Reactions In Organic Media Research Articles

Understanding Differential Interaction of Protic and Aprotic Ionic Liquids inside Molecular Confinement.

Considering the contemporary interests of water-free reverse micelles (RMs) in the field of organic reaction medium and potential drug delivery carrier, we synthesized two different classes of ionic liquids (ILs), protic N-methyl-2-pyrrolidonium hexanoate, [NMP][Hex], and aprotic choline hexanoate, [Chl][Hex], and subsequently incorporated them in a mixture of polyoxyethylene (20) sorbitan monooleate (Tween-80) and cyclohexane. In order to understand the differential nature of interinterionic interaction of two ILs, we performed DFT calculations on pure ILs to correlate with experimental results. The formation of IL-in-oil RMs was confirmed from phase behavior and DLS studies. Interestingly, [NMP][Hex]-based systems showed a larger monophasic region and droplet size along with higher shear viscosity compared to [Chl][Hex]-based systems. Stronger interaction between [NMP]+ and Tween-80 due to their protic nature might be the driving force for such observations which supported the resonance stabilization energy [E(2)] and charge population analysis by NBO calculation. Smaller E(2) values along with lesser NBO charges on atoms involved in H-bonding in pure [NMP][Hex] than [Chl][Hex] corroborated with the experimental observations. This primary hypothesis was further confirmed from FTIR and time-resolved fluorescence studies. These systems showed efficient thermal stability. Taking all of the results together, we anticipate that these RMs could be used as efficient delivery systems and for nanomaterial synthesis.

Insight into microwave assisted enzyme catalysis in process intensification of reaction and selectivity: Kinetic resolution of (R,S)-flurbiprofen with alcohols

Biocatalysis has potential applications in pharmaceuticals, fine chemicals and drug industries for the synthesis and separation of chiral compounds. The current work deals with the kinetic resolution of (R,S)-flurbiprofen using immobilized Candida antarctica lipase B under the influence of microwave irradiation. Flurbiprofen (R,S)-[2-(3-fluro-4-phenyl) phenyl] propionic acid is one of the most widely used non-steroidal anti-inflammatory drugs (NSAID). It exists in two enantiomeric forms as (R,S)-flurbiprofen because it has a single stereogenic center. Pharmacological action of flurbiprofen resides with the S form by inhibiting Cox-2 activity and results in anti-inflammatory action and hence (R)-flurbiprofen causes gastrointestinal infection. Novozym 435 was found to be most active among others for the stereoselective esterification of the R-enantiomer in organic reaction media. Microwave irradiation shows a synergistic effect on enzyme catalysis by enhancing both rate of the reaction and conversion of R-enantiomer into an ester. Effects of various reaction parameters such as solvent, speed of agitation, mole ratio, type of alcohol, temperature, catalyst loading, and reusability were studied. Maximum conversion of R-flurbiprofen ester under microwave irradiation was found to be ∼44.4% with enantioselectivity (E) of 478, eeP=98.9% and eeS=79.07% in 6h, whereas in conventional heating the maximum conversion was 17% with enantioselectivity (E) of 126, and eeS=20.12% in 6h. The ping-pong bi–bi mechanism with inhibition by methanol was proposed for the kinetic resolution of (R,S)-flurbiprofen and validated against experimental data.

Studies on the alkylation of phenolate in an organofluorine solvent and its application to the synthesis of myrsinoic acids A and E

ABSTRACTAmong the distinct features of organofluorines, solubility properties to molecules often enable unique applications. More importantly, organofluorines can be compatible with chemical reactions in general, even under harsh conditions. In this context, a study on the alkylation of phenolate using an organofluorine solvent were performed for the preparation of ortho-alkyl phenols. Herewith, the study on the alkylation of phenolate in an organofluorine solvent as well as its application to the synthesis of bioactive terpenylated phenolic natural products, myrsinoic acids A and E, will be reported. Our study suggested that organofluorine solvents could be better alternatives to the conventional nondissociating solvents as organic reaction media to suppress the nondesirable and nonselective side reactions such as in the ortho-alkylation of phenolate.

