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Enantiomer Separation Through Biocatalysis Using NADES

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Enantiomer Separation Through Biocatalysis Using NADES Cristiana Sofia Ferreira de Sousa Licenciada em Química Aplicada Enantiomer separation through biocatalysis using NADES Dissertação para obtenção do Grau de Mestre em Biotecnologia Orientador: Dr. Alexandre Paiva, Investigador Pós-Doc, FCT UNL Co-orientador: Prof. Dr. Susana Barreiros, Professora Associada com agregação, FCT UNL Júri: Presidente: Prof. Carlos Salgueiro Arguente(s): Dra. Luísa Neves o Vogal(ais): Dr. Alexandre Paivato Setembro 2015 II Enantiomer separation through biocatalysis using NADES. Copyrights © belongs to Cristiana Sousa and Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa. The Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa has the perpetual and geographically unlimited wright of archiving and publishing this thesis through printed or digital copies, or by any other means known or to be invented, and to divulgate its contents through scientific repositories and of admitting its copy and distribution with educational, research, non- commercial goals, as long as its author and editor are properly credited. III IV Agradecimentos Primeiramente queria agradecer aos meus orientadores, a Professora Susana Barreiros e o Doutor Alexandre, por me terem aceite para realizar este trabalho e por todo o apoio que me foi dado ao longo do mesmo, com eles foi tudo muito mais fácil. Agradeço em especial ao Alexandre, o meu Darth Vader (eheh), que teve que lidar com todos os meus dramas laboratoriais quando nada dava bem e que “festejava” comigo quando finalmente apareciam resultados! Queria também agradecer ao Ângelo, do Instituto Superior Técnico que contribuiu para que este trabalho pudesse ter bons resultados e à Professora Paula Branco que se disponibilizou para me auxiliar no processo de síntese. Aos meus coleguinhas de laboratório, Bruno Pedras, João Nogueira, Sandra Abrantes, Francisca Mano, Rita Craveiro, Silvia Rebocho, José Pinto e todos os que por cá passaram e que de forma mais ou menos cientifica contribuíram para uma boa realização deste trabalho. Fica também um agradecimento aos amiguitos das pausas! Tiago Mestre, Lúcia Pinto, Telma Simões e Luísa Campelo pelos bons momentos passados nas horas livres! Deixo também um agradecimento aos meus amigos e namorado, que sempre me apoiaram nos bons e maus momentos ao longo deste ano, nem sempre foi fácil, mas eles estiveram sempre por perto para me apoiar e para me ajudarem no que fosse preciso. E por fim, mas não menos importante, à minha família, que desde o inicio sempre foi uma grande força e inspiração para alcançar este objetivo e ter força para continuar perante as dificuldades, a eles dedico todo este trabalho pois sem o apoio deles nada disto seria possível. V VI Abstract Currently, the separation process of racemic secondary alcohols has a great environmental impact because it involves the use of large amounts of organic solvents and energy. Based on the principles of green chemistry, the main purpose of this work is the development of a sustainable process, without the use of organic solvents and using reusable catalysts (enzymes) in order to make the most efficient separation process in terms of energy and reduce the associated environmental impact. In this work we developed a process for the separating of the enantiomers of (±)-menthol, via a transesterification reaction with vinyl decanoate. At optimum conditions, this reaction will yield the pure enantiomer (-)-menthyl decanoate, while (+)-menthol will remain unreacted. The use of reusable biological catalysts is possible due to the enantioselectivity of the enzyme, allowing the resolution of secondary alcohols to obtain pure enantiomers of high added value. Candida Rugosa lipase is a selective enzyme capable of selectively converting the (-)- menthol into a different chemical compound and with different characteristics the (+)-menthol. At the end of the reaction, the menthol enantiomers will be present in the reaction medium in the form of (+)-menthol and (-)-menthyl decanoate. As such it is necessary to use a method based on the properties of alternative solvents to physically separate the compounds. The main objective of this study is to evaluate deep eutectic solvents as solvents for the transesterification reaction, but also to experiment if whether they themselves are able to act as substrates. Another approach is to test whether they can also act as separating agents of (+)- menthol and menthyl decanoate. In the first phase it is intended to develop a DES using combinations of choline chloride, urea, and glycerol. The second objective is to synthesize DES based on menthol, containing one or both of the reaction substrates in the composition. The transesterification reaction is conducted in these