Design, Synthesis and Characterization of N-Containing Organic Compounds

The needed of new intermediates/products for screening in the fields of drug discovery and material science is the driving force behind the development of new methodologies and technologies. Organic scaffolds are privileged targets for this scouting. Among them a priority place must be attributed to those including nitrogen functionalities in their scaffolds. It comes out that new methodologies, allowing the introduction of the nitrogen atom for the synthesis of an established target or for the curiosity driven researches, will always be welcome. The target of this PhD Thesis’ work is framed within this goal. Accordingly, Chapter 1 reports the preparation of new N-Heteroarylmethyl 3-carboxy-5-hydroxy piperidine scaffold, as potential and selective α-glucosidase inhibitors. The proposed reversible uncompetitive mechanism of inhibition makes them attractive as interesting candidate for drug development. Chapter 2 is more environmentally method-driven research. Eco-friendly studies on the synthesis of enantiomerically pure 1,4-dihydropyridines using “solid” ammonia (magnesium nitride) is reported via classical Hantzch method. Chapter 3 and Chapter 4 may be targeted as the core of the Thesis’s research work. Chapter 3 reports the studies addressed to the synthesis of N-containing heterocycles by using N-trialkylsilylimine/hetero-Diels–Alder (HAD) approach. New eco-friendly methodology as MAOS (Microwave Assisted Organic Synthesis) has been used as witness of our interest to a sustainable chemistry. Theoretical calculations were adopted to fully clarify the reaction mechanism. Chapter 4 is dedicated to picture the most recent studies performed on the application of N-Metallo-ketene imines (metallo= Si, Sn, Al), relatively new intermediates which are becoming very popular, in the preparation of highly functionalized N-containing derivatives, accordingly to the Thesis’ target. Derivatives obtained are designed in such a way that they could be of interest in the field of drug and new material chemistry.

One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.

Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar Cycloadditions of Azomethine Ylides: An Experimental and Computational Assessment of the Origin of Stereocontrol

Azomethine ylides, generated from imine-derived O-cinnamyl or O-crotonyl salicylaldeyde and α-amino acids, undergo intramolecular 1,3-dipolar cycloaddition, leading to chromene[4,3-b]pyrrolidines. Two reaction conditions are used: (a) microwave-assisted heating (200 W, 185 °C) of a neat mixture of reagents, and (b) conventional heating (170 °C) in PEG-400 as solvent. In both cases, a mixture of two epimers at the α-position of the nitrogen atom in the pyrrolidine nucleus was formed through the less energetic endo-approach (B/C ring fusion). In many cases, the formation of the stereoisomer bearing a trans-arrangement into the B/C ring fusion was observed in high proportions. Comprehensive computational and kinetic simulation studies are detailed. An analysis of the stability of transient 1,3-dipoles, followed by an assessment of the intramolecular pathways and kinetics are also reported.

Metallomics and chemical speciation: towards a better understanding of metal-induced stress in plants

Most metal ions are toxic to plants, even at low concentrations, despite the fact that some are essential for growth and play key roles in metabolism. The majority of metals induce the formation of reactive oxygen species, which require the synthesis of additional antoxidant compounds and enzymes for their removal. New techniques that have greatly improved the identification, localisation and quantification of metals within plant tissues have led to the science of metallomics. This advancement in knowledge should eventually allow the characterisation of plants used in the process of phytoremediation of soils contaminated with toxic metals.

Efficient sonochemical synthesis of novel 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides

An Ultrasound-assisted preparation of a series of novel 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides that proceeds via the efficient reaction of chalcones with aminoguanidine hydrochloride under clean conditions is described. (C) 2009 Elsevier B.V. All rights reserved.

Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyltellurides

An ultrasound-assisted synthesis of symmetrical 1,3-diyne compounds with electron-withdrawing or donating substituents is described and illustrated by the palladium-catalyzed homocoupling reaction of n-butyl alkynyltellurides. This procedure offers easy access to 1,3-diynes in very short reaction times, and the products are achieved in good to excellent yields. (C) 2009 Elsevier Ltd. All rights reserved.

