Heavy metals are non-degradable and their persistence constitutes ecotoxicological ramifications. Their presence in wastewater is inhibitory to microbial digestion processes and can lead to biomagnification in the environment. Clay minerals have been widely studied as inexpensive sorbent materials of aqueous-phase contaminants. Particularly in the case of kaolinite, a non-swelling clay with a low cation-exchange capacity, chemically enhanced derivatives exposing its OH-rich interlayer space to interactions with its external environment are of exceptional interest. The objective of this study was to prepare a novel functionalised kaolinite with the aim of significantly improving its heavy-metal sorption capacity. Due to the robustness of sulfur-metal linkages, the compound 3,6-dithia-1,8-octanediol (HO(CH2)2S(CH2)2S(CH2)2OH) was grafted onto both urea- and DMSO precursors of two kaolinitic clays: the Source clay KGa-1b and a Portuguese clay sample collected from the Clays of Taveiro formation. All samples were characterised by X-ray diffraction and 13C nuclear magnetic resonance spectroscopy (NMR). Initial materials and final samples were also characterised by thermal gravimetric analysis and infrared spectroscopy. The results describe nanohybrid materials that are resistant to hydrolysis and exhibit different grafting fashions. Application as a heavy metal sorbent was tested in ZnCl2 solutions as well as in zinc-spiked raw wastewater. Zinc concentrations were analysed concomitant with other metal species by inductively coupled plasma – mass spectrometry, demonstrating variable sorption capacities of the different clay samples tested and a consistently greater zinc removal in the wastewater system compared to simple zinc solutions. Measured concentrations of concomitantly analysed metals reveals a potentially alarming release of certain heavy metal species from some clay samples as a result of zinc sorption.

This MSc. Thesis deals with electrochemical studies of the analytical utilization of self-assembled monolayers of thiolated calix[4]arene (C4A) and/or undecanthiole (C11SH) on the surface of a polycrystalline gold electrode. Hydroquinone, nitrobenzene, 2-nitrophenole and 4-nitrophenole have been used as tested model compounds. The real surface area of the electrode was determined using these two methods: From the charge of desorption peak of α-gold oxides (5.72±0.48 mm2 ) and using the Randles- Ševčík equation. (6.14±0.59 mm2 ). The preparation of the electrode consisted of polishing on alumina, immersing into piranha solution and cyclic voltammetry. The area of electrode surface was well reproducible. Stability of thiol monolayer in the area of negative potentials was tested. The C11SH layer is very stable; the desorption peak was recorded in basic solutions only (at −1.3 V vs. 3M Ag/AgCl). The position of the desorption peak of C4A is more pH dependent and it was recorded at −1.08 V at pH 13. The properties of the electrode modified by C11SH and or C4A were investigated using the model compound hydroquinone. It is assumed that the oxidation of the hydroquinone does not take place inside the C4A cavity; hence the hydroquinone molecule is too big to pass through the cavity. C11SH and C4 + C11SH act...

Taxol (1) was first isolated from the bark of the Pacific yew about 35 years ago by Drs. Wall and Wani. Although its development as an anticancer agent was delayed by numerous reasons, including its scarcity and insolubility, the discovery of its tubulin-assembly activity and other factors motivated oncologists to overcome these problems. It has since become one of the most important current drugs for the treatment of several cancers, including breast and ovarian cancers. Like almost all anticancer drugs taxol does have some toxic side effects and many tumors also show significant resistance to therapy with taxol. Drug targeting studies aimed at improving its selectivity and efficacy is described. Two targeting methods, the estrogen receptor (ER) directed targeting and colloidal gold (cAu)directed targeting, were used in our research. In this dissertation, a series of estradiol-taxol conjugates (ETCs) were synthesized. They were active in four cytotoxicity assays and tubulin polymerization assay, but less active than taxol. One of them showed the desired selectivity for ER positive cancer cells. Recently, several studies have attempted to elucidate the bioactive binding conformation of taxol on microtubules. Three models have been proposed for this conformation. The T-taxol conformation was proposed by Dr. Snyder based on electron crystallographic density and molecular modeling. In this dessertation, a series of cyclopropyl-containing taxol analogs and macrocyclic taxol lactones were synthesized. The bioassay results showed they are less active than taxol. The molecular modeling studies suggested that the cyclopropyl-containing taxol analogs could not adopt the T-taxol conformation, which would result in the loss of bioactivities. It is an indirect evidence to support T-taxol conformation. As for macrocyclic taxol lactones, it is proposed that they would have a close contact between the ester moiety on the C-3' phenyl ring and Phe272 of the β-tubulin protein when they adopt T-taxol conformation. It will push the macrocyclics out of the binding pocket and lead to the lost of bioactivities. / Ph. D.

