Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of twelve NH-pyrazoles from the cyclocondensation reaction of β-dimethylaminovinylketones ([R1C(O)C(R2)=CHN(Me)2], where R1 = Me, C6H5, 3- MeO-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, fur-2-il, tien-2-il; R2 = H, 2-MeO-C6H4 and R1, R2 = -(CH2)3C(O)- with hydrazine sulfate is reported. In this work, it was also demonstrated the synthesis of twelve isoxazoles from the cyclocondensation reaction of β-dimethylaminovinylketones where R1 = Me, C6H5, 3-MeO-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-biphenyl, naphthalen-2-yl, 4-O2N-C6H4, thien-2-yl and R2 = H, 2-MeOC6H4 with hydroxylamine hydrochloride. The reactions were performed in the presence of p-toluene sulfonic acid as the catalyst through two methodologies: (i) by the solvent-free grinding method, and (ii) using the conventional method, ethanol reflux. In addition, the Grindstone Chemistry methodology demonstrated that largescale synthesis is also possible. Making a comparison with the classical reaction conditions, which employ molecular solvent (ethanol), the grinding method has as main advantages of shorter reaction time (5-15 min), higher product yields (60-92%), mild reaction conditions as well as being environmentally friendly. / Neste trabalho é descrita a síntese de uma série de doze NH-pirazóis a partir da reação de ciclocondensação de β-dimetilaminovinilcetonas ([R1C(O)C(R2)=CHN(Me)2], onde R1 = Me, C6H5, 3-MeO-C6H4, 4-Me-C6H4, 4-MeOC6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, fur-2-il, tien-2-il; R2 = H, 2-MeOC6H4 e R1, R2 = -(CH2)3C(O)- com sulfato de hidrazina. Também foi realizada a síntese de uma série de doze isoxazóis a partir da reação de ciclocondensação de β-enamino cetonas, onde R1 = Me, C6H5, 3-MeO-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4- F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-bifenil, naft-2-il, 4-O2N-C6H4, tien-2-il e R2 = H, 2-MeO-C6H4 com cloridrato de hidroxilamina. As reações para obtenção dos compostos heterocíclicos foram realizadas na presença de ácido p-tolueno sulfônico (ác. p-TsOH) como catalisador através de duas metodologias: (i) utilizando o método grinding na ausência de solvente, e (ii) utilizando metodologia convencional, refluxo em etanol. O método Grindstone Chemistry foi testado e demonstrou que a síntese em grande escala também é possível. Os resultados obtidos mostraram que o grinding proporciona uma redução no tempo da reação (5-15 min), altos rendimentos (60-92%), condições de reação brandas, além de ser uma metodologia ambientalmente aceitável.

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-07T21:45:34Z (GMT). No. of bitstreams: 1 Camilo_NiltonSoares_D.pdf: 3180029 bytes, checksum: 2847c04256e604434393243a35c4298a (MD5) Previous issue date: 2006 / Doutorado / Quimica Organica / Doutor em Ciências

Ce manuscrit traite de la mise au point d’une méthode d’accès éco-compatible à des squelettes carbocycliques et hétérocycliques, présents dans de nombreux composés d’intérêt biologique. Cette méthode met en œuvre une réaction de cycloaddition [2+2+2] catalysée par un métal de transition. Dans un premier temps, une voie d’accès à des fluorénones hautement substituées, ainsi qu’à des analogues a été développée. Cette voie utilise une réaction de cycloaddition [2+2+2] de diynes-[alpha, omega] pontés par un groupe benzoyle, avec des alcynes, en présence de RuCl3·nH2O. Dans un deuxième temps, des dérivés 2-aminopyridines diversement fonctionnalisés ont été synthétisés via une catalyse au ruthénium neutre (RuCl3·nH2O) ou cationique (Cp*Ru(CH3CN)3PF6), et ce à partir de la cycloaddition [2+2+2] de diynes et de cyanamides. Dans le cas où Cp*Ru(CH3CN)3PF6 a été utilisé comme catalyseur, une excellente régiosélectivité a été observée, ce qui a permis d’isoler une grande variété de 2-aminopyridines, dont des halopyridines, des vinylpyridines, ou des amino-aza-fluorénones. Dans une dernière partie, la cycloaddition [2+2+2] énantiosélective de triynes prochiraux avec des mono alcynes a été examinée. Elle a été conduite en utilisant un catalyseur cationique au rhodium, le complexe [Rh(cod)2]BF4/(R)-BINAP, et a permis la préparation de dérivés de 1,3-dihydroisobenzofuranes énantiomériquement enrichis, contenant un