When designing novel materials for organic photovoltaic (OPV) applications, it is important to consider the significance of structural design on both the chemical and physical properties of the resulting material. The designed targets should promote efficient charge transport along a planar backbone, be solution processable and ideally, both the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) should be able to be easily tuned via synthetic modifications. Using a concise synthetic route, a variety of novel semiconducting polymers and small molecules based on 2,6-di(aryl)benzo[1,2-b:4,5-b']difuran (BDF), an electron donating unit, have been developed and characterized. This benzodifuran moiety is of particular interest in this work as it is able to be synthesized in concise, high yielding steps and the core structure has the potential to be readily modified. Chapters Two through Four will demonstrate the power of fine-tuning this molecular species and how a facile synthetic route lends itself to the application specific design and development of BDF polymers and small molecules. The field of organic electronics primarily focusses on polymers and small molecules; however, each of these categories of materials have intrinsic drawbacks. Polymers are generally difficult to solubilize and the batch-to-batch consistency (involving parameters such as molecular weight and material uniformity) is almost impossible to control. Small molecules, while being very uniform and having a defined molecular structure, are difficult to deposit as uniform device films since they are typically not solution processed and are, instead, thermally evaporated onto a substrate. As a result of these key issues, a material of intermediate size and length, namely oligomers, which combine the benefits of small molecules and polymers is highly desired. Towards the realization of this goal, the Chapter Five of this work will share various flow reactor designs specifically geared towards modified flow platforms that allow for the synthesis of oligomeric materials. / 2022-02-08T00:00:00Z

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A intensificação de processos é importante na busca de equipamentos e reações menos nocivos e seguros, um exemplo é a aplicação de microrreatores. A indústria farmacêutica é a maior beneficiária dessa tecnologia, pois os microrreatores, dispositivos com microcanais de até 100 µm, podem reduzir em anos o tempo necessário para desenvolver e produzir um novo fármaco e podem ser montados em unidades industriais extremamente pequenas e compactas. O aumento de casos de diabetes no Brasil na última década vem incentivando a busca por novos fármacos. Neste trabalho, a aplicação de microrreatores capilares é estudada na síntese do (Z)-5-(4-hidroxi-3-metoxibenzilideno)2,4-tiazolidinadiona (HMTZD) e do (Z)-5-(3-hidroxi-4-metoxibenzilideno)2,4-tiazolidinadiona (MHTZD), obtidos da reação de 2,4-tiazolidinediona (TZD) com 4-hidroxi-3-metoxibenzaldeído (Vanilina) e com seu isômero, 3-hidroxi-4-metoxibenzaldeído (Isovanilina), que podem ser utilizados na síntese de moléculas com atividade biológica. Foram obtidos rendimentos máximos do produto HMTZD, 98% em 480 min de reação e do produto MHTZD, 73% em 120 min de reação, contrariando a literatura que apresenta um tempo de reação para essa síntese de 20 h a 40 h. Na síntese em fluxo no microrreator, ficou evidente que quanto maior a temperatura maior a conversão de TZD e o rendimento do produto, chegando a valores de 100%, para a temperatura de 160°C em etanol. A produção no processo batelada e no microrreator foram calculadas e, quando comparadas, mostraram que apenas dois microrreatores de 1 mL em sua melhor condição de operação são capazes de produzir três vezes mais que um reator batelada de 60 mL. Pelo estudo de cinética, a reação utilizando etanol não favorece a formação de reações em paralelo ou em série. As análises qualitativas comprovaram que os produtos esperados foram formados e com alto grau de pureza. / The process intensification is important in the search for less harmful and safe equipment and reactions, an example is the application of microreactors. The pharmaceutical industry is the largest beneficiary of this technology because microreactors, devices with microchannels up to 100 µm, can reduce the time required to develop and produce a new drug in years and can be mounted in extremely small and compact industrial units. The increase in diabetes cases in Brazil in the last decade has been encouraging the search for new drugs. In this work, the application of capillary microreactors is studied in the synthesis of (Z)-5-(4-hydroxy-3-methoxybenzylidene)2,4-thiazolidinedione (HMTZD) and (Z)-5-(3-hydroxy-4- methoxybenzylidene)2,4-thiazolidinedione (MHTZD), obtained from the reaction of 2,4-thiazolidinedione (TZD) with 4-hydroxy-3-methoxybenzaldehyde (Vanillin) and its isomer, 3-hydroxy-4-methoxybenzaldehyde (Isovanillin), which can be used in the synthesis of molecules with biological activity. Maximum yields of 98% in 480 min, for the product HMTZD, and 73% in 120 min, for the product MHTZD, were obtained, contradicting literature that shows a reaction time for this synthesis of 20 h to 40 h. In the flow synthesis in the microreactor, it was evident that the higher the temperature the higher the conversion of TZD and the yield of the product, reaching 100%, in ethanol working with the temperature of 160°C. The production in the batch process and the microreactor were calculated and, when compared, showed that only two 1 mL microreactors in their best operating condition are able to produce three times more than a 60 mL batch reactor. By the study of kinetics, the reaction using ethanol does not favor the formation of reactions in parallel or in series. The qualitative analyzes showed that the expected products was formed and with a high degree of purity.

Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

A intensificação de processos é importante na busca de equipamentos e reações menos nocivos e seguros, um exemplo é a aplicação de microrreatores. A indústria farmacêutica é a maior beneficiária dessa tecnologia, pois os microrreatores, dispositivos com microcanais de até 100 µm, podem reduzir em anos o tempo necessário para desenvolver e produzir um novo fármaco e podem ser montados em unidades industriais extremamente pequenas e compactas. O aumento de casos de diabetes no Brasil na última década vem incentivando a busca por novos fármacos. Neste trabalho, a aplicação de microrreatores capilares é estudada na síntese do (Z)-5-(4-hidroxi-3-metoxibenzilideno)2,4-tiazolidinadiona (HMTZD) e do (Z)-5-(3-hidroxi-4-metoxibenzilideno)2,4-tiazolidinadiona (MHTZD), obtidos da reação de 2,4-tiazolidinediona (TZD) com 4-hidroxi-3-metoxibenzaldeído (Vanilina) e com seu isômero, 3-hidroxi-4-metoxibenzaldeído (Isovanilina), que podem ser utilizados na síntese de moléculas com atividade biológica. Foram obtidos rendimentos máximos do produto HMTZD, 98% em 480 min de reação e do produto MHTZD, 73% em 120 min de reação, contrariando a literatura que apresenta um tempo de reação para essa síntese de 20 h a 40 h. Na síntese em fluxo no microrreator, ficou evidente que quanto maior a temperatura maior a conversão de TZD e o rendimento do produto, chegando a valores de 100%, para a temperatura de 160°C em etanol. A produção no processo batelada e no microrreator foram calculadas e, quando comparadas, mostraram que apenas dois microrreatores de 1 mL em sua melhor condição de operação são capazes de produzir três vezes mais que um reator batelada de 60 mL. Pelo estudo de cinética, a reação utilizando etanol não favorece a formação de reações em paralelo ou em série. As análises qualitativas comprovaram que os produtos esperados foram formados e com alto grau de pureza. / The process intensification is important in the search for less harmful and safe equipment and reactions, an example is the application of microreactors. The pharmaceutical industry is the largest beneficiary of this technology because microreactors, devices with microchannels up to 100 µm, can reduce the time required to develop and produce a new drug in years and can be mounted in extremely small and compact industrial units. The increase in diabetes cases in Brazil in the last decade has been encouraging the search for new drugs. In this work, the application of capillary microreactors is studied in the synthesis of (Z)-5-(4-hydroxy-3-methoxybenzylidene)2,4-thiazolidinedione (HMTZD) and (Z)-5-(3-hydroxy-4- methoxybenzylidene)2,4-thiazolidinedione (MHTZD), obtained from the reaction of 2,4-thiazolidinedione (TZD) with 4-hydroxy-3-methoxybenzaldehyde (Vanillin) and its isomer, 3-hydroxy-4-methoxybenzaldehyde (Isovanillin), which can be used in the synthesis of molecules with biological activity. Maximum yields of 98% in 480 min, for the product HMTZD, and 73% in 120 min, for the product MHTZD, were obtained, contradicting literature that shows a reaction time for this synthesis of 20 h to 40 h. In the flow synthesis in the microreactor, it was evident that the higher the temperature the higher the conversion of TZD and the yield of the product, reaching 100%, in ethanol working with the temperature of 160°C. The production in the batch process and the microreactor were calculated and, when compared, showed that only two 1 mL microreactors in their best operating condition are able to produce three times more than a 60 mL batch reactor. By the study of kinetics, the reaction using ethanol does not favor the formation of reactions in parallel or in series. The qualitative analyzes showed that the expected products was formed and with a high degree of purity.