Screening of carbamates and ureas in fresh and processed tomato samples using micowave-assisted extraction and liquid chromatography

An analytical method, based on microwave-assisted extraction and liquid chromatography with diode array detection, for the determination of six carbamate and three urea pesticides in fresh and processed tomato samples is described. Significant parameters affecting extraction efficiency were optimized. Under optimum microwave-assisted extraction conditions (20mL acetonitrile, for 10 minutes, at 60º C), pesticides were extracted with recoveries ranging from 57.6 to 102% (RSDs<7%). Quantification limits between 6.5 and 39.6 µg=kg were obtained. A total number of 28 different fresh tomato samples and 6 processed tomato products were analysed. Confirmation of suspicious samples was performed by LC-MS.

Mu-Chlorido-Bridged Dimanganese(II) complexes of the schiff base derived from [2+2] condensation of 2,6-diformyl-4-methylphenol and 1,3-bis(3-aminopropyl)tetramethyldisloxane: structure, magnetismo, electrochemical behaviour, and catalytic oxidation of secondary alcohols

The reaction of 2,6-diformyl-4-methylphenol with 1,3-bis(3-aminopropyl)tetramethyldisiloxane in the presence of MnCl2 in a 1:1:2 molar ratio in methanol afforded a dinuclear -chlorido-bridged manganese(II) complex of the macrocyclic [2+2] condensation product (H2L), namely, [Mn2Cl2(H2L)(HL)]Cl center dot 3H(2)O (1). The latter afforded a new compound, namely, [Mn2Cl2(H2L)(2)][MnCl4]center dot 4CH(3)CN center dot 0.5CHCl(3 center dot)0.4H(2)O (2), after recrystallisation from 1:1 CHCl3/CH3CN. The co-existence of the free and complexed azomethine groups, phenolato donors, mu-chlorido bridges, and the disiloxane unit were well evidenced by ESI mass spectrometry and FTIR spectroscopy and confirmed by X-ray crystallography. The magnetic measurements revealed an antiferromagnetic interaction between the two high-spin (S = 5/2, g = 2) manganese(II) ions through the mu-chlorido bridging ligands. The electrochemical behaviour of 1 and 2 has been studied, and details of their redox properties are reported. Both compounds act as catalysts or catalyst precursors in the solvent-free low-power microwave-assisted oxidation of selected secondary alcohols, for example, 1-phenylethanol, cyclohexanol, 2- and 3-octanol, to the corresponding ketones in the absence of solvent. The highest yield of 72% was achieved for 1-phenylethanol by using a maximum of 1% molar ratio of catalyst relative to substrate.

µ-Chlorido-bridged dimanganese(II) complexes of the schiff base derived from [2+2] condensation of 2,6-diformyl-4-methylphenol and 1,3-bis(3-aminopropyl)tetramethyldisiloxane: structure, magnetismo, electrochemical behaviour, and catalytic oxidation of secondary alcohols

The reaction of 2,6-diformyl-4-methylphenol with 1,3-bis(3-aminopropyl)tetramethyldisiloxane in the presence of MnCl2 in a 1:1:2 molar ratio in methanol afforded a dinuclear -chlorido-bridged manganese(II) complex of the macrocyclic [2+2] condensation product (H2L), namely, [Mn2Cl2(H2L)(HL)]Cl center dot 3H(2)O (1). The latter afforded a new compound, namely, [Mn2Cl2(H2L)(2)][MnCl4]center dot 4CH(3)CN center dot 0.5CHCl(3 center dot)0.4H(2)O (2), after recrystallisation from 1:1 CHCl3/CH3CN. The co-existence of the free and complexed azomethine groups, phenolato donors, mu-chlorido bridges, and the disiloxane unit were well evidenced by ESI mass spectrometry and FTIR spectroscopy and confirmed by X-ray crystallography. The magnetic measurements revealed an antiferromagnetic interaction between the two high-spin (S = 5/2, g = 2) manganese(II) ions through the mu-chlorido bridging ligands. The electrochemical behaviour of 1 and 2 has been studied, and details of their redox properties are reported. Both compounds act as catalysts or catalyst precursors in the solvent-free low-power microwave-assisted oxidation of selected secondary alcohols, for example, 1-phenylethanol, cyclohexanol, 2- and 3-octanol, to the corresponding ketones in the absence of solvent. The highest yield of 72% was achieved for 1-phenylethanol by using a maximum of 1% molar ratio of catalyst relative to substrate.

