New synthetic methodologies from biorenewable resources

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2014In this thesis will be presented new synthetic methodologies for the production of 5- (hydroxymethyl) furfural (HMF) and its derivatives as one important biorenewable platform molecules available via dehydration from sugars. The new approaches aim to overcome the major difficulties related with HMF synthesis and isolation on industrial and laboratory scale and to study the synthesis and possible toxic effects in humans of important HMF derivatives which could be produced on industrial scale in the near future as a replacement of existing fossil based chemical building blocks. Scalable protocol for the isolation of HMF via simple precipitation was developed together with chemo-enzymatic, and heterogeneous chromium catalyzed methodologies for its synthesis from glucose. Biorefinery and biorenewable resources are certainly topics of interest from educational point. Batch and flow student laboratory experiments for the dehydration of fructose to HMF have been optimized to meet this purpose. The synthesis, physical properties, toxicity and some unconventional applications of specific a class Ionic Liquids namely Magnetic ionic Liquids (MIL) were also studied in collaboration with other laboratories. The environmental friendly solvents are certainly an important part of developing more “green” and sustainable chemistry methodologies. The stability, basicity and their effect on the organic transformations performed in relatively newly discovered and based mostly on biorenewable resources ionic fluids namely deep eutectic solvents (DES) were studied. It was discovered that one of the most commonly used urea based DES undergo urea decomposition at unexpectedly low temperatures to form ammonia which was assign as responsible for their observed basicity. The readily available from Lupinus genus alkaloid Lupanine was employed as a platform molecule for the synthesis of new sparteine derivatives. Lupanine is a structural analog of sparteine, bearing amide functionality, which was subjected to various transformations resulting in sparteine analogs with potential biological activity and application in asymmetric catalysis.Nesta tese são apresentadas novas metodologias sintéticas para a produção de 5- (hidroximetil)furfural (HMF) e derivados como um dos mais importantes produtos provenientes de fontes bio-renováveis via desidratação de açucares. Estas novas abordagens têm como objectivo contornar as extremas dificuldades relacionadas com a síntese do HMF e isolamento a escala industrial e laboratorial. Adicionalmente, efectuou-se a síntese de derivados do HMF, que poderão substituir compostos baseados em combustíveis fosseis existentes, e estudo de possíveis efeitos tóxicos em humanos. Desenvolveu-se um protocolo com potencial aplicação à escala industrial para o isolamento do HMF através de uma simples precipitação e combinada com metodologias catalíticas quimioenzimáticas e catálise heterogénea com crómio, a partir da glucose. Do ponto de vista educacional, recursos bio-renovaveis e biorefinaria são certamente tópicos de interesse. Consequentemente, optimizaram-se experiências laboratoriais em lote e em contínuo para a desidratação da frutose para produzir HMF, vocacionada para o ambiente de ensino. A síntese, propriedades físicas, toxicologia e algumas aplicações não convencionais de uma classe específica de Líquidos Iónicos, nomeadamente Líquidos Iónicos Magnéticos (MIL) também foram estudadas através de colaborações. Outro tópico de interesse foi o desenvolvimento de solventes mais verdes e amigos do ambiente para o desenvolvimento de metodologias mais sustentáveis do ponto de vista ambiental. Foram ainda estudadas a estabilidade, basicidade e o efeito em transformações orgânicas de fluidos iónicos baseados principalmente em recursos bio-renováveis, nomeadamente misturas eutécticas (DES). Assim, descobriu-se que uma das mais comuns misturas eutécticas baseada em ureia decompõe-se inesperadamente a temperaturas baixas para formar amónia, que consequentemente é responsável pela basicidade observada no meio. A molécula Lupanina, um alcaloide facilmente retirado do Tremoço (Lupinus genus), é um análogo estrutural da esparteína com um grupo funcional amida. Esta funcionalidade amida foi usada para produzir diferentes derivados da esparteína com potencial atividade biológica e aplicação em catalise assimétrica.Fundação para a Ciência e a Tecnologia (FCT

Tautomerism of 4,4′-dihydroxy-1,1′-naphthaldazine studied by experimental and theoretical methods

BACKGROUND: The title compound belongs to the class of bis-azomethine pigments. On the basis of comparative studies on similar structures, insight into the complex excited state dynamics of such compounds has been gained. It has been shown, for example, that only compounds that possess hydroxyl groups are fluorescent, and that the possibility for cis-trans isomerisation and/or bending motions of the central bis-azomethine fragment allows for different non-radiative decay pathways. RESULTS: The compound, 4,4'-dihydroxy-1,1'-naphthaldazine (1) was synthesized and characterized by means of spectroscopic and quantum chemical methods. The tautomerism of 1 was studied in details by steady state UV-Vis spectroscopy and time resolved flash photolysis. The composite shape of the absorption bands was computationally resolved into individual subbands. Thus, the molar fraction of each component and the corresponding tautomeric constants were estimated from the temperature dependent spectra in ethanol. CONCLUSIONS: According to the spectroscopic data the prevalent tautomer is the diol form, which is in agreement with the theoretical (HF and DFT) predictions. The experimental data show, however, that all three tautomers coexist in solution even at room temperature. Relevant theoretical results were obtained after taking into account the solvent effect by the so-called supermolecule-PCM approach. The TD-DFT B3LYP/6-31 G** calculated excitation energies confirm the assignment of the individual bands obtained from the derivative spectroscopy

Ru-Catalyzed Isomerization of Achmatowicz Derivatives : A Sustainable Route to Biorenewables and Bioactive Lactones