Enzymatic monoesterification of symmetric diols: restriction of molecular conformations influences selectivity.

We have experimentally demonstrated that by 'locking' the molecular conformation through the introduction of a double or triple bond in the center of a symmetric diol, enzymatic monoesterification can be achieved selectively. The enzyme Candida antarctica lipase B, generally used for the transesterification of diols, can be effectively used for the monoesterification of symmetrical diols in an unbuffered system also. By varying the chain length of a carboxylic acid moiety, we have established that optimum selectivity and efficiency can be achieved in the range of 4.8 to 5.0 pKa values. Selectivity can be improved up to 98.75% for a monoester in an overall 73% yield (mixture of a monoester and a diester) when but-2-yne-1,4-diol reacted with hexanoic acid. Water, a by-product, provides an interfacial environment for the enzyme to work in the organic reaction medium. The uniqueness of the reported monoesterification protocol is that it involves only the mechanical stirring of the reaction mixture at room temperature in the presence of the enzyme for 24 h. High percentage yield with selectivity for a monoester, easier product isolation and overall, environmental sustainability are added advantages. The synthesized monoesters are characterized by using HNMR and high resolution mass spectrometry (HRMS).

Bio-based Polymer from Ferulic Acid by Electropolymerization

Electropolymerization was carried out in order to obtain a bio-based polymer by a simple procedure. Ferulic acid, a component of gramineous plants, was selected for this purpose. A thin polymer film was produced in an organic solvent medium (i.e., CH2Cl2/methanol (4:1 v/v) in the presence of 0.2 M LiClO4), whereas it was not obtained in a totally aqueous medium (0.2 M NaOH). Scanning electron microscopic analysis showed that the polymer film had a porous lamellar structure of ~10 μm thickness. Most of the carboxyl groups remained, and IR spectroscopy and time-of-flight secondary ion mass spectrometry (TOF-SIMS) analyses revealed that o-quinones existed in the polymer film. After electropolymerization, caffeic acid, sinapic acid, 3,6-bis(4-hydroxy-3-methoxyphenyl)tetrahydrofuro[3,4-c]furan-1,4-dione (1), and 4,4’-dihydroxy-3,3’-dimethoxy-β,β’-bicinnamic acid (2) were detected in the organic reaction medium; this suggested that demethylation, methoxyl group addition, and radical coupling reactions occurred at the electrode surface.

Towards preparative peroxygenase-catalyzed oxyfunctionalization reactions in organic media

The peroxygenase from Agrocybe aegerita (AaeUPO) has been evaluated for stereoselective oxyfunctionalization chemistry under non-aqueous reaction conditions.The stereoselective hydroxylation of ethylbenzene to (R)-1-phenylethanol was performed in neat substrate as reaction medium together with the immobilized biocatalyst and tertBuOOH as oxidant.Stability and activity issues still have to be addressed. Nevertheless, gram-scale production of enantiopure (R)-1-phenylethanol was achieved with respectable 90,000 turnovers of the biocatalyst.

One-pot stereoselective synthesis of chiral 1, 3-oxathiolane by Trichosporon laibachii lipase: Optimization by response surface methodology integrated a desirability function approach

The asymmetric synthesis of chiral 1,3-oxathiolan-5-ones has attracted a great deal of attention owing to their broad biological activities and importance as intermediates for a range of useful pharmaceuticals. However, the enantiomeric purity of desired enantiomer was moderate while maintaining high yield. Here, high enantiomerically pure chiral 1,3-oxathiolane intermediate was synthesized by cyclization-acetylation reaction in organic media using immobilized Trichosporon laibachii (T. laibachii) lipase with one-pot process. Response surface methodology (RSM) integrated a desirability function approach was used to study and optimize the reaction conditions. The effects of several reaction parameters (initial water content of reaction medium, lipase amount and reaction temperature) on enantiomeric excess (ee) and the conversion of benzoyl aldehyde (C) were evaluated. The enzyme activity as well as enantioselectivity was markedly influenced by the initial water content of reaction medium and reaction temperature. The maximum overall desirability (D) of 0.958 was achieved at initial water content of 0.46%, lipase amount of 4.58% and reaction temperature 43°C. The corresponding maximum ee and C were 94.33% and 97.40%, respectively. A good correlation between the predicted and actual responses showed that the generated model could adequately predict ee and C.

