinated by: : 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. This lead us the conclusion that from the energetical point of view the coordination of Cu2+ to nitrogen or to negative oxigen in these cases are equivalent, at or our resolution is not sufficent to differentiate between them.

Ressonância Paramagnética Eletrônica (RPE) e Absorção Ótica Eletrônica foram utilizadas para estudar-se os complexos de Cobre (II) com tris-hidroximetil aminometano em solução. A análise dos parâmetros de RPE e óticos medidos na solução a diversos pHs foi feita tendo-se à mão as curvas de formação dos complexos. Estas curvas foram construídas em função do pH da solução, usando os dados de equilíbrio químico publicado por K. S. Bai e Martell (J. Inorg. Nucl. Chem. 31 (1969) 1697-1707), numa faixa de concentração de tris na qual este reagente é usando como tampão em estudos biológicos e químicos. Determinou-se cinco conjunto de parâmetros de RPE (go, ao, a11 e A11, correspondentes a diferentes complexos de íon metálico. Cada um desses espectros é encontrado em determinados intervalos de pH, sendo possível associá-los aos complexos previstos nas curvas de formação. A maior estabilidade dos complexos que se formam a pHs mais altos segundo as constantes de equilíbrio é evidenciada pelos valores e go isotrópico (RPE) menores pelos desdobramentos hiperfino isotrópico ao (RPE) e de campo cristalino (ótica) maiores do que os encontrados nas soluções menos alcalinas. A formação do complexo quelato neutro a pH alcalino foi observada, e obteve-se seu tensor g, das medidas do cristal simples. Este tensor encontra-se em bom acordo com o valor de g isotrópico determinado em solução (go=1/3(gxx+gyy+gzz)). Existe evidência de que este complexo seja pentacoordenado). Observou-se similaridade entre os parâmetros para os complexos coordenados por: 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. Isto leva à conclusão de que do ponto de vista energético a coordenação de nitrogênio Cu2+ e a coordenação do oxigênio negativo ao Cu2+ nestes complexos são equivalentes, pelo menos dentro de nossa resolução experimental. / Electron Paramagnetic Ressonance (EPR) and optical visible spectroscopies were used to study the complexes of Cu (II) íon with tris-hydroxymethylamino methane (tris) in solution. Analyses of EPR and optical parameters measured in solution were made using the calculated formation curvesof the complexes. These formation curves were calculated as function of the solution pH, on the basis of the equilibrium constants published by K.S. Bai and Martell (J. Inorg.Nucl. Chem. 31 (1969)-1967-1707), for a concentration of this normally employed in a buffer in biochemical studies. Five sets of EPR parameters ((go, ao, a11 e A11) were determined corresponding to different metal complexes. Each det is found in a characteristic pH range and it was possible to make a correlation of these complexes with the appear in the formation curve plot. The greater stability of the complexes in the high pH range is indicated by the values of go, wich are smaller and the values of the hyperfine splittings ao and the crystal field splittings (from optical measurements) which are greater tahn at the less alcaline solutions. The formation of the neural chelate complexa t alcaline pH was observed, and its g-factors were obtained from measurements with the single crystal. These g-factors agree very well with the solution value (go=1/3(gxx+gyy+gzz)) and the orthorombic symmetriy is obtained. Evidence is present that this complex is penta-coordinated. It was observed a similarity between the EPR parameters for the complexes coordinated by: : 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. This lead us the conclusion that from the energetical point of view the coordination of Cu2+ to nitrogen or to negative oxigen in these cases are equivalent, at or our resolution is not sufficent to differentiate between them.