solvents in order to assess whether the reaction is feasible in the presence of a biocatalyst. After the reaction, the enantiomers can be separated, since they are different entities. This separation is based on the interaction of the compounds with the DES, which allows the physical separation of the two compounds ((+)-menthol and (-)-menthyl decanoate). Through this work, we got the required proof of concept for all experiments performed in DES. Using hexane as reaction medium, a (±)-menthol conversion of 26.3 % was achieved, nevertheless controlling the water content in the reaction medium and in the atmosphere a maximum conversion of 50.9 % was achieved after 24 hours at 40°C. In DES ChCl:glycerol (1:2) and ChCl:urea (1:2) conversions are similar to those obtained in hexane at the same conditions, with values of 10.9 % and 10.2 % respectively. In DES menthol:camphor (4:1) was obtained 23% conversion at 40°C after 50 hours. In DES menthol:lauric acid (2:1) and menthol:phenylpropionic acid (1:1) conversions are higher with a maximum of 79.6 % and 62.1 % respectively. For the separation of compounds, DES choline dodecanediote:glycerol (1:1) was most effective with a separation factor of 16±6.5. Keywords: Candida rugosa lipase, enantioselectivity, racemic menthol, deep eutectic solvents, green solvents. VII VIII Resumo Atualmente, o processo de separação de álcoois secundários racémicos tem um grande impacto ambiental, uma vez que envolve o uso de grandes quantidades de solventes orgânicos e de energia. Com base nos princípios da química verde, o principal objetivo do presente trabalho consiste no desenvolvimento de um processo sustentável, sem a utilização de solventes orgânicos e utilizando catalisadores reutilizáveis (enzimas), a fim de tornar o processo de separação mais eficiente em termos de energia e reduzir o impacto ambiental associado. Neste trabalho foi desenvolvido um processo para a separação dos enantiómeros de (±)- mentol, por meio de uma reação de transesterificação com decanoato de vinilo. Em condições ótimas, esta reação dará o enantiómero puro (-)-decanoato de mentilo, enquanto o (+)-mentol não reage. A utilização de catalisadores biológicos reutilizáveis é possível devido à enantiosselectividade da enzima, permitindo a resolução de álcoois secundários para se obter enantiómeros puros de elevado valor acrescentado. Cândida rugosa lipase é uma enzima seletiva capaz de converter seletivamente o (-)- mentol, num composto químico diferente e com características diferentes do (+)-mentol. No final da reação, os enantiómeros de mentol estarão presentes no meio reacional sob a forma de (+)-mentol e (-)-decanoato de mentilo. Como tal, é necessário utilizar um método com base nas propriedades de solventes alternativos para separar fisicamente os compostos. O principal objetivo deste estudo é avaliar solventes eutécticos como solventes para a reação de transesterificação, mas também para experimentar se se eles próprios são capazes de agir como substratos. Outra abordagem é para testar se eles também podem agir como agentes separação do (+)-mentol e do (-)-decanoato de mentilo. Na primeira fase pretende-se desenvolver um DES usando combinações de cloreto de colina, ureia, e glicerol. O segundo objetivo é sintetizar DES baseados em mentol, contendo um ou ambos os substratos de reação na sua composição. A reação de transesterificação é conduzida nestes solventes, a fim de avaliar se a reação é possível na presença de um biocatalisador. Após a reação, os enantiómeros podem ser separados, uma vez que são entidades diferentes. Esta separação é baseada na interação dos compostos com o DES, que permite a separação física dos dois compostos ((+)-mentol e (-)-mentil decanoato). Através deste trabalho, temos a prova de conceito para todas as experiências realizadas em DES. Utilizando hexano como meio reacional, uma conversão de (±)-mentol de 26.3% foi conseguida, no entanto, controlando o teor de água no meio reacional e na atmosfera, um máximo de conversão de 50.9% foi atingida após 24 horas a 40°C. Em DES ChCl:glicerol (1:2) e ChCl:ureia (1:2) os valores de conversão são semelhantes aos obtidos em hexano com as mesmas condições, com os valores de 10.9% e 10.2%, respetivamente. Em DES mentol:cânfora (4:1) obteve-se a conversão de 23% a 40°C depois de 50 horas. Em DES mentol:ácido láurico (2:1) e mentol:ácido fenilpropiónico (1:1) obtiveram-se conversões elevadas com um máximo de 79,6% e 62,1% respetivamente. Para a separação de compostos, o DES dodecanediote de colina:glicerol (1:1) foi o mais eficaz com um fator de separação de 16±6.5. Palavras-chave: Cândida rugosa lipase, enantiosselectividade, mentol racémico, solventes eutécticos, solventes verdes. IX X Contents I. Introduction .........................................................................................................................
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