Dans cette thèse, quelques problèmes courants rencontrés lors de l'électroraffinage et l'extraction par voie électrochimique du cuivre ont été étudiés à l'aide de la technique récente du bruit électrochimique (BE) effectuée dans la condition galvanostatique. Les travaux peuvent être divisés en deux sections soient la déposition cathodique et la dissolution anodique. Dans la section cathodique, l'électrodéposition du cuivre en présence de thiourée et de gélatine en tant qu'additifs a été étudiée par BE. Les analyses statistiques et spectrales du BE ont démontré que cette technique peut révéler des informations pertinentes concernant la morphologie et la qualité du dépôt, particulièrement la rugosité, étroitement reliée aux résultats des études macroscopiques et microscopiques. L'influence du sélénium comme impureté lors de la déposition du cuivre a également été investiguée par des mesures de BE dans le domaine du temps. Dans ce travail, une bonne corrélation a été établie entre la morphologie spongieuse et poreuse du dépôt et les résultats des analyses de signaux (skewness et kurtosis). La section anodique a été concentrée sur la passivation de différentes anodes d'alliages de cuivre. Les analyses statistiques, spectrales et ondelettes (wavelet) ont été effectuées sur les signaux du BE reliés aux courbes de chronopotentiogramme dans différentes régions de passivation. Différents paramètres de signaux ont été identifiés comme indicateur d'apparition de la passivation lors de la dissolution d'une anode de cuivre impur. Le potentiel de cette technique considéré comme étant un outil de suivi en continue de la passivation, indépendamment du type d'impuretés d'anode, a également été démontré dans cette thèse. Cette généralisation est importante pour examiner le phénomène d'apparition de la passivation et sa prévision au cours du processus. L'influence des additifs (2 mg/1 de gélatine et de 4 mg/1 de thiourée) sur la passivation de deux alliages de cuivre Cu-Pb et Cu-Sb a été évaluée en utilisant différentes techniques d'analyse du BE. Cette étude a montré que les analyses des signaux du BE sont utiles et prometteuses pour surveiller la passivation pour des études de la corrosion anodique dans des conditions de raffinage simulées en présence d'additifs. Finalement, des formes de corrosion possibles des anodes d'alliages de cuivre ont également été examinées dans différentes régions des courbes choronopotentiométrique correspondantes et ont été corrélées avec certains paramètres obtenus lors des analyses de signaux du BE.

Chitin ist ein Polysaccharid, welches aus N-Acetylglucosamin (GlcNAc) aufgebaut ist. Das Biopolymer kommt in der Natur in Invertebraten, Algen, Pilzen und Einzellern vor. Chitinasen hydrolysieren Chitin. Diese Enzyme sind essentiell für die Regulierung und Entwicklung von Arthropoden und Mikroorganismen. Sie fungieren in Pflanzen als Phytoalexine. <br> Das verstärkt das Interesse am Design neuer natürlicher und synthetischer Chitinase-inhibitoren, die als potentielle Insektizide, Fungizide, Antimalaria bzw. Antiasthmatika eingesetzt werden können. <br><br> Ziel dieser Arbeit war die Synthese von neuen Thioglycosidanaloga von N-Acetyl-chitooligosacchariden und deren Untersuchung als Enzyminhibitoren. <br><br> Die geschützten 4-O-Tf-galactopyranosylthioglycoside wurden aus den korrespondierenden p-Methoxyphenylglycosiden von GlcNAc nach einer neuen Methode in einer Stufe hergestellt. Die Reaktion der galacto-Triflate mit 2-Acetamido-3,4,6-tri-O-acetyl-2-desoxy-1-thio-ß-D-glucopyranose in Gegenwart von Natriumhydrid und 15-Krone-5 in THF lieferte die Pseudo-Trisaccharide.<br><br> Die Herstellung der Glycosyl-Thiazoline aus den entsprechenden p-Methoxyphenyl-glycosiden mit Lawesson's Reagenz ist nach einem neuen Reaktionsweg beschrieben wie auch die Synthese der Thioacetamide von GlcNAc-Oligomeren.<br><br> Die Pseudo-Oligosaccharide wurden als Inhibitoren der Chitinasen von Serratia marcescens, Chironomus tentans, Acanthocheilonema viteae und Hevaea brasiliensis sowie der N-Acetyl-glucosaminidase von Chironomus tentans getestet. In einigen Fällen ergab sich eine Hemmung (IC50) im µM-Bereich. / Chitin is a polysaccharide composed of N-acetylglucosamine (GlcNAc). The biopolymer is distributed in Invertebrates, algae, fungi and Protozoa. Chitinases hydrolyse chitin. These enzymes are essential for the regulation and development of Arthropoda and micro organisms. In bacteria chitinase degrade chitin as source of carbon and act in plants as phytoalexins. Currently, there is a great interest in the design of novel natural and synthetic chitinase inhibitors, which may act as potential insecticides, fungicides, antimalaria or antiasthmatics.