Métodos "verdes" de produção de nanomateriais que promovem nanotecnologias sustentáveis

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Química

Multi-elemental analysis of ready-to-eat “baby leaf” vegetables using microwave digestion and high-resolution continuum source atomic absorption spectrometry

The mineral content (phosphorous (P), potassium (K), sodium (Na), calcium (Ca), magnesium (Mg), iron (Fe), manganese (Mn), zinc (Zn) and copper (Cu)) of eight ready-to-eat baby leaf vegetables was determined. The samples were subjected to microwave-assisted digestion and the minerals were quantified by High-Resolution Continuum Source Atomic Absorption Spectrometry (HR-CS-AAS) with flame and electrothermal atomisation. The methods were optimised and validated producing low LOQs, good repeatability and linearity, and recoveries, ranging from 91% to 110% for the minerals analysed. Phosphorous was determined by a standard colorimetric method. The accuracy of the method was checked by analysing a certified reference material; results were in agreement with the quantified value. The samples had a high content of potassium and calcium, but the principal mineral was iron. The mineral content was stable during storage and baby leaf vegetables could represent a good source of minerals in a balanced diet. A linear discriminant analysis was performed to compare the mineral profile obtained and showed, as expected, that the mineral content was similar between samples from the same family. The Linear Discriminant Analysis was able to discriminate different samples based on their mineral profile.

Síntese hidrotermal assistida por micro-ondas como metodologia sintética eficiente para obtenção da rede metalorgânica [ZN(BDC)(H2O)2]n

This work presents the optimization of the microwave-assisted hydrothermal synthesis of [Zn(BDC)(H2O)2]n . The reactions were carried out at the fixed temperature of 120 ºC for 10, 20, 30 and 40 min. Pure crystalline [Zn(BDC)(H2O)2]n was obtained in high yield (ca. 90%) with a reaction time of 10 min. The phase obtained and its purity was confirmed by Rietveld refinement, with a final value for Rwp/Rexp equal to 1.48. Increased reaction times (20, 30 and 40 min) favored the formation of unwanted by products, resulting in mixtures of several crystalline phases.

Síntese da fenitoína assistida por micro-ondas: proposta de aula prática para alunos de graduação

Microwave synthesis is considered a breakthrough in the field of chemistry due to its benefits over conventional heating methods. We describe, for the first time, the total synthesis of phenytoin adapted for a microwave reactor, proposed as an experiment for undergraduate courses. When carried out with microwaves, the synthetic route provided phenytoin in 6 min and 30 s, while for conventional heating the total time was 170 min. The experiment also involves rapid identification of compounds by TLC, ¹H NMR, FT-IR and melting points determination.

Use of heterogeneous catalysts in methylic biodiesel production induced by microwave irradiation

The effect of different heterogeneous catalysts on the microwave-assisted transesterification of sunflower oil for the production of methylic biodiesel in a monomode microwave reactor is described. The experiments were carried out at 70 ºC with a 16:1 methanolsunflower oil molar ratio and different heterogeneous basic and acidic catalysts. The results showed that the microwave-heated reactions occur up to four times faster than those carried out with conventional heating. The reactions were performed with 24 catalysts; pure calcium oxide (CaO) and potassium carbonate, either pure or supported by alumina (K2CO3/Al2O3), were the most efficient catalysts.

Simple, mild, and highly efficient synthesis of 2-substituted benzimidazoles and bis-benzimidazoles

A new convenient method for preparation of 2-substituted benzimidazoles and bis-benzimidazoles is presented. In this method, o-phenylenediamines were condensed with bisulfite adducts of various aldehydes and di-aldehydes under neat conditions by microwave heating. The results were also compared with results of synthesis by conventional heating under reflux. Structures of the products were confirmed by infrared, ¹H- and 13C-NMR spectroscopy. Short reaction times, good yields, easy purification of products, and mild reaction conditions are the main advantages of this method.