Exploring the generation and use of acylketenes with continuous flow processes

The generation and use of reactive intermediates is well suited to continuous flow processing owing to the ability to scale up reactions, contain hazards and heat solvents past their atmospheric temperature boiling points. Herein we explore the chemistry of acylketenes, generated from commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD, 10) under continuous flow conditions. The developed flow chemistry system is capable of permitting a wide range of applications of these acylketene intermediates, including access to equilibrating processes that result in ketone exchange. Some of the dioxinone products resulting from this study are destabilised towards acylketene generation, this is demonstrated through their ability to generate acylketene at lower reaction temperatures

Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin.

An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (15) (20.9 g prepared over 3 hours), with a productivity of 7 g.h-1. An asymmetric Brown allylation protocol was also evaluated under continuous flow conditions. This approach employing (–)-Ipc2B(allyl) provided (S)-goniothalamin intermediate in 98% yield and 91.5% enantiomeric excess (ee) with a productivity of 1.8 g.h-1. For the final step, a ring-closing metathesis reaction was investigated under a variety of conditions in both batch and flow regimes. In a batch operation, Grubbs second-generation catalyst proved to be efficient and highly selective for the desired ring closure product over those arising from other modes of reactivity, and the reaction was complete in 1.5 h. In a flow operation, reactivity and selectivity was attenuated relative to batch mode, however after further optimisation, residence time could be reduced to 16 minutes with good selectivity and good yield of the desired product. A tube-in-tube reactor was investigated for in-situ ethylene removal to favor ring-closing over cross-metathesis, in this context. These results provide further evidence of the utility of flow chemistry for organometallic processing and reaction telescoping. Using the developed integrated batch and flow methods, a total of 7.75 g of goniothalamin (1) was synthesized

Continuous flow processing as a tool for the generation of terpene-derived monomer libraries

We report the development of a continuous flow approach for the preparation of two bio-derived monomer libraries. A small range of terpenes (ocimene, myrcene, α-terpinene, α-phellandrene, isoprene, and farnesene) have been used as the base set for the library, with the first library derived from a Diels–Alder reaction with the platform chemical maleic anhydride. The second library requires the derivatization of the first through a hydrogenation reaction. The potential for scale-up of both libraries has been demonstrated, with the Diels–Alder process delivering 10.5 grams of the product in 3 hours and the hydrogenation process delivering 10 grams of the material in 16 hours

Petroleomics by ion mobility mass spectrometry: resolution and characterization of contaminants and additives in crude oils and petrofuels

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Ion mobility-mass spectrometry (IM-MS), performed with exceptional resolution and sensitivity in a new uniform-field drift tube ion mobility quadrupole time-of-flight (IM-QTOF) instrument, is shown to provide a useful tool for resolving and characterizing crude oils and their contaminants, as well as petrofuels and their additives. Whereas direct analysis of a crude oil sample contaminated with demulsifiers by the classical ESI(+/-)-FTICR-MS petroleomic approach was unsatisfactory since it responds only with abundance and m/z, and ionization is impaired due to suppression of polar compounds of crude oil by additives likely used in petroleum industry, IM-MS enables mobility separation of ions, particularly of double bond equivalent (DBE) series for a giving CnX class providing separated spectra which are typical obtained either for the crude oil or the contaminants, even suffering of ion suppression or low ionization efficiency. The combination of improved IM resolution and high mass resolving power (40,000@400) of the QTOF instrument provides useful information on class (N, NO, NS, etc.), carbon number (C-n), and unsaturation (DBE) levels for crude oils, allowing one to infer geochemical properties from DBE trends that can be compared with IM-MS data. As demonstrated by results of gasoline samples with additives, the IM-MS system also allows efficient separation and characterization of additives and contaminants in petrofuels.Ion mobility-mass spectrometry (IM-MS), performed with exceptional resolution and sensitivity in a new uniform-field drift tube ion mobility quadrupole time-of-flight (IM-QTOF) instrument, is shown to provide a useful tool for resolving and characterizing71144504463FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2013/19161-4]2013/19161-4sem informaçãosem informaçãoWe would like to thank the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) for the scholarship awarded to J.M.S. (process number 2013/19161-4), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Des