ChemInform Abstract: Quinoline Synthesis by Improved Skraup—Doebner—Von Miller Reactions Utilizing Acrolein Diethyl Acetal.

A robust synthetic method has been developed as an improvement to the venerable Skraup–Doebner–Von Miller reaction providing access to various quinoline products. The straightforward procedure utilizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic, organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be compatible with the reaction conditions and the corresponding quinoline products are isolated in moderate to good yields.

Quinoline synthesis by improved Skraup–Doebner–Von Miller reactions utilizing acrolein diethyl acetal

A robust synthetic method has been developed as an improvement to the venerable Skraup–Doebner–Von Miller reaction providing access to various quinoline products. The straightforward procedure utilizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic, organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be compatible with the reaction conditions and the corresponding quinoline products are isolated in moderate to good yields.

Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media

Dithiocarbamates (DTCs) are ligands known to chelate with Cu and other transition metals to form insoluble complexes. Wastewater treatment protocols have utilized DTCs to remove trace (ppb) metals from waste streams. We have extended the applicability of DTCs to a protocol that readily enables control of the residual Cu in isolated material in a quick and cost-effective manner. Formation of the chelate complex typically results in purging of Cu and a variety of other metals in an array of reaction media to ≤10 ppm. Furthermore, the simplicity of the method makes it very attractive for large-scale applications late in a synthetic sequence because of the low toxicity and efficient removal of the metal complex by filtration.

Selectivity of lipases for estolides synthesis

Abstract Lipase-catalyzed synthesis of estolides starting from different saturated (C16 16OH, C18 12OH) and unsaturated (C18:1 9 cis 12-OH) hydroxy-fatty acids was investigated. For this reason, the catalytic efficiency of several native and immobilized lipases in different organic reaction media at temperatures up to 75 °C was studied. The formation of mono- and di-lactone as well as estolide’s chain elongation depends on the type and source of lipase. The lipase from Pseudomonas stutzeri immobilized by cross-linking as cross-linked enzymes aggregates (CLEAs) was the best biocatalyst in terms of chain elongation. Estolides with polymerization degree up to 10 were obtained at substrate conversions higher than 80 %.

Isolation and characterization of a thermotolerant ene reductase from Geobacillus sp. 30 and its heterologous expression in Rhodococcus opacus.

Rhodococcus opacus B-4 cells are adhesive to and even dispersible in water-immiscible hydrocarbons owing to their highly lipophilic nature. In this study, we focused on the high operational stability of thermophilic enzymes and applied them to a biocatalytic conversion in an organic reaction medium using R. opacus B-4 as a lipophilic capsule of enzymes to deliver them into the organic medium. A novel thermo- and organic-solvent-tolerant ene reductase, which can catalyze the enantioselective reduction of ketoisophorone to (6R)-levodione, was isolated from Geobacillus sp. 30, and the gene encoding the enzyme was heterologously expressed in R. opacus B-4. Another thermophilic enzyme which catalyzes NAD(+)-dependent dehydrogenation of cyclohexanol was identified from the gene-expression library of Thermus thermophilus and the gene was coexpressed in R. opacus B-4 for cofactor regeneration. While the recombinant cells were not viable in the mixture due to high reaction temperature, 634mM of (6R)-levodione could be produced with an enantiopurity of 89.2% ee by directly mixing the wet cells of the recombinant R. opacus with a mixture of ketoisophorone and cyclohexanol at 50°C. The conversion rate observed with the heat-killed recombinant cells was considerably higher than that obtained with a cell-free enzyme solution, demonstrating that the accessibility between the substrates and enzymes could be improved by employing R. opacus cells as a lipophilic enzyme capsule. These results imply that a combination of thermophilic enzymes and lipophilic cells can be a promising approach for the biocatalytic production of water-insoluble chemicals.