<br><br> Thio-oligosaccharides and related thio-glycosides are rarely described in the literature. Thio-analogues of oligosaccharides derived from N-acetylglucosamine are of interest as potential enzyme inhibitors. The synthesis and enzymatic investigations of thio-glycoside analogues of N-acetyl-chitooligosaccharides are described in this thesis.<br><br> The protected 4-O-Tf-galactopyranosyl thioglycosides were prepared by a new method in one step from the corresponding p-methoxyphenyl glycosides of N-acetylglucosamine. Coupling of galacto-triflates with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-1-thio-ß-D-glucopyranose in the presence of sodium hydride and 15-crown-5 in THF, followed by deprotection, afforded the pseudo-trisaccharides. <br><br> The preparation of glycosyl thiazolines by a new manner from the analogues p-methoxyphenyl glycosides with Lawesson's reagent is also described however the synthesis of thioacetamides of N-acetylglucosamine.<br><br> The pseudo-oligosaccharides were tested for inhibition of chitinases from Serratia marcescens, Chironomus tentans, Acanthocheilonema viteae, and Hevaea brasiliensis, and also with N-acetyl-glucosaminidase from Chironomus tentans. Inhibition with IC50 values in the µM range was found in a few cases.

¤@¡BRole of 5-thio-(2-nitrobenzoic acid)-capped gold nanoparticles in the sensing of chromium(VI): remover and sensor This study describes a simple, rapid method for sensing Cr(VI) using 5-thio-(2-nitrobenzoic acid) modified gold nanoparticles (TNBA-AuNPs) as a remover for Cr(III) and as a sensor for Cr(VI). We discovered that TNBA-AuNPs were dispersed in the presence of Cr(VI), whereas Cr(III) induced the aggregation of TNBA-AuNPs. Due to this phenomenon, TNBA-AuNPs can be used as a sorbent material for the removal of > 90% Cr(III), without removing Cr(VI). After centrifuging a solution containing Cr(III), Cr(VI), and TNBA-AuNPs, Cr(III) and Cr(VI) were separately present in the precipitate and supernatant. In other words, TNBA-AuNPs are capable of separating a mixture of Cr(III) and Cr(VI). The addition of ascorbic acid to the supernatant resulted in a reduction of Cr(VI) to Cr(III), driving the aggregation of TNBA-AuNPs. The selectivity of this approach is more than 1000-fold for Cr(VI) over other metal ions. The minimum detectable concentration of Cr(VI) was 1 £gM using this approach. Inductively coupled plasma mass spectrometry provided an alternative for the quantification of Cr(III) and Cr(VI) after a mixture of Cr(III) and Cr(VI) had been separated by TNBA-AuNPs. The applicability of this approach was validated through the analysis of Cr(VI) in drinking and tap water. ¤G¡BFluorescent Sensing of Total, Protein-bound, Free, and Oxidized Homocysteine in Plasma through the Combination of Tris(2-carboxyethyl)Phosphine Reduction, Fluorosurfactant-Capped Gold Nanoparticles Extraction, and o-Phthaldialdehyde Derivatization This study reports a simple, selective, and sensitive method for fluorescent detection of total, protein-bound, free, and oxidized homocysteine (HCys) using tris(2-carboxyethyl)phosphine (TCEP) as a reducing agent, fluorosurfactant-capped gold nanoparticles (FSN-AuNP) as a preconcentrating probe, and o-Phthaldialdehyde (OPA) as a derivatizing agent. TCEP was used to reduce the disulfide bonds of protein-bound and oxidized HCys. FSN-AuNPs were capable of extracting HCys from a complicated complex because the FSN capping layer can stabilize the AuNPs in a high-salt solution and inhibit non-specific adsorption. HCys was selectively derivatized with OPA in the absence of a nucleophile. By taking advantage of these features, the selectivity of the proposed system is greater than 100-fold for HCys and homocystine (HCys-HCys disulfide; diHCys) compared to any aminothiols. The limits of detection (LODs) for HCys and diHCys were 4.4 and 4.6 nM, respectively. Compared to other sensors, the proposed system provides an approximately 3-300-fold improvement in the detection of HCys. Different forms of plasma HCys were determined by varying the order of disulfide reduction with TCEP. The proposed system was successfully applied to determine the total, protein-bound, free, and oxidized HCys in plasma. To the best of our knowledge, the proposed system not only provides the first method for detecting various forms of plasma HCys, but also has the lowest LOD value for HCys when compared to other sensors.