s-Hillman reaction (aza, classic and asymmetric) by mass spectrometry

Orientadores: Marcos Nogueira Eberlin, Fernando Antonio Santos CoelhoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: Essa dissertação de Mestrado visa estudar o mecanismo da reação de Morita-Baylis-Hillman (MBH) em três versões (Clássica, Aza e Assimétrica) utilizando a técnica de espectrometria de massas com ionização por eletrospray (ESI-MS). Para o monitoramento mecanístico das versões clássica e Aza (MBH/Aza-MBH) foi introduzida uma nova abordagem, que é a utilização de reagentes marcados com etiquetas de carga (líquidos iônicos), a fim de facilitar a detecção dos intermediários e maximizar a aquisição de dados obtidos pelo monitoramento destas reações. Entre os reagentes de partida, (eletrófilo, catalisador e alceno ativado) o alceno ativado foi o reagente marcado, utilizou-se o íon metil imidazólio como etiqueta de carga. Além do uso de um reagente marcado, ambas as versões foram monitoradas utilizando reagentes neutros, com o propósito de avaliar em nível de comparação as metodologias abordadas, marcada e não-marcada. Para versão assimétrica da reação de MBH, foram utilizadas duas aminas hidroxiladas quirais derivadas de alcalóides cinchona, quinidina e ?-isocupreidina. O monitoramento mecanístico da versão assimétrica foi realizado utilizando um espectrômetro de massas com mobilidade iônica IM-MS. O tipo de mobilidade utilizada nesse estudo foi a Traveling Wave, comercialmente conhecida como TWIM-MS (Traveling Wave Ion Mobility Mass Spectrometry). A utilização desta possibilitou a separação e caracterização de intermediários estereoisoméricos formados no percurso da reação. Cálculos teóricos dos estados de transição para formação desses intermediários foram realizados a fim de suportar os dados obtidos por TWIM-MS. A utilização de um reagente marcado no monitoramento completo da reação de MBH/Aza-MBH mostrou melhores resultados em relação à reação não-marcada. Intermediários não detectados pela metodologia não-marcada foram detectados e caracterizados pela metodologia marcada, além do fato que a intensidade desses intermediários foi maior quando comparado à versão não-marcada. Para versão assimétrica, os dados obtidos por TWIM-MS e cálculos teóricos possibilitaram um melhor entendimento acerca da enantiosseletividade da reação de MBH quando diferentes catalisadores quirais são utilizadosAbstract: This dissertation aims to study the mechanism of the Morita-Baylis-Hillman reaction in three versions (Classical, Aza and Asymmetric) using Electrospray Ionization Mass Spectrometry (ESI-MS). For the mechanistic monitoring of the classical and Aza versions (MBH/Aza-MBH) a new approach was introduced, that is the use of marked reagents with charge tag (ionic liquid) in order to facilitate the detection of the reaction intermediates and maximize the data acquisition when monitoring these reactions. Among the start material, (electrophile, catalyst and activated alkene) the activated alkene was the marked reagent, using imidazolium ion as charge tag. Besides the use of a marked reagent, both versions (MBH/Aza-MBH) were monitored using neutral reagents, in order to compare the methodologies used, with and without charge tag. For the asymmetric MBH reaction, were used two hidroxylated chiral amines derived from cinchona alkaloids, quinidine and ?-isocupreidine. The mechanistic monitoring of the asymmetric reaction was performed using an ion mobility mass spectrometry IM-MS. The type of mobility used in this study was "traveling wave", commercially known as TWIM-MS (Traveling Wave Ion Mobility Mass Spectrometry). Using this instrument was possible to separate and characterize stereoisomerics intermediates formed in the course of the reaction. Theoretical calculations of the transition states for the formation of these intermediates were performed in order to support the data obtained by TWIM-MS. The use of a marked reagent in complete monitoring of the MBH/Aza-MBH reaction showed better results than non-tag reaction. Intermediates not detected by the non-tag methodology were detected and characterized by the charge tag methodology, furthermore, the intensity of these intermediates were higher than non-tag reaction. For the asymmetric version, the data obtained by TWIM-MS and theoretical calculations enabled a better understanding of the enantioselectivity of the MBH reaction when different chiral catalysts are usedMestradoQuimica OrganicaMestre em Químic

Exploring the benefits of continuous flow chemistry in the synthesis of compounds from biomass and ketene chemistry

