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J. Chil. Chem. Soc. v.50 n.1 Concepción mar. 2005
J. Chil. Chem. Soc., 50, N 1 (2005)
Oxime-Derivatives of Dihydroeuparin
M. GUZMÁN, P. ORTEGA*, L. VERA and E. ASTUDILLO
Depto de Química, Universidad Católica del Norte Casilla 1280, Antofagasta, CHILE, E-mail: firstname.lastname@example.org
The synthesis of derivatives of dihydroeuparin, a secondary metabolite of the shrub Senecio graveolens, is described. The main modifications were the introduction of a hydrocarbon branch and the transformation of a ketone group into its oxime. Structure identification was carried out by IR, 1H-NMR and 13C-NMR spectroscopy. These compounds may have application in the process of copper extraction.
Keywords: Dihydroeuparin, Solvent Extraction, Senecio Graveolens
The objective of this study was to describe the synthesis of some derivatives of dihydroeuparin DHEU, which is a secondary metabolite of the shrub Senecio graveolens. To do this, the starting compound was transformed into b-hydroxyoximes with a hydrocarbon branch on different parts of the molecule. These derivatives may have eventual applications in the mining industry, based on their structural similarity with other compounds having similar properties.
Dihydroeuparin (2-isopropenyl-6-hydroxy-5-acetyl-2,3- dihydrobenzofuran) is extracted from the plant Senecio graveolens, whose leaves contain approximately 3% DHEU . This shrub is commonly known as "chachacoma" (Quechua language meaning "poor man"), and is typical of the endemic flora of northern Chile above an altitude of 3000 meters. The plant is used medicinally in combating the effect of altitude known as "puna" or "soroche". The structure 1) of dihydroeuparin and its properties 2) have been described previously.
b-Hydroxyoximes are used industrially for the extraction of Cu2+ ions in solvent extraction processes due to their formation of stable complexes as will be noted below.
Fig. 1. b-Hydroxyoxime-copper complex
The R group (generally C10-12H21-25) of this structure functions in the solubilization of the b-hydroxyoxime and its complexes in paraffins, from which the copper is recovered by acid attack. The b-hydroxyoximes are synthesized from b-hydroxyacetones through their reaction with hydroxylamine in a basic medium controlled to produce only the E(anti) isomer, which is capable of extracting the Cu2+ ions. The structure of the complex contains an aromatic ring and is relatively simple, and it has been shown to be efficient in the extraction process under relatively normal conditions.
A large number of models have been proposed 3-8) to describe the kinetics of the extraction process. Experimental results have given contrasting points of view concerning the localization of the formation of the chelate, the steps which control the process, and the factors influencing the yield 9-14). Among the latter are included the position of the substituent in the aromatic ring, which may increase or decrease the extraction yield 11) up to a factor of 23. This fact is probably related to the shape and direction relative to the penetration of the extractant at the interface. There is a general consensus that in the extraction of copper ions from acidic aqueous solutions with b-hydroxyoximes, the two main steps are a fast interfacial reaction between a (hydrated) copper ion and a monomeric reagent molecule, followed by a bulk organic phase reaction with a second reagent molecule. According to Whewell et al., 15) oximes can exist in the aqueous phase through penetration across the interface during the reaction. In systems which have been studied, the copper extraction process has a low activation energy of about 1520 kJ/mol, which makes it one of the fastest extraction processes.
The b-hydroxyoximes undergo a degradation16) with the formation of aldehydes and ketones during the extraction processes. This situation can be summarized by saying that the reaction of the mineral acid on the oxime group is the main factor in the degradation of the b-hydroxyoximes. The process is speeded by the addition of water soluble substances which increase the activity of the proton. Also, the decomposition is reduced by the formation of the copper ligand. It is not affected by the addition of diluents, except for nonylphenol. It can be estimated that the activation energy of this reaction is greater than that of the copper extraction process, making it a slower reaction than the extraction, with low yield.
However, when nitrate ions are present in the water during the extraction process, important decompositions 17) occur with the subsequent formation of new copper complexes which are very difficult to break down and remain circulating in the system. Technology has been able to partially overcome this drawback by installing recycling processes of low efficiency and relatively moderate cost.
As a method for decreasing the effect of the nitrate ion, the dihydroeuparin was modified (taking advantage of a natural product with an adequate geometry) by transformation of the keto group into the E form of the oxime, and by the incorporation of the hydrocarbon branch to make it more soluble in paraffin, and with different geometries in order to obtain different shapes and directions of penetration at the interface. In this way an attempt was made to present less exposure to the aqueous conditions of the medium (especially nitrates) and at the same time make its copper complexes more soluble in paraffin. Extraction yields and determination of other parameters are beyond the scope of this contribution.