The thesis entitled “Controlling Stereochemistry at the Quaternary Center Using Bifunctional (Thio)urea Catalysis” is divided into five chapters. Chapter 1: Catalytic Enantioselective Construction of Quaternary Stereocenters through Direct Vinylogous Michael Addition of Deconjugated Butenolides to Nitroolefins The direct use of deconjugated butenolides in asymmetric C–C bond forming reaction is a powerful but challenging task because of the additional problem of regioselectivity along with the issues of diastereo- and enantioselectivity. In this chapter, a direct asymmetric vinylogous Michael addition of deconjugated butenolides to nitroolefins has been demonstrated for the construction of quaternary stereocenter at the γ-position of butenolides. A novel thiourea-based bifunctional organocatalyst, containing two elements of chirality, was synthesized starting from commercially available quinine and (S)-tert-leucine. Remarkably, the sense of stereoinduction in this process is dominated by the tert-leucine segment of the catalyst. Synthetically versatile & highly functionalized γ-butenolides with contiguous quaternary and tertiary stereocenters were synthesized stereoselectively. The reaction was found to be general and a wide range of nitroolefins, with both electron-rich and electron-deficient substituents, underwent smooth reaction under these mild conditions. Similarly, deconjugated butenolides, having various substituents at the γ-position were well tolerated under these reaction conditions and the products were obtained in excellent yields and with uniformly high diastereo- and enantioselectivities. Reference: Manna, M. S.; Kumar, V.; Mukherjee, S. Chem. Commun. 2012, 48, 5193–5195. Chapter 2: Catalytic Asymmetric Direct Vinylogous Michael Addition of Deconjugated Butenolides to Maleimides for the Construction of Quaternary Stereogenic Center In this chapter, a mild and operationally simple protocol for the direct vinylogous Michael addition of deconjugated butenolides to maleimides has been illustrated. Using bifunctional tertiary amino thiourea organocatalyst, derived from a ‘matched’ combination of trans-(1R,2R)-diaminocyclohexane (DACH) and (S)-tert-leucine, the Michael adducts were obtained in excellent yields and with good to high diastereoselectivities and outstanding enantioselectivities. Application of the corresponding diastereomeric catalyst indicated the dominance of the ‘DACH’ unit over the chiral side chain in determining the sense of stereoinduction. The practicality of this protocol is illustrated by substantial low catalyst loading (down to 5 mol%) and one-pot catalyst recycling. Based on the X-ray structure of the catalyst and observed stereochemistry of the Michael adduct, a stereochemical model is proposed which was further supported by additional experiment. Reference: Manna, M. S.; Mukherjee, S. Chem.–Eur. J. 2012, 18, 15277–15282. Chapter 3: Enantioselective Desymmetrization of Cyclopentenedione through Direct Catalytic Vinylogous Michael Addition of Deconjugated Butenolides Five-membered carbocycles containing one or more stereogenic centers on the ring are privileged structural motifs found in many biologically active natural and non-natural compounds. Among various methods for accessing these enantioenriched carbocyclic frameworks, desymmetrization of prochiral or meso-compounds through catalytic enantioselective transformations represents a powerful strategy. The biggest advantage of such asymmetric desymmetrization reactions lies in their ability in controlling stereochemistry remote from the reaction site. This chapter deals with a highly efficient desymmetrization protocol for 2,2-disubstituted cyclopentene-1,3-diones via direct vinylogous nucleophilic addition of deconjugated butenolides with the help of a tertiary amino thiourea bifunctional catalyst. In contrast to the existing desymmetrization protocols, this method represents a unique example where quaternary stereocenter is generated not only within the ring but also outside the cyclopentane ring. Densely functionalized products are obtained in excellent yields and with outstanding diastereo- and enantioselectivities. The robustness screening indicated that the reaction is highly tolerant to a variety of competing electrophiles and nucleophiles. The remarkable influence of the secondary catalyst site on the enantioselectivity points towards an intriguing mechanistic scenario. To the best of our knowledge, this is the first time such an effect is observed in the context of asymmetric catalysis. Reference: (1) Manna, M. S.; Mukherjee, S. Chem. Sci. 2014, 5, 1627–1633. (2) Manna, M. S.; Mukherjee, S. Org. Biomol. Chem. 2015, 13, 18–24. (Perspective) Chapter 4: Enantioselective Desymmetrization of Cyclopentenediones through Organocatalytic C(sp2)–H Alkylation Organic compounds are characterized by the presence of various C–H bonds. Functionalization of a specific C–H bond in a molecule with a selected atom or group are among the most straightforward and desirable synthetic transformations