carbone quaternaire stéréogène. / This manuscript focused on the development of eco-friendly and mild processes to access original carbocyclic and heterocyclic scaffolds of biological interest through transition-metal-catalyzed [2+2+2] cycloaddition reactions. Initially, an efficient and practical route for the preparation of highly substituted fluorenones and analogues via solventless RuCl3·nH2O-mediated [2+2+2] cycloaddition of benzoyl bridged [alpha, omega]-diynes and alkynes was developed. Secondly, various functionalized 2-aminopyridine derivatives were synthesized using both neutral RuCl3·nH2O and cationic Cp*Ru(CH3CN)3PF6 complexes to catalyze the [2+2+2] cycloaddition of diynes and cyanamides under solvent-free conditions. With Cp*Ru(CH3CN)3PF6 as catalyst, excellent regioselectivities were achieved to provide a wide range of 2-aminopyridines of high synthetic utility involving halopyridines, vinyl pyridines and amino-aza-fluorenones. Finally, the enantioselective rhodium-catalyzed [2+2+2] cycloaddition of prochiral triynes and monoalkynes was carried out in the presence of cationic [Rh(cod)2]BF4/(R)-BINAP complex to provide enantioenriched 1,3-dihydroisobenzofuran derivatives containing a quaternary carbon stereogenic center.

The search for the ideal, environmentally friendly and preferably cheap solvent has been a persistent topic in general chemistry. Hence, the effort in the development of “green” solvents and processes skyrocketed in the recent past. However, a replacement of solvents does not deal with the problem at hand – it is just a small fix, not a big innovation. Taking this into consideration, what is the big innovation needed in chemistry? If one considers solvents as the problem, then the logical step is to simply get rid of them altogether. One approach to conduct reactions in the absence of solvents is mechanochemistry. Initiated and/or sustained by mechanical energy, mechanochemical reactions offer a sustainable alternative to many wet-chemical methods. Innovative uses thereof have made their way into the fields of pharmaceuticals, material synthesis and, foremost, organic chemistry, where the vast potential of this rediscovered field has been demonstrated. In this context, I have dedicated this thesis to establish mechanochemical protocols for the fields of polymers and nanographenes. Both of those topics are, at the moment, dominated by solution-based synthesis, although the compounds produced are hardly soluble.

This project utilised a novel solvent-free continuous cocrystallisation (SFCC) method to manufacture pharmaceutical co-crystals. The objectives were to optimize the process towards achieving high co-crystal yields and to understand the behaviour of co-crystals under different conditions. Particular attention was paid to the development of near infrared (NIR) spectroscopy as a process analytical technology (PAT). Twin screw, hot melt extrusion was the base technique of the SFCC process. Changing parameters such as temperature, screw speed and screw geometry was important for improving the co-crystal yield. The level of mixing and shear was directly influenced by the screw geometry, whilst the screw speed was an important parameter for controlling the residence time of the material during hot melt extrusion. Ibuprofen – nicotinamide 1:1 cocrystals and carbamazepine – nicotinamide 1:1 co-crystals were successfully manufactured using the SFCC method. Characterisation techniques were important for this project, and NIR spectroscopy proved to be a convenient, accurate analytical technique for identifying the formation of co-crystals along the extruder barrel. Separate thermal and model shear deformation studies were also carried out to determine the effect of temperature and shear on co-crystal formation for several different pharmaceutical co-crystal pairs. Finally, NIR spectroscopy was used to create two partial least squares regression models, for predicting the 1:1 co-crystal yield of ibuprofen – nicotinamide and carbamazepine – nicotinamide, when in a powder mixture with the respective pure API. It is believed that the prediction models created in this project can be used to facilitate future in-line PAT studies of pharmaceutical co-crystals during different manufacturing processes.