Short-Chain Flavor Ester Synthesis in Organic Media by an E. coli Whole-Cell Biocatalyst Expressing a Newly Characterized Heterologous Lipase

Short-chain aliphatic esters are small volatile molecules that produce fruity and pleasant aromas and flavors. Most of these esters are artificially produced or extracted from natural sources at high cost. It is, however, possible to ‘naturally’ produce these molecules using biocatalysts such as lipases and esterases. A gene coding for a newly uncovered lipase was isolated from a previous metagenomic study and cloned into E. coli BL21 (DE3) for overexpression using the pET16b plasmid. Using this recombinant strain as a whole-cell biocatalyst, short chain esters were efficiently synthesized by transesterification and esterification reactions in organic media. The recombinant lipase (LipIAF5-2) showed good affinity toward glyceryl trioctanoate and the highest conversion yields were obtained for the transesterification of glyceryl triacetate with methanol. Using a simple cetyl-trimethylammonium bromide pretreatment increased the synthetic activity by a six-fold factor and the whole-cell biocatalyst showed the highest activity at 40°C with a relatively high water content of 10% (w/w). The whole-cell biocatalyst showed excellent tolerance to alcohol and short-chain fatty acid denaturation. Substrate affinity was equally effective with all primary alcohols tested as acyl acceptors, with a slight preference for methanol. The best transesterification conversion of 50 mmol glyceryl triacetate into isoamyl acetate (banana fragrance) provided near 100% yield after 24 hours using 10% biocatalyst loading (w/w) in a fluidized bed reactor, allowing recycling of the biocatalyst up to five times. These results show promising potential for an industrial approach aimed at the biosynthesis of short-chain esters, namely for natural flavor and fragrance production in micro-aqueous media.

Combination of Asymmetric Organo- and Biocatalytic Reactions in Organic Media Using Immobilized Catalysts in Different Compartments

A proof of concept for the combination of an asymmetric organocatalytic reaction with a biotransformation toward a “one-pot like” process for 1,3-diols based on immobilized organo- and biocatalysts, which are utilized in different compartments, is demonstrated. This process which runs completely in organic media consists of an initial proline-derivative-catalyzed aldol reaction and a subsequent reduction of the aldol adduct catalyzed by an alcohol dehydrogenase (ADH) without the need for intermediate isolation. Economically attractive superabsorber-based coimmobilization for the ADH and its cofactor NAD+ turned out to give a highly efficient biocatalyst with excellent reusability and simple product separation from the immobilizate under avoidance of any tedious extraction steps during the overall process.

Catalytic asymmetric aldol reactions in aqueous media – a 5 year update

Asymmetric reactions in water and in aqueous solutions have become an area of fast growing interest recently. Although for a long time neglected as a medium for organic reactions, water has attracted attention as the most widely distributed solvent in the world. Indeed, water is the solvent used by nature for biological chemistry including aldol reactions being essential for glycolysis, gluconeogenesis and related processes. Consequently, artificial catalysts designed and used for aldol reactions in water can be promising for the synthesis of enantiopure molecules and are also important for the understanding of complex chemistry of life. This tutorial review summarizes recent developments in the area of aqueous asymmetric aldol reactions highlighting two fundamental directions--development of water compatible chiral Lewis acids and amine-based organocatalysts.

Clean and efficient synthesis of flavanone in sub-critical water

Subcritical water (SbcW) is one of the environmentally benign medium for organic chemical reactions, especially for acid/base catalyzed reactions without using acid or base. However, problems such as low reaction rates and poor selectivity that greatly hinder the application of this attractive technique in industrially interesting processes. Synthesis of flavanones was studied in water at subcritical temperature (250°C). SbcW was found to be a very promising solvent. The highest flavone product yield in subcritical water was 64% in 60min at 250°C. Any side reactions or by-products were did not observed under these conditions.