A Ru-catalyzed isomerization of Achmatowicz derivatives that opens unexplored routes to diversify the biogenic furanic platform is reported. The mechanistic insights of this formally redox-neutral intramolecular process were studied computationally and by deuterium labeling. The transformation proved to be a robust synthetic tool to achieve the synthesis of bioderived-monomers and a series of 4-keto-δ-valerolactones that further enabled the development of a flexible strategy for the synthesis of acetogenins. A concise and protective group-free asymmetric total synthesis of two natural products, namely, (S,S)-muricatacin and the (S,S)-L-factor, is also described.publishedVersionPeer reviewe

Valorization of Oleuropein via Tunable Acid-Promoted Methanolysis

The acid-promoted methanolysis of oleuropein was studied using a variety of homogeneous and heterogeneous acid catalysts. Exclusive cleavage of the acetal bond between the glucoside and the monoterpene subunits or further hydrolysis of the hydroxytyrosol ester and subsequent intramolecular rearrangement were observed upon identification of the most efficient catalyst and experimental conditions. Furthermore, selected conditions were tested using oleuropein under continuous flow and using a crude mixture extracted from olive leaves under batch. Formation of (−)-methyl elenolate was also observed in this study, which is a reported precursor for the synthesis of the antihypertensive drug (−)-ajmalicine.Centro de Investigación y Desarrollo en Ciencias Aplicada

Controlled tautomeric switching in azonaphthols tuned by substituents on the phenyl ring

A series of new tautomeric azonaphthols are synthesized and the possibilities for molecular switching are investigated using molecular spectroscopy, X-ray analysis and density functional theory quantum chemical calculations. Two opposite effects that influence switching are studied: attaching a piperidine sidearm, and adding substituents to the phenyl ring. On the one hand, the attached piperidine moiety stabilizes the enol form leading to a controlled shift of the equilibrium upon protonation. On the other hand, the relative stability of the azonaphthol tautomers strongly depends on the effects of the substituents on the phenyl ring: electron donors tend to stabilize the enol tautomer, whereas electron acceptors lead to stabilization of the keto form. However, these effects do not shift fully the equilibrium towards either of the tautomers. Nevertheless, the effect of the substituents can be an additional tool to affect the switching between “on” and “off” states. Electron-withdrawing substituents stabilize the keto form and impede switching to the off state, whereas electron donors stabilize the enol form. The effect of the piperidine unit is dominant overall, and with strongly electron-withdrawing substituents at the phenyl ring, the enol form exists as a zwitterion

Magnetic ionic plastic crystal: choline[FeCl4]

A novel organic ionic plastic crystal (OIPC) based on a quaternary ammonium cation and a tetrachloroferrate anion has been synthesized with the intention of combining the properties of the ionic plastic crystal and the magnetism originating from the iron incorporated in the anion. The thermal analysis of the obtained OIPC showed a solid?solid phase transition below room temperature and a high melting point above 220 1C, indicating their plastic crystalline behaviour over a wide temperature range, as well as thermal stability up to approximately 200 1C. The magnetization measurements show the presence of three-dimensional antiferromagnetic ordering below 4 K. The results from electrochemical characterization display a solid-state ionic conduction sufficiently high and stable (between 10 2.7 and 10 3.6 S cm 1 from 20 to 180 1C) for electrochemical applications

Tautocrowns: a concept for a sensing molecule with an active side-arm

A new sensing molecule containing aza-15-crown-5 as a receptor and 4- (phenyldiazenyl)naphthalen-1-ol as a signal converter has been synthesized. In the free ligand, the hydrogen bonding between the tautomeric OH group and the nitrogen atom from the macrocycle fully shifts the tautomeric equilibrium towards the enol form. The complexation reverses the equilibrium as a result of the strong interaction between the metal ion captured in the macrocyclic moiety and the tautomeric carbonyl group. The complex formation is accompanied by strong bathochromic (between 60 and 100 nm) and hyperchromic effects on the absorption spectra. Obviously, the tautomeric OH/C=O groups play the role of an active side-arm in the complexation, supporting it via formation of a 3D cavity and giving possibility for ejection of the guest compound under stimuli to shift the tautomeric process back

Base-promoted direct amidation of esters : beyond the current scope and practical applications

The base-promoted direct amidation of unactivated esters is among the most useful reactions for amide bond formation in contemporary organic chemistry. The intensive research in this area has led to the development of a number of new methods to achive this transformation. However, to date, the existing literature is more methodological and in many instances lacks practical directions. Therefore, the full potential of this transformation is yet to be revealed by broadening the substrate scope. In a search for new practical applications of the amidation reaction, herein we present a comprehensive study of a number of base-promoted direct amidations that encompass a wide range of amines and esters. Furthermore, we applied our findings in the synthesis of phosphoramidates and several industrially relevant products.peerReviewe

CO2 Adsorption on Modified Mesoporous Silicas: The Role of the Adsorption Sites

The post-synthesis procedure for cyclic amine (morpholine and 1-methylpiperazine) modified mesoporous MCM-48 and SBA-15 silicas was developed. The procedure for preparation of the modified mesoporous materials does not affect the structural characteristics of the initial mesoporous silicas strongly. The initial and modified materials were characterized by XRD, N2 physisorption, thermal analysis, and solid-state NMR. The CO2 adsorption of the obtained materials was tested under dynamic and equilibrium conditions. The NMR data revealed the formation of different CO2 adsorbed forms. The materials exhibited high CO2 absorption capacity lying above the benchmark value of 2 mmol/g and stretching out to the outstanding 4.4 mmol/g in the case of 1-methylpiperazin modified MCM-48. The materials are reusable, and their CO2 adsorption capacities are slightly lower in three adsorption/desorption cycles