La régénération des défauts osseux de taille critique reste un défi majeur pour la santé. Les limitations des greffes de tissus communes nous ont incités à développer une alternative synthétique basée sur la construction d’un biomatériau, des facteurs ostéoinductifs et des cellules souches. Pour la construction du biomatériau, nous nous sommes concentrés sur les microporteurs polymères poreux, car ils supportent une expansion cellulaire à grande échelle et un assemblage modulaire des tissus, contournant deux goulots d'étranglement importants pour la traduction clinique. Pour assurer l'approvisionnement industriel et l'approbation réglementaire, nous avons conçu une méthode de fabrication sans solvant organique basée sur la cristallisation sphérulitique du poly(L-lactide) (PLLA) dans ses mélanges avec du polyéthylène glycol (PEG). Les sphérulites de PLLA ont été facilement récupérées sous forme de microporteurs en éliminant par rinçage le PEG soluble dans l'eau. Leur taille et leur porosité pourraient être contrôlées indépendamment en ajustant le rapport PLLA / PEG et la température de cristallisation. La biocompatibilité et l'ostéoconductivité des microporteurs à PLLA ont été confirmées par l'expansion et la différenciation ostéogénique des cellules souches adipeuses humaines (hASC). Comme cette dernière fonction hASC est sensible à différents paramètres de culture, nous avons ensuite utilisé l'approche de conception d'expériences pour leur dépistage rapide. En combinaison avec l'analyse à haut débit, nous avons identifié plusieurs paramètres ayant une influence marquée sur leur différenciation ostéogénique. Enfin, pour la délivrance de facteurs ostéoinducteurs, nous avons élaboré des multicouches de polyélectrolytes (PEM) à base de poly (L-ornithine) et d'acide hyaluronique biocompatibles. Ces PEM ont été caractérisées en termes de croissance, de morphologie, d'aptitude à incorporer des protéines morphogénétiques osseuses (BMP) et à fonctionner en tant que revêtements sur des microporteurs à PLLA. Nos résultats préliminaires ont montré que l’incorporation de BMP dans les PEM avait un effet important sur l’adhérence des hASC. Bien que des études supplémentaires soient nécessaires, les microporteurs à PLLA recouverts de PEM chargés de BMP et ensemencés avec hASC pourraient être un implant synthétique prometteur pour une régénération osseuse améliorée. / The regeneration of critical-sized bone defects remains a major healthcare challenge. The limitations of common tissue grafts prompted us to develop a synthetic alternative based on a biomaterial construct, osteoinductive factors and stem cells. For biomaterial construct, we focused on porous polymeric microcarriers as they support large-scale cell expansion and modular tissue assembly, circumventing two important bottlenecks for clinical translation. To insure industrial supply and regulatory approval, we designed an organic-solvent-free method for their fabrication based on the spherulitic crystallization of poly(L-lactide) (PLLA) in its blends with polyethylene glycol (PEG). The PLLA spherulites were easily recovered as microcarriers by rinsing away the water-soluble PEG. Their size and porosity could be independently controlled by tuning the PLLA/PEG ratio and crystallization temperature. The biocompatibility and osteoconductivity of PLLA microcarriers were confirmed through the expansion and osteogenic differentiation of human adipose stem cells (hASCs). Because the latter hASC function is sensitive to different culture parameters, we then used the Design of Experiments approach for their rapid screening. In combination with high-throughput analysis, we identified several parameters that had a pronounced influence on their osteogenic differentiation. Finally, for the delivery of osteoinductive factors, we elaborated polyelectrolyte multilayers (PEM) based on biocompatible poly(L-ornithine) and hyaluronic acid. These PEMs were characterized in terms of their growth, morphology, the ability to incorporate bone morphogenetic proteins (BMP) and to function as coatings on PLLA microcarriers. Our preliminary results showed that the incorporation of BMPs inside PEMs had a strong effect on hASC adhesion. While further studies are needed, hASC-seeded PLLA microcarriers coated with BMP-loaded PEMs could be a promising synthetic implant for improved bone regeneration.