Orientador: Julio Cezar PastreTese (doutorado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: Esta tese de doutorado teve por objetivo geral avaliar a síntese de compostos com alto valor agregado a partir de biomassa sob condições de fluxo contínuo. Dentre os trabalhos explorados, foi avaliado a síntese de 5-(Hidroximetil)furfural (5-HMF) a partir da D-frutose em condições de batelada (71%) quanto em fluxo contínuo (95%). Destaca-se que ambos os processos foram avaliados pela ferramenta planejamento de experimentos (DoE). Para o processo contínuo, foi avaliado o monitoramento online do sistema reacional usando uma cela de infravermelho (FT-IR) própria para este tipo de sistema. Nesta mesma linha, foi demonstrado em um segundo estudo o acoplamento entre o equipamento de fluxo contínuo e uma técnica analítica ultracompacta e de baixo custo (microNIR, $2,500) para o monitoramento online de reações orgânicas. Para este propósito, uma reação bem estabelecida em nosso grupo de pesquisa (formação de 5-HMF) foi utilizada como exemplo. Além disso, estudou-se a aplicação de 5-HMF para a síntese de uma resina 100$ 2,500) for the online monitoring of an organic transformation. For this purpose, a well-established reaction in our research group (5-HMF synthesis) was used in this application and demonstrated the robustness/reproducibility of the flow-microNIR coupled system. In another study, it was also demonstrated an application using 5-HMF as starting material for the synthesis of a green resin (derived from biomass), in which it can be used as a heterogeneous acid catalyst for organic reactions. Continuing our interest in the field of biomass valorization, two libraries of terpene-based monomers were synthesized in flow and such monomers were used for the production of green polyesters and polyamides. During the Ph.D., the student had an accepted scholarship in the CNPq program called Sandwich Doctorate Abroad (SWE). In that way, Cardiff University (UK) was chosen as abroad university and the student worked for 10 months under the supervision of Prof. Dr. Duncan L. Browne. During this period, the student was involved with the generation and application of reactive acylketene species for the synthesis of dioxinones, 1,3-dicarbonyl compounds, oxazine-diones, and coumarins in the continuous flow process. In view of the foregoing, in general, this Ph.D. thesis focus on three major aspects of chemistry, which are; Green Chemistry, Continuous Flow Chemistry, and Biomass ValorisationDoutoradoQuimica OrganicaDoutor em Ciência

Charge Tags For Most Comprehensive Esi-ms Monitoring Of Morita-baylis-hillman (mbh)/aza-mbh Reactions: Solid Mechanistic View And The Dualistic Role Of The Charge Tagged Acrylate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Neutral and charge tagged reagents were used to investigate the mechanism of the classical Morita-Baylis-Hillman (MBH) reaction as well as its aza-version using mass spectrometry with electrospray ionization (ESI-MS). The use of an acrylate (activated alkene) with a methylimidazolium ion as a charge tag eliminates the requirement for adding acids as ESI(+) additives, which are normally used to favor protonation and therefore detection of reaction partners (reagents, intermediates, and products) by ESI(+)-MS. For both charge tagged reactions (MBH/aza-MBH), most reactants, intermediates, and the final adducts were efficiently detected in the form of abundant doubly and singly charged ions. Characterization of the reactions partners was performed-via both tandem mass spectrometry (ESI(+)-MS/MS) and accurate m/z measurements. The charge tagged reactions also showed faster conversion rates when compare to the neutral reaction, indicating a dualistic role for the charge tagged acrylate. It acts as both the reagent and a cocatalyst due to the inherent ionic-coordination nature of the methylimidazolium ion, which stabilizes the zwitterionic intermediates and reagents through different types of coordination ion pairs. Hemiacetal intermediates for the rate-limiting proton transfer step were also intercepted and characterized for both classical and aza-MBH charge tagged reactions.81310891098Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Fapesp) [2013/10449-5, 2012/10701-3]CNPqFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Conversion of d‑Fructose to 5‑(Hydroxymethyl)furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-Line FTIR Monitoring

The dehydration reaction of d-(−)-fructose into 5-(hydroxymethyl)­furfural (HMF) in both batch and continuous flow conditions was comprehensively studied using the statistical tool design of experiments (DoE), employing <i>i</i>-PrOH/DMSO as the solvent system in the presence of the solid acid catalyst Amberlyst-15. Initially, screening of different alcohols (MeOH, EtOH, <i>i</i>-PrOH, and <i>t</i>-BuOH) showed that <i>i</i>-PrOH provides better selectivity and yield compared to the other alcohols, along with minimum formation of byproducts when associated with small amounts of DMSO (15% v/v) as a cosolvent. To confirm the selectivity of the reaction, all of the possible byproducts (HMF-ethers and/or ketals) formed during the reaction between HMF and <i>i</i>-PrOH were synthesized. Factors like temperature, amount of DMSO, time (flow rate), and catalyst loading were evaluated by a full factorial design, and the results indicated that temperature presents the greatest influence in both batch (HMF in 71% yield) and continuous flow regime (HMF in 95% yield). In addition, a FTIR device was coupled to the continuous flow micro reactor, allowing for the first time constant in-line monitoring for this transformation, thereby showing the long-term stability of Amberlyst-15 and process robustness

Continuous flow processing as a tool for the generation of terpene-derived monomer libraries

We report the development of a continuous flow approach for the preparation of two bio-derived monomer libraries. A small range of terpenes (ocimene, myrcene, -terpinene, -phellandrene, isoprene, and farnesene) have been used as the base set for the library, with the first library derived from a Diels-Alder reaction with the platform chemical maleic anhydride. The second library requires the derivatization of the first through a hydrogenation reaction. The potential for scale-up of both libraries has been demonstrated, with the Diels-Alder process delivering 10.5 grams of the product in 3 hours and the hydrogenation process delivering 10 grams of the material in 16 hours42362367CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP386452/2014-42014/26378-2, 2014/25770-