in organic chemistry. In this chapter, a simple protocol for the direct alkylation of olefinic C(sp2)–H bond has been developed, not only enantioselectively using an organocatalyst but more importantly without using any directing group. This alkylative desymmetrization of prochiral 2,2-disubstituted cyclopentene-1,3-diones is catalyzed by a dihydroquinine-based bifunctional urea derivative. Using easily accessible, inexpensive and air-stable nitroalkanes as the alkylating agent, this C(sp2)−H alkylation represents a near-ideal desymmetrization and delivers products containing an all-carbon quaternary stereogenic center in good to excellent yields and with high enantioselectivities. The mild reaction conditions allow for the introduction of various functionalized alkyl groups. The possibility of a second alkylation and its applications has also been demonstrated. This protocol is the first example of the use of nitroalkane as the alkyl source in an enantioselective transformation. It is expected that, these findings would have broader consequences and applications to other alkylative and related transformations. Reference: Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130–133. (Highlighted in Synform 2015, 67–70) Chapter 5: Enantioselective Desymmetrization of Cyclopentenediones through Organocatalytic Formal C(sp2)–H Vinylation The development of catalytic enantioselective C(sp2)–H vinylation reactions remained relatively underexplored for a long time because of various challenges associated with it. As C(sp2)–H functionalization reactions do not generate any stereocenter at the reaction site, development of enantioselective C(sp2)−H functionalization must rely on desymmetrization of prochiral or meso-substrates. More important issue is the identification of a suitable directing group which can efficiently control the regioselectivity during the activation of C(sp2)−H bond. In this chapter, an efficient formal C(sp2)−H vinylation of prochiral 2,2-disubstituted cyclopentene-1,3-dione is developed without using any directing group. This formal C(sp2)−H vinylation of 2,2-disubstituted cyclopentene-1,3-dione is realized using a two-step operation: catalytic enantioselective Michael addition of deconjugated butenolides followed by a base mediated decarboxylation. The vinylated products, containing a remote all-carbon quaternary stereogenic center, are obtained in good yields and with good to high enantioselectivities. Synthetic utility of this protocol is demonstrated by converting the resulting chiral electron-deficient diene into various important building blocks. Significant erosion in enantioselectivity during the decarboxylation process was explained by a plausible mechanism, which was further supported by control experiments. Reference: Manna, M. S.; Sarkar, R.; Mukherjee, S. manuscript under preparation.

A presente tese trata da análise conformacional e estudo das interações eletrônicas de algumas 2-(fenilseleno)-2-(etiltio)acetofenonas (série I), 2-(fenilseleno)-2-(etilsulfinil)- acetofenonas [série IIa para (CRSR/CSSS) e série IIb para (CRSS//CSSR)] e 2-(fenilseleno)-2- (etilsulfonil)acetofenonas (série III) contendo substituintes doadores e atraentes de elétrons, além de hidrogênio na posição para do grupo fenacila. Foi constatada a ocorrência de isomerismo conformacional por espectroscopia no infravermelho em solventes de constante dielétrica crescente (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) em todas as séries estudadas. Os resultados obtidos por infravermelho são concordantes com as estruturas obtidas por otimização estrutural no nível de teoria B3LYP/6-31+G(d,p) com o efeito do solvente simulado pelo método PCM. As interações eletrônicas foram investigadas a partir dos contatos interatômicos e por meio da análise das interações orbitalares (NBO). Foram obtidas as estruturas cristalográficas de alguns compostos selecionados das séries IIa, IIb e III por difração de raio-X. Na série I, o confôrmero mais estável é caracterizado pelas interações orbitalares entre carbonila e enxofre, com o grupo etiltio numa geometria sinclinal em relação à carbonila, enquanto o grupo fenilselenila se aproxima da carbonila devido à repulsão eletrostática ser pequena. O efeito do solvente nas populações relativas dos confôrmeros ao longo da série I é menor que nas demais séries. As interações são significativamente modificadas com o grupo etilsulfinila (séries IIa e IIb): o átomo de enxofre é positivo, de modo que as interações orbitalares &#960;CO&#8594;&#963;*CS e &#960;*CO&#8594;&#963;*CS são mais intensas. Assim, em solventes de baixa polaridade, o grupo etilsulfinila mantém a preferência conformacional sinclinal em relação à carbonila na série IIa enquanto na série IIb esse confôrmero é altamente desestabilizado devido à repulsão eletrostática O&#948;-(CO)...O&#948;-(SO). O aumento na constante dielétrica do solvente favorece a conformação na qual o grupo etilsulfinila tende a geometria sinperiplanar em relação à carbonila, com os dipolos S=O e C=O apontando