ABSTRACT SOLVENT-FREE MICROWAVE EXTRACTION AND MICROWAVEASSISTED HYDRODISTILLATION OF ESSENTIAL OILS FROM SPICES Bayramoglu, Beste M.S., Department of Food Engineering Supervisor: Assoc. Prof. Dr. Serpil Sahin Co-Supervisor: Assoc. Prof. Dr. S. G&uuml / l&uuml / m S&uuml / mn&uuml / September 2007, 130 pages The undesirable effects of conventional methods generated the need for economical and safe techniques in the extraction of essential oils. Microwave-assisted hydrodistillation (MAHD) and solvent-free microwave extraction (SFME) are recently developed techniques, which are thought to overcome this problem. Oregano (Origanum vulgare L.), laurel (Laurus nobilis L.) and rosemary (Rosmarinus officinalis L.) were chosen in this study since they have high antimicrobial and antioxidant effects and are widely grown and consumed in Turkey. The objectives of this study were to examine the applicability of SFME in the extraction of essential oils from oregano and laurel, and MAHD in the extraction of rosemary essential oil. The effects of microwave power and extraction time on the yield, composition, and other quality parameters of the extracts were also investigated. Hydrodistillation was performed as control. SFME offered significantly higher essential oil yields (0.054 mL oil/g oregano) from oregano as compared to hydrodistillation (0.048 mL oil/g oregano). Conventional process time was reduced by 80%. Main aroma compound was thymol (650-750 mg thymol/mL oil). For laurel, no significant differences were obtained in yields (about 0.022 mL oil/g laurel) obtained by SFME and hydrodistillation. Process time was reduced by 55-60%. Main aroma compound was 1,8-cineole (630-730 mg 1,8-cineole/mL oil). In the case of rosemary, no significant differences were obtained in yields (about 0.026 mL oil/g rosemary) obtained by MAHD at 622 W and hydrodistillation. The process time was reduced by about 65%. Main aroma compounds were 1,8-cineole (430-500 mg 1,8-cineole/mL oil) and camphor (150-210 mg camphor/mL oil). Keywords: Solvent-free microwave extraction (SFME), Microwave-assisted hydrodistillation (MAHD), Origanum vulgare L., Laurus nobilis L., Rosmarinus officinalis L.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The solvent-free microwave-assisted regiospecific synthesis of a series of 5-trihalomethyl-4,5-dihydro-1H-pyrazole (7 - 10) from the cyclocondensation of 1,1,1- trihalo-4-alkoxy-3-alken-2-ones (5 - 6),[ CX3COC(R)2=C(R)1OR, where X = Cl, F; R = Me, Et; R2 = H, Me and R1 = H, Me, Et, Pr, iso-Pr, Bu, iso-Bu, tert-Bu, iso - Pen, Ph, 4-Me-Ph, 4-MeO-Ph, 4-NO2-Ph, 4-Cl-Ph, 4-Br-Ph, 4-F-Ph, H, OEt,] with carboxymethyl hydrazine or pentafluorophenyl hydrazine is described. The reaction was performed in a 1:1.2 molar ratio of alken-2-ones and hydrazine, in a single reaction step, for 6-12 minutes, in good yields (70-98%). The advantages obtained by using microwave irradiation under solvent-free conditions, rather than a conventional method, were also demonstrated. The 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (4-5) were obtained from the reaction of cloreto de trichloroacetyl cloride or trifluoroacetic anhydride with enol ethers or acetals in presence of pyridine, solvent free and microwave induced techniques. / Este trabalho descreve a sintese rgeioespecifica de uma serie de 4,5-diidro-1Hpirazóis (7 - 10), por ciclocondensação de 4-alcóxi-1,1,1-trialo-3-alquen-2-onas, [ CX3COC(R)2=C(R)1OR, com X = Cl, F; R = Me, Et; R2 = H, Me; R1 = H, Me, Et, Pr, i-Pr, c-Pr, Bu, i-Bu, t-Bu, i-Pen, Pen, Ph, 4-Me-Ph, 4-MeO-Ph, 4-NO2-Ph, 4-Cl-Ph, 4-Br-Ph, 4-F-Ph, H, OEt] com carboximetil ou pentafluorfenil hidrazinas. As condições reacionais utilizadas para a síntese dos 4,5-diidropirazóis envolveu técnicas ambientalmente corretas, em um único passo e na ausência de solvente, usando 1:1.2 de relação molar das β-alcoxivinil cetonas e hidrazinas, em um único passo com um tempo de 6-12 minutos, com bons rendimentos (70-98%). Foram demonstradas as vantagens da condição, sem solvente e com uso de irradiação de microondas sobre o metodo convencional. A sintese das 4-alcóxi-1,1,1-trialo-3- alquen-2-onas (5 - 6) foram obtidas por reações de cloreto de tricloro acetila ou anidrido trifluoracetico com enoleteres ou acetais na presensa de piridina, livre de sonvente e tecnicas induzidas por microondas.