Hierarchical TS-1 zeolite as an efficient catalyst for oxidative desulphurization of hydrocarbon fractions

The catalytic oxidative desulphurization (ODS) of S-containing aromatic compounds has been investigated over a hierarchical TS-1 zeolite prepared from silanized protozeolitic units, characterized by having, additionally to the zeolitic micropores, a secondary porosity within the supermicro/mesopore region. A standard TS-1 sample has been employed as reference catalyst. The influence of both the solvent (n-heptane and acetonitrile) and the oxidizing agent (hydrogen peroxide and tert-butylhydroperoxide, TBHP) was first studied using dibenzothiophene (DBT) as model substrate. In all cases, the catalytic activity exhibited by the hierarchical TS-1 was much higher than that obtained with the conventional TS-1 as a consequence of the improved accessibility caused by the presence of the secondary porosity. A very high desulphurization activity was obtained with the combination of heptane and TBHP, as solvent and oxidant, respectively, leading to an almost total DBT conversion. This fact has been attributed to the fully miscibility of the oxidant solution (TBHP in decane) in the organic reaction medium. Moreover, it is noteworthy that, in these conditions, the oxidation product (sulphone) is insoluble in the reaction medium, which facilitates its removal by filtration or centrifugation. Additionally, the oxidation of different aromatic organosulphur compounds [benzothiophene (BT), 2-methylbenzothiophene (2-MBT), 2,5-dimethylthiophene (2,5-DMT) and dibenzothiophene (DBT)] was investigated using the hierarchical TS-1 catalyst. The trend in the conversion values obtained was 2,5-DMT<BT<2-MBT<DBT. These results indicate that the oxidation conversion is determined by the nucleophilic character of the sulphur atom, and not by the molecular size of the S-containing compound, provided that the steric and diffusional limitations are overcome by the presence of the hierarchical TS-1 porosity.

Lipase-catalyzed acylation of lily polysaccharide in ionic liquid-containing systems

A comparative study was made of immobilized Burkholderia cepacia lipase (PSL-C)-catalyzed acylation of lily polysaccharide (LP) with vinyl acetate in organic solvents, ionic liquids (ILs) and IL-containing systems. The degree of substitution (DS) of the modified LP was used to evaluate the extent of acylation and thus enzymatic activity. In this manner, an eco-friendly solvent, 2-methyltetrahydrofuran (MeTHF), was found to be the most suitable organic reaction medium. However, compared to MeTHF, enhanced enzyme activity was observed when 1-butyl-3-methylimidazolium tetrafluorobrate ([C4MIm][BF4]) was used as the solvent. To further enhance the DS of the modified LP product, co-solvent mixtures of [C4MIm][BF4] and MeTHF were investigated. Among the various MeTHF–[C4MIm][BF4] systems examined, 20% (v/v) MeTHF–[C4MIm][BF4] produced the highest DS. In this reaction medium, the optimal water activity, reaction temperature and time were 0.33, 55°C and 18h, respectively, producing a product DS as high as 0.67. The PSL-C enzyme exhibited a much higher stability in the IL-containing system. Additionally, PSL-C-catalyzed acylation of LP was highly regioselective, causing acylation of only C6OH.

Aldol reactions mediated by a tetrahedral boronate

The base is a key factor in aldol reactions in organic media, determining the selectivity. Here, we describe a tetrahedral phenylboronate salt as a mild non-nucleophilic base that is able to catalyse the aldol reaction and significantly decrease the formation of undesired elimination products.

E-factor minimized protocols for the polystyryl-BEMP catalyzed conjugate additions of various nucleophiles to α,β-unsaturated carbonyl compounds

Efficient protocols for the addition of carbon-, sulphur- and nitrogen-nucleophiles to α,β-unsaturated carbonyl compounds catalyzed by PS-BEMP have been reported. The adoption of solvent-free conditions (SolFC) was crucial for improving the efficiency of all the processes, while by using an organic reaction medium poor results were obtained. Addition reactions were performed by using equimolar amounts of reagents, and the products were isolated by simple filtration with the minimal amount of organic solvent. This approach allowed the E-factor, a measure of the waste of a reaction, to be minimized. Further waste minimization (95.7% compared to batch protocol) has been accomplished by defining a larger scale continuous-flow protocol operating under SolFC.