Dans ce manuscrit sont décrites de nouvelles procédures pour la synthèse stéréosélective d’un composé d’intérêt pharmacologique ainsi que leurs implémentations pour la production en continu. Plusieurs procédures de modification de catalyseurs hétérogènes commerciaux ont été développées et ont permis d’augmenter significativement la diastéréosélectivité de la réaction d’hydrogénation d’un intermédiaire de synthèse. Une voie de synthèse alternative par dérivatisation a également été développée, permettant d’atteindre une diastéréosélectivité pus élevée. De plus, des réacteurs modulaires dédiés à la réalisation de réactions triphasiques gas/liquide/solide sous haute pression ont été conçus. Un prototype a été fabriqué et a pu être utilisé pour les procédures d’hydrogénation développées. Enfin, un intermédiaire de synthèse a été préparé sans solvant ni additifs et avec une grande productivité en utilisant un microréacteur. / In this thesis, we present new procedures for the highly stereoselective synthesis of an active pharmaceutical ingredient and initiate their implementation in continuous flow for production. We developed several procedures for the highly diastereoselective hydrogenation reactions using chemically modified commercial heterogeneous catalysts. In addition, a three step reaction pathway through hydrolysis, highly diastereoselective hydrogenation reaction and conversion back to primary amide was developed to prepare. Modular high pressure continuous reactors have been designed and a prototype has been manufactured to perform the gas/liquid/solid triphasic hydrogenation reactions. Finally, we prepared a synthesis intermediate without solvents nor additives in continuous flow using a home-made micro-reactor, dramatically increasing the productivity of the process.

Success of newly discovered chemistry in academia is often scored in terms of its novelty and level of scholarship. In industrial settings, cost, safety and quality are often times the ruler by which new processes are measured. Our group has identified that there is a gap between these two measures of success and has sought to develop principles in order formalize an approach to synthetic strategy and developing ready-to-implement manufacturing processes for molecules, simple and complex. Some of these principles include (1) the development and application of new chemical methods and reactor technologies (2) recognition of globally amenable chemical environments for each chemical step to consolidate unit operations and obviate the need for purification (3) vertical integration of starting materials to generate complexity from the most elementary building blocks in a chemical supply space and (4) the development of new materials that allow for recovery and reuse. These principles are iteratively scored and redeveloped through various metrics that our group has identified as effective tools in maximizing efficiency such as cost of goods (CoG), process mass intensity (PMI) and volume-time output (VTO). The intended benefits of this approach is that these processes become not only cost effective but sustainable and impactful in the manufacturing landscape and increase access of these products to consumers.

In recent years, the exploitation of flow technologies as an enabling tool to access unique chemical reactivity has flourished. This dissertation describes the utilisation of these flow methods to access new sets of highly versatile, unstable diazo compounds and their application in coupling reactions. In the first chapter, an introduction into the structure and reactivity of diazo compounds is provided, as well as a discussion of currently available methods for their generation. The second chapter describes the coupling of flow-generated, semi-stabilised diazo compounds with terminal alkynes for the synthesis of racemic di- and trisubstituted allenes, using copper(I) catalysis. The third chapter follows with an account of creating chiral disubstituted allenes by asymmetric coupling of flow-generated, semi-stabilised aryl aldehyde-derived diazo compounds with terminal alkynes, using a copper(I) catalyst and a newly developed pyridine(bisimidazoline) ligand. The fourth chapter describes the generation of new, highly reactive non-stabilised diazo compounds and their reaction with arylboronic acids to allow metal-free ‘protodeboronative’ and ‘oxidative’ C(sp2)-C(sp3) cross-couplings. Finally, the fifth chapter describes the experimental procedures relevant for the results described in Chapters 2-4.