Le couplage covalent sur surface métallique en UHV (Ultra High Vacuum) est une technique émergente permettant de synthétiser des structures moléculaires impossibles à obtenir par la chimie en solution (nanorubans de graphène, polymères 2D par exemple). Aujourd'hui, le plus grand défi reste le développement de ces réactions sur des surfaces isolantes pour différentes applications comme, par exemple, l'électronique moléculaire. En particulier, le couplage de dérivés d'acides benzoïques, greffés sur les surfaces de carbonate de calcium en UHV par des groupes carboxyliques, a été démontré récemment pour la première fois. Lors de ces travaux, nous avons dans un premier temps synthétisé des molécules précurseurs de réactions de couplage (homo-couplage d'éthyne, photopolymérisation, polycondensation et réaction d'Ullmann) sur des surfaces de carbonate de calcium en UHV. Par la suite, nous avons mené cette étude à l'échelle macroscopique (semi-préparatoire), par greffage de molécules sur des microparticules de carbonate de calcium, puis activation de la réaction, et enfin dissolution du substrat afin d'extraire le produit final. Les microparticules ont été obtenues par broyage de produit commercial ainsi que par spray pyrolyse et complètement caractérisées par FTIR, ATG/DTG, DRX, MEB et BET. Les réactions de couplage ont été activées par deux méthodes sans solvant: par broyage dans une broyeuse planétaire ou par traitement thermique sous vide. Alors qu'en UHV le couplage de l'acide 4-iodobenzoïque donne l'acide biphenyldicarboxylique, en mécanochimie nous avons obtenu l'acide benzoïque et par activation thermique l'éther dibenzoïque. / Covalent coupling on metallic surfaces in UHV (Ultra High Vacuum) conditions is a new method for preparing molecular structures otherwise impossible to achieve in solution (graphene nanoribbons, 2D polymers for instance). The major challenge is now to extend these reactions from metallic to insulating surfaces, for future applications as, for instance, in molecular electronics. In particular, the coupling reaction of benzoic acid derivatives, grafted on calcite via carboxylic groups, has been demonstrated for the first time in UHV conditions. In the first part of this work, we synthesized precursor molecules for specific reactions (homocoupling of ethynes, photopolymerization, polycondensation and Ullmann reaction) on calcium carbonate in UHV conditions. In the second part of this work we extended this investigation up to the macroscale level (semi-preparative) by grafting molecules on calcium carbonate microparticles, followed by reaction activation and finally by dissolution of the substrate in order to recover the coupling products. The calcium carbonate microparticles were prepared by grinding commercial product or by spray pyrolysis and were fully characterized by FTIR, TG/DTG, XRD, SEM and BET techniques. Then, after grafting of organic reactant, the reactions were activated with two different solvent-free methods: by grinding in a planetary milling machine or by heating the samples in a furnace under vacuum. Whereas in UHV conditions, 4-iodobenzoic acid affords biphenyldicarboxylic acid, mechanochemical condition gives benzoic acid and thermal activation the dibenzoic acid ether.

No description available.