na mesma direção. Na série IIb o grupo fenilselenila adota a geometria sinclinal (que favorece as interações orbitalares) enquanto o grupo etilsulfinila tende à geometria sinperiplanar em relação à carbonila nos dois confôrmeros estáveis. A orientação do oxigênio sulfinílico em relação ao oxigênio carbonílico define a estabilidade dos confôrmeros da série IIb: enquanto solventes apolares e grupos doadores de elétrons estabilizam a conformação na qual os dipolos S=O e C=O apontam em direções opostas, solventes polares e grupos atraentes de elétrons estabilizam a conformação na qual os referidos dipolos apontam na mesma direção. Por fim, na série III (que contém o grupo etilsulfonila) a atração eletrostática cruzada entre os grupos carbonila e sulfonila é suficientemente forte para estabilizar uma mesma conformação em todos os solventes. Nessa conformação, o arranjo geométrico desfavorece as interações orbitalares entre heteroátomos e carbonila, reforçando a importância do fator eletrostático para o equilíbrio conformacional nos compostos estudados. Conclui-se que a soma das interações orbitalares envolvendo enxofre ou selênio são praticamente as mesmas para os diferentes confôrmeros de todas as séries estudadas (I-III), sendo o balanço entre as interações eletrostáticas repulsivas e atrativas o fator principal que determina a estabilidade relativa dos confôrmeros em solução. / This thesis reports the conformational analysis and the electronic interactions study of some 2-(phenylseleno)-2-(ethylthio)acetophenones (series I), 2-(phenylseleno)-2-(ethylsulfinyl)- acetophenones [series IIa (CRSR/CSSS) and series IIb (CRSS//CSSR)] and 2-(phenylseleno)-2- (ethylsulfonyl)acetophenones (series III) bearing in the para position of the phenacyl group electron donating, hydrogen and electron attracting substituents. It has been found the occurrence of conformational isomerism through infrared spectroscopy in solvents of increasing dielectric constant (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) in all studied series. The infrared results are consistent with the conformers obtained by structural optimization on the B3LYP/6-31+G(d,p) level of theory along with the solvent effect simulated by the PCM method. The electronic interactions were investigated from interatomic contacts and by orbital interactions analysis (NBO). Structures for selected solids of series IIa, IIb and III were obtained through X-ray diffraction analysis. In the series I, the most stable conformer is characterized by interactions between carbonyl and sulfur orbitals, with the ethylthio group bearing a synclinal geometry relative to the carbonyl group while the phenylselenyl moiety approaches the carbonyl group, due to the reduced electrostatic repulsion. The solvent effect on the relative population of the conformers through the series I is smaller than the other series. The interactions are significantly modified due the ethylsulfinyl group (series IIa and IIb): the sulfur atom is positive, leading to stronger &#960;CO&#8594;&#963;*CS and &#960;*CO&#8594;&#963;*CS orbital interactions. Thus, in solvents of low polarity, the ethylsulfinyl group retains the synclinal geometry relative to the carbonyl group in the serie IIa while in serie IIb this conformer is highly desistibilized due the O&#948;-(CO)...O&#948;-(SO) electrostatic repulsion. The increase in the dielectric constant of the solvent stabilizes the conformation in which the ethylsulfinyl group adopts a sinperiplanar geometry in relation to the carbonyl group, with the S=O and C=O dipoles pointing towards the same direction in both series. In the series IIb, the phenylselenyl group adopts the synclinal geometry (which favors the orbital interactions) while the ethylsulfinyl group tends to a sinperiplanar geometry relative to the carbonyl group in both conformers. The orientation of the sulfinyl oxygen relative to the carbonyl oxygen defines the stability of the conformers in series IIb: while nonpolar solvents and electron donating substituents stabilize the conformation in which the S=O and C=O dipoles point in opposite directions, on the other hand, polar solvents and attractive electron groups stabilize the conformation in which these dipoles point in the same direction. Finally, in the series III (which contains the ethylsulfonyl group) the crossed electrostatic attraction between the carbonyl and sulfonyl groups is strong enough to stabilize the same conformation in all solvents. In this conformation, the geometrical arrangement disfavors the orbital interactions between heteroatoms and carbonyl group, reinforcing the importance of the electrostatic factor for the conformational equilibrium in the studied compounds. It may be concluded that the sum of the orbital interactions involving sulfur or selenium atoms are practically the same for the different conformers of the studied series (I-III), being the balance of the attractive and repulsive electrostatic interactions the main factor which determine their relative stabilization in solution.