<p>Tris(hydroxymethyl)aminomethane (THAM) was a readily-available and economical amino-triol that was viewed as having a large untapped potential as a starting material. The full chemoselective functionalization and differentiation of the amino group and the three primary alcohol residues present in THAM was extensively investigated. The development of this methodology allowed for the rapid assembly of a differentiated core that lead to existing and new potential drug scaffolds.</p> <p>The discovery of a novel oxidative fragmentation and rearrangement process was made leading to the synthesis of differentiated oxazolidinone rings. This process allowed for the creation of novel chemical library situated around THAM-based oxazolidinones, as well as THAM-based 1,3-dioxanes.</p> <p>THAM was also used as a starting material for sphingosine analogs, including sphingosine 1-phosphate (S1P) and anticancer S1K inhibitors. Selective functionalization of the amine and one alcohol within an oxazolidinone ring allowed access to a new family of Linezolid-type oxazolidinones as well. Additionally, various triazole-based compounds were prepared, which allowed access to a new family of potential antifungal agents based on the lead compound Fluconazole.</p> <p>A total synthesis of the immunosuppressant molecule FTY720 was also reported, employing double Wittig-olefination protocol, from THAM. This synthesis avoided certain pitfalls that were present in previously documented literature methods. Along the pathway to FTY720, many intermediates and analogs were synthesized and tested for biological activity alongside the novel oxazolidinone compounds, resulting in interesting lead compounds for various biological applications. A UV-active FTY720 scaffold was also synthesized for potential future <em>in vivo</em> tracking of the immunosuppressant and its metabolites.</p> / Doctor of Philosophy (PhD)

Yes / One-pot reaction between 8-hydroxyquinoline-2-carboxaldehyde (HQC) and tris(hydroxymethyl)aminomethane (TRIS) followed by in situ cyclization yielded an oxazolidine based ligand which produced four mononuclear complexes of MnII(1), CoII(2), NiII(3), ZnII(4), a tetranuclear iron (FeIII4) complex (5) and a trinuclear cobalt (CoIICoIII2) complex (6). Magnetic studies show dominant antiferromagnetic interaction in tetranuclear iron (FeIII4) complex 5 and presence of the slow relaxation of magnetisation in 6. The compounds were also studied for their antibacterial properties. The oxazolidine ligand (H3L2) of this study showed good antimicrobial activity not only against Gram-positive bacteria but against Gram-negative bacteria too. The antimicrobial efficacy of the metal complexes (1–6) is also reported.

La réévaluation des impacts toxicologique et environnemental des répulsifs synthétiques conduit à reconsidérer les répulsifs d'origine naturelle pour la prévention des maladies transmises par les insectes (dengue, chikungunya, paludisme,…). Cette étude se rapporte aux structures de type bis(oxazolidine) envisagées comme prodrogues de répulsifs naturels par leur conversion avec le tris(hydroxyméthyl)aminométhane (TRIS). Différents protocoles et voies de synthèse ont été étudiés sur une série représentative d'aldéhydes pour définir l'étendue et les limites de l'approche permettant de concentrer deux unités d'un même principe actif au sein de bis(oxazolidines) symétriques et de reproduire un effet synergique avec deux unités différentes formant des bis(oxazolidines) dissymétriques. La fonctionnalisation des bis(oxazolidines) a été également envisagée pour moduler leur balance hydrophile-lipophile. L'étude de la réaction de cyclocondensation met en évidence l'influence des paramètres structuraux sur le procédé de synthèse des bis(oxazolidines), la stabilité des intermédiaires (monooxazolidines) et la stéréosélectivité de la réaction. L'interprétation des résultats est proposée sur la base des effets (stéréo)-électroniques. Cette étude démontre l'intérêt de cette approche chimique pour la production de prodrogues de répulsifs naturels qui peuvent constituer des atouts pour le développement durable. / The more sensitive human and environmental risk assessments of non natural repellents have encouraged the rehabilitation of botanical-based repellents for the prevention of insect-transmitted diseases (dengue, chikungunya, malaria…). This study is related to bis(oxazolidine) structures envisaged as prodrug derivatives of natural repellents by their conversion with tris(hydroxymethyl)aminomethane (TRIS). The scope and limitations of various procedures and pathways have been assessed with structurally diverse aldehydes to concentrate two identical units in the symmetrical structures and to reproduce a synergistic effect with two different units in the unsymmetrical ones. Subsequent functionalization of the heterocyclic derivatives has been achieved to modulate their hydrophilic-lipophilic balance. The study of the cyclocondensation reaction shows evidence for the influence of structural effects not only on the chemical process but also on the relative stability of the monocyclic intermediates and the stereochemical outcomes of the reaction. The results are discussed on the basis of (stereo)-electronic effects. Finally, this study confirms the feasibility of this chemical approach to produce prodrugs of natural repellents which could appear as a contributive effort to sustainable development.