The last 15 years have seen tremendous advances in using different metal catalysts to functionalize traditionally unreactive C–H bonds. Given the high potential of these seemingly ideal strategic bond forming reactions, the uptake of C–H activation in fine chemical manufacture is slow. Part of the reason for this deficiency is limited mechanistic understanding of these complex reactions. This can preclude industrial applications of either batch or continuous C–H activation processes. Owing to the synthetic utility of C–H activation reactions, it is highly desirable to design intensified processes for this family of transformations, what can possibly facilitate industrialisation of C–H activation reactions. Firstly, an ab initio process design of a novel C(sp3)–H activation reaction giving access to aziridines yielded a predictive mechanistic model that has been used in an in silico optimisation. The identified set of conditions was suitable for a scalable continuous process. A separation technique was developed, and the utility of the process was extended by a subsequent reaction, a nucleophilic ring opening. Secondly, a black-box optimisation of the investigated reaction was performed. The applied algorithm was able to identify a set of conditions fulfilling the set targets within few experimental trails. The second project has set out to design a process for a C–H oxidative carbonylation. A kinetic study has shown that the reaction is CO-starved even at elevated pressures and that there is an optimal CO concentration. The turn-over number was increased from 8 to nearly 500. Two scalable processes were then developed. The first was a batch process, characterised by a very low catalyst loading. The second was, to the best of author’s knowledge, the first continuous process for an oxidative carbonylation reaction. The continuous process was tested on several oxidative carbonylations yielding excellent results with virtually no optimisation performed. Finally, an environmental sustainability assessment was performed using both, simplified metrics and an LCI analysis. The developed mechanistic understanding allowed identification of sources of inherent inefficiencies of C–H activation reactions. Appropriate solutions to these obstacles were suggested. Thus, it is believed that a step towards generic principles of design of intensified, scalable processes for C–H activation-type reactions has been made.

Submitted by Livia Mello (liviacmello@yahoo.com.br) on 2016-10-05T19:33:10Z No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:34Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:39Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Made available in DSpace on 2016-10-20T18:49:47Z (GMT). No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) Previous issue date: 2014-11-28 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / The derivatization of organocatalysts with functional appendages suitable to anchor onto solid supports is usually achieved by stepwise syntheses. As an alternative to such a strategy, this work describes a one-pot approach to silylated prolyl-peptide catalysts by a multicomponent reaction that enables the simultaneous incorporation of the catalytic and the heterogenizable (triethoxysilane) moieties. A microreactor with high catalytic efficacy and reproducibly in the conjugate addition of aldehydes to nitroolefins was obtained by grafting onto HPLC-grade silica (10 μm) and packing into a column with a selected catalyst. A 3 D continuous-flow system that includes the on-line monitoring of the reaction outcome was set up. For that, the microreactor was coupled to a chromatographic column for the separation of the remaining substrates from the Michael adduct in the second dimension, followed by a chiral polysaccharide column for the analysis of conversion and stereoselectivity. This approach represents a new instrumental setup that combines the advantages of multidimensional chromatography and flow catalysis. / A derivação de Organocatalisadores com apêndices funcionais adequados para ancorar em suportes sólidos é geralmente obtida por síntese “passo a passo”. Como uma alternativa para tal estratégia, este trabalho descreve uma abordagem de síntese one-pot de catalisadores prolil-peptio sililados através de uma reação multicomponentes, que permite a incorporação simultânea do sítio catalítico e o grupo funcional de ancoragem (trietoxisilano). Um micro-reactor foi obtido, tendo elevada eficácia catalítica e reprodutibilidade, na adição conjugada de aldeídos a nitro-olefinas, enxertando sobre sílica de grau HPLC (10 um) e preenchendo uma coluna com um catalisador escolhido. Um sistema de fluxo contínuo 3D que inclui a monitoração em linha do resultado da reação foi ajustado para cima. Para isso, o micro-reator foi acoplado a uma coluna cromatográfica para a separação dos substratos restantes do aduto de Michael na segunda dimensão, seguido por uma coluna de polissacarídeo quiral para a análise de conversão e estereosselectividade. Essa abordagem representa uma nova configuração do instrumento que combina as vantagens de cromatografia multidimensional e reações catálisadas em fluxo.