A presente tese trata da análise conformacional e estudo das interações eletrônicas de algumas 2-(fenilseleno)-2-(etiltio)acetofenonas (série I), 2-(fenilseleno)-2-(etilsulfinil)- acetofenonas [série IIa para (CRSR/CSSS) e série IIb para (CRSS//CSSR)] e 2-(fenilseleno)-2- (etilsulfonil)acetofenonas (série III) contendo substituintes doadores e atraentes de elétrons, além de hidrogênio na posição para do grupo fenacila. Foi constatada a ocorrência de isomerismo conformacional por espectroscopia no infravermelho em solventes de constante dielétrica crescente (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) em todas as séries estudadas. Os resultados obtidos por infravermelho são concordantes com as estruturas obtidas por otimização estrutural no nível de teoria B3LYP/6-31+G(d,p) com o efeito do solvente simulado pelo método PCM. As interações eletrônicas foram investigadas a partir dos contatos interatômicos e por meio da análise das interações orbitalares (NBO). Foram obtidas as estruturas cristalográficas de alguns compostos selecionados das séries IIa, IIb e III por difração de raio-X. Na série I, o confôrmero mais estável é caracterizado pelas interações orbitalares entre carbonila e enxofre, com o grupo etiltio numa geometria sinclinal em relação à carbonila, enquanto o grupo fenilselenila se aproxima da carbonila devido à repulsão eletrostática ser pequena. O efeito do solvente nas populações relativas dos confôrmeros ao longo da série I é menor que nas demais séries. As interações são significativamente modificadas com o grupo etilsulfinila (séries IIa e IIb): o átomo de enxofre é positivo, de modo que as interações orbitalares &#960;CO&#8594;&#963;*CS e &#960;*CO&#8594;&#963;*CS são mais intensas. Assim, em solventes de baixa polaridade, o grupo etilsulfinila mantém a preferência conformacional sinclinal em relação à carbonila na série IIa enquanto na série IIb esse confôrmero é altamente desestabilizado devido à repulsão eletrostática O&#948;-(CO)...O&#948;-(SO). O aumento na constante dielétrica do solvente favorece a conformação na qual o grupo etilsulfinila tende a geometria sinperiplanar em relação à carbonila, com os dipolos S=O e C=O apontando na mesma direção. Na série IIb o grupo fenilselenila adota a geometria sinclinal (que favorece as interações orbitalares) enquanto o grupo etilsulfinila tende à geometria sinperiplanar em relação à carbonila nos dois confôrmeros estáveis. A orientação do oxigênio sulfinílico em relação ao oxigênio carbonílico define a estabilidade dos confôrmeros da série IIb: enquanto solventes apolares e grupos doadores de elétrons estabilizam a conformação na qual os dipolos S=O e C=O apontam em direções opostas, solventes polares e grupos atraentes de elétrons estabilizam a conformação na qual os referidos dipolos apontam na mesma direção. Por fim, na série III (que contém o grupo etilsulfonila) a atração eletrostática cruzada entre os grupos carbonila e sulfonila é suficientemente forte para estabilizar uma mesma conformação em todos os solventes. Nessa conformação, o arranjo geométrico desfavorece as interações orbitalares entre heteroátomos e carbonila, reforçando a importância do fator eletrostático para o equilíbrio conformacional nos compostos estudados. Conclui-se que a soma das interações orbitalares envolvendo enxofre ou selênio são praticamente as mesmas para os diferentes confôrmeros de todas as séries estudadas (I-III), sendo o balanço entre as interações eletrostáticas repulsivas e atrativas o fator principal que determina a estabilidade relativa dos confôrmeros em solução. / This thesis reports the conformational analysis and the electronic interactions study of some 2-(phenylseleno)-2-(ethylthio)acetophenones (series I), 2-(phenylseleno)-2-(ethylsulfinyl)- acetophenones [series IIa (CRSR/CSSS) and series IIb (CRSS//CSSR)] and 2-(phenylseleno)-2- (ethylsulfonyl)acetophenones (series III) bearing in the para position of the phenacyl group electron donating, hydrogen and electron attracting substituents. It has been found the occurrence of conformational isomerism through infrared spectroscopy in solvents of increasing dielectric constant (n-C6H14, CCl4, CHCl3, CH2Cl2, CH3CN) in all studied series. The infrared results are consistent with the conformers obtained by structural optimization on the B3LYP/6-31+G(d,p) level of theory along with the solvent effect simulated by the PCM method. The electronic interactions were investigated from interatomic contacts and by orbital interactions analysis (NBO). Structures for selected solids of series IIa, IIb and III were obtained through X-ray diffraction analysis. In the series I, the most stable conformer is characterized by interactions between carbonyl and sulfur orbitals, with the ethylthio group bearing a synclinal geometry relative to the carbonyl group while the phenylselenyl moiety approaches the carbonyl group, due to the reduced electrostatic repulsion. The solvent effect on the relative population of the conformers through the series I is smaller than the other series. The interactions are significantly modified due the ethylsulfinyl group (series IIa and IIb): the sulfur atom is positive, leading