The purpose of this research was to investigate the kinetics and mechanisms of the photocatalytic degradation of organic substances in the presence of anions (bromide and chloride), using titanium dioxide as a photocatalyst. Tris(hydroxymethyl)aminomethane (Tris) and methanol were the organic substances used as probes. Photocatalytic degradation of the probes produces formaldehyde through reaction with hydroxyl radicals at the surface of the photocatalyst. The product was quantified using a modified Hantzsch reaction and UV-Vis spectroscopy at the fixed wavelength 368 nm. It was found that having bromide present in the reaction mixture resulted in an increase in the rate of formation of formaldehyde from Tris, while it resulted in a decrease from methanol. Bromide on the surface of the photocatalyst reacts with the hydroxyl radicals to form reactive halogen species (RHS). This study proposes that the RHS Br2•- oxidises the probe into a cation radical, which initialises the probe degradation and the subsequent formation of formaldehyde. Conversion from hydroxyl radicals to RHS leads to a greater selectivity in formaldehyde production. Increased selectivity of attack towards electron-rich centres can explain the observed results with the different probes in this study. A linear combination expression of the total production of formaldehyde was developed, through which the X-factor, a ratio of the production of formaldehyde by RHS relative to the production of formaldehyde by hydroxyl radicals, was calculated. However, no realistic values were obtained when calculating the X-factor for different anion concentrations, thus indicating that factors other than competition kinetics affect the degradation. No conclusions could be drawn regarding the effect of chloride on the formation of formaldehyde from Tris and methanol, as the results were ambiguous. / Syftet med denna studie var att undersöka mekanismer och kinetik bakom fotokatalytisk nedbrytning av organiska molekyler i närvaro av anjoner (bromid och klorid), där titandioxid användes som fotokatalysator. Tris(hydroxymetyl)aminometan (Tris) och metanol var de organiska substanserna som studerades. Den fotokatalytiska nedbrytningen av proberna resulterar i formaldehyd via reaktion med hydroxylradikaler på fotokatalysatorns yta. Produkten kan sedan kvantifieras genom en modifierad version av Hantzsch-reaktionen följt av UV-Vis spektroskopi vid en fixerad våglängd på 368 nm. Studien kom fram till att närvaron av bromid i reaktionslösningen resulterade i en ökad produktionshastighet av formaldehyd från Tris, medan det resulterade i en minskning från metanol. Bromid på ytan av fotokatalysatorn reagerar med hydroxylradikaler och bildar reaktiva halogena molekyler (RHS). Denna studie föreslår att RHS:en Br2•- oxiderar proben till en radikalkatjon, som initierar nedbrytningen av proben och efterföljande bildning av formaldehyd. Omvandling från hydroxylradikaler till RHS leder till högre selektivitet av bildning av formaldehyd. Ökad selektivitet av attacker mot elektronrika center kan förklara de observerade resultaten med de olika proberna i denna studie. Ett linjärkombinationsuttryck av den totala produktionen av formaldehyd utvecklades, från vilket X-faktorn, ett förhållande av produktionen av formaldehyd via RHS relativt till produktionen av formaldehyd via hydroxylradikaler, kunde beräknas. Inga realistiska värden erhölls dock vid beräkningen av X-faktorn för olika anjonskoncentrationer, vilket indikerar att andra faktorer än konkurrenskinetik påverkar nedbrytningen. Inga slutsatser kunde dras gällande klorids effekt på bildningen av formaldehyd från Tris och metanol, då resultaten var tvetydiga.