to stronger &#960;CO&#8594;&#963;*CS and &#960;*CO&#8594;&#963;*CS orbital interactions. Thus, in solvents of low polarity, the ethylsulfinyl group retains the synclinal geometry relative to the carbonyl group in the serie IIa while in serie IIb this conformer is highly desistibilized due the O&#948;-(CO)...O&#948;-(SO) electrostatic repulsion. The increase in the dielectric constant of the solvent stabilizes the conformation in which the ethylsulfinyl group adopts a sinperiplanar geometry in relation to the carbonyl group, with the S=O and C=O dipoles pointing towards the same direction in both series. In the series IIb, the phenylselenyl group adopts the synclinal geometry (which favors the orbital interactions) while the ethylsulfinyl group tends to a sinperiplanar geometry relative to the carbonyl group in both conformers. The orientation of the sulfinyl oxygen relative to the carbonyl oxygen defines the stability of the conformers in series IIb: while nonpolar solvents and electron donating substituents stabilize the conformation in which the S=O and C=O dipoles point in opposite directions, on the other hand, polar solvents and attractive electron groups stabilize the conformation in which these dipoles point in the same direction. Finally, in the series III (which contains the ethylsulfonyl group) the crossed electrostatic attraction between the carbonyl and sulfonyl groups is strong enough to stabilize the same conformation in all solvents. In this conformation, the geometrical arrangement disfavors the orbital interactions between heteroatoms and carbonyl group, reinforcing the importance of the electrostatic factor for the conformational equilibrium in the studied compounds. It may be concluded that the sum of the orbital interactions involving sulfur or selenium atoms are practically the same for the different conformers of the studied series (I-III), being the balance of the attractive and repulsive electrostatic interactions the main factor which determine their relative stabilization in solution.

Orientador: Fernando Lucas Primo / Resumo: O avanço tecnológico cresce rapidamente no mundo, inclusive na área farmacêutica. Nesse contexto, sistemas nanoestruturados ganham progressivo destaque, porquanto carregam um enorme potencial para o aperfeiçoamento das práticas terapêuticas atuais. A administração de fármacos na forma livre pode apresentar problemas como baixa concentração no sítio ativo, inadequada distribuição pelo organismo, baixa biodisponibilidade, presença de efeitos adversos, entre outros. As nanocápsulas poliméricas são capazes de contornar tais vieses, possibilitando, inclusive, a diminuição da toxicidade com a diminuição de doses e aumento da estabilidade de fármacos em meios biológicos. Foram desenvolvidas nanocápsulas poliméricas contendo Anfotericina B (AMB) e Fenil-tio-ftalocianina de zinco (ZnS4Pc) na concentração teórica de 0,05 mg.mL-1 objetivando, com a associação entre os dois ativos, melhorar a atividade antifúngica conseguida pelo antifúngico isoladamente utilizando-se a Terapia Fotodinâmica Antimicrobiana. A avaliação das características físico-químicas das nanocápsulas mostraram diâmetro médio de partícula de 253,8 ± 17,3 nm, índice de polidispersidade médio de 0,36 ± 0,01 e potencial Zeta médio de – 31,03 ± 5,54 mV. Tais análises revelaram-se satisfatórias já que o diâmetro de partícula conseguido pelo método de deposição interfacial de polímero pré-formado utilizado na produção das nanocápsulas varia de 250 a 500 nm (MORA-HUERTAS et. al., 2010), enquanto que o potencial zeta considera... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Technological advancement is growing rapidly in the world, including the pharmaceutical area. In this context, nanostructured systems gains progressive prominence, as they carry enormous potential for the improvement of current therapeutic practices. The drugs administration in the free-form may present problems such as low active site concentration, inadequate distribution throughout body, low bioavailability, presence of adverse effects, among others. Polymeric nanocapsules allowing the reduction of toxicity with decreasing doses and increasing the stability of drugs in biologic media. Polymeric nanocapsules containing Amphotericin B (AMB) and zinc phenyl-thio-phthalocyanine (ZnS4Pc) were developed at a 0.05 mg/mL theoretical concentration to improve antifungal activity with the association between the two actives over antifungal alone. The nanocapsules physical-chemical characteristics showed an average particle diameter of 253,8 ± 17,3 nm, an average polydispersity index of 0,36 ± 0,01 and negative Zeta potential -31,03 ± 5,54 mV. These analyzes proved satisfactory since the particle diameter achieved by the preformed polymer interfacial deposition method used in nanocapsule production ranges from 250 to 500 nm (MORA-HUERTAS et. al., 2010), while the Zeta potential considered for a stable formulation should be bigger than 30 mV in modulus (RAVAL et al., 2019). Absorption and emission spectroscopy analyzes performed in the UV-Vis region found no changes in the steady state... (Complete abstract click electronic access below) / Mestre