Reaction schemes carried out:
Scheme No. 2. Synthesis of hydrocarbon arm
The isolated DHEU was used as indicated below. The reagents 1-dodecanol, HBr, sulfuric acid, ethyl acetate, activated carbon, and anhydrous sodium sulfate were obtained from Merck Darmstadt. Acetonitrile, tetrahydrofuran, cyclohexane, hydroxylamine chloride, pentane, ethanol, ethyl ether, petroleum ether, and carbon tetrachloride were obtained from Aldrich Chemical Corp. The equipment used for analysis of the dihydroeuparin derivatives included a PERKIN-ELMER model 1310 infra-red spectrophotometer (KBr tablet), BRUCKER 300 MHz 1H and 13C nuclear magnetic resonance spectrometer (spectra were taken in CDCl3 with TMS as internal standard; the base resonance frequency for 13C was 75 MHz), and a PERKIN- ELMER Lambda 3 UV-vis spectrophotometer.
Compounds 3 and 6 were waxy solids. Their melting points have a huge range of variation due to the presence of a long side chain. Under these circumstances the melting points were not recorded and identification was done through spectroscopy. The melting point of compound 7 is indicated in its synthesis.
Synthesis of 1-bromododecane. 35 g (0.21 mol) hydrobromic acid (48%), 11 g (6 ml) of concentrated sulfuric acid, and 20 g (0.11 mol) of 1-dodecanol were placed in a 250 ml round-bottom flask and the mixture was refluxed with stirring for six hours. The solution was diluted with water and the phases were separated. The organic phase was washed with 10% sodium bicarbonate solution and the crude 1-bromododecane was extracted with successive fractions of dichloromethane. The collected organic phase was dried over anhydrous sodium sulfate. The 1-bromododecane (18.7 g) was concentrated by rotary evaporation.
Synthesis of 1-dodecanethiol. 18) A mixture of 11 g (0.044 mol) of 1-bromododecane and 3.36 g (0.044 mol) of thiourea in 25 ml of 95% ethanol were refluxed for three hours under a fume hood. A solution of 2.7 g (0.0675 mol) of sodium hydroxide in 25 ml of water was added, and the reaction mixture was again refluxed with stirring for two hours. The aqueous phase was acidified with dilute sulfuric acid and extracted with successive fractions of benzene. The benzene extracts were added to the crude mercaptan of the organic phase.
Synthesis of sodium 1-dodecanethiolate. The previously obtained mass of 1-dodecylthiol dissolved in benzene was added to a 500 ml beaker and stirred with 50% sodium hydroxide solution. About 5.64 g of precipitate which was formed was filtered off and dried in a drying oven. More NaOH solution was added to the benzene until no further precipitate appeared.
Extraction of dihydroeuparin [DHEU]. Dihydroeuparin, DHEU, was obtained from Senecio graveolens as noted above. Plants were collected near El Tatio, formerly a geothermal station in Chile's II Region at 4200 meters of altitude. The plants were dried and the leaves were macerated in petroleum ether for one week; this procedure was repeated three times with fresh changes of solvent. The ether extracts were combined and evaporated to 5% of the initial volume, yielding crystalline dihydroeuparin. The crystals were washed with cold petroleum ether, and then recrystallized from a 75:25 mixture of petroleum ether and ethyl acetate.
Synthesis of 2(1-bromo-1-methylethyl)-6-hydroxy-5-acetyl-2,3-dihydrobenzofuran .
To 10.3 g (0.13 mol) of hydrobromic acid in 40 ml of water in a 100 ml round-bottom flask was added 1.5 g (0.01 mol) of DHEU . The mixture was then slowly refluxed in a steam bath for 2 h. Upon cooling, the reaction mixture was extracted twice with 10 ml portions of pentane. The combined organic phases were washed with 5% sodium bicarbonate and dried with anhydrous sodium sulfate; the solvent was then eliminated by rotary evaporation to yield 1.6 g of product.
Synthesis of 2-(1-methylethylthiododecyl)-6-hydroxy-5-acetyl-2,3-dihydrobenzofuran . To 1.48 g (0.005 mol) of  in 40 ml of acetonitrile in a 250 ml Erlenmeyer flask was added dropwise with stirring a solution of 0.92 g (0.0041 mol) of sodium 1-dodecanethiolate in 40 ml of carbon tetrachloride. The mixture was stirred vigorously for 54 h at room temperature, filtered off and washed with three successive portions of water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation, yielding 1.62 g of product.
Synthesis of 2(1-methylethylthiododecyl)-6-hydroxy-5-acetyloxime-2,3-dihydrobenzofuran . 1.46 g of , 2.62 g of hydroxylamine, and 12.82 g NaOH (molar ratio of hydroxyketone: hydroxylamine hydrochloride: sodium hydroxide = 1:1.8:8.8) were dissolved in 30 ml of distilled water in a 100 ml round-bottom flask. The solution was stirred vigorously for 30 min, followed by acidification with glacial acetic acid (pH = 5), to obtain a dark brown precipitate which was extracted with successive portions of benzene. The phases were separated and the benzene extracts were combined and dried over anhydrous sodium sulfate. The solvents were then removed by rotary evaporation to give a yield of 0.84 g of product.
Synthesis of 2-isopropenyl-6-hydroxy-5-bromoacetyl-2,3-dihydrobenzofuran 19) . 1.12 g (0.005 mol) of copper(II) bromide in 20 ml of ethyl acetate and 0.5564 g (0.003 mol) of DHEU in 20 ml chloroform were placed in a 100 ml round-bottom flask. The reaction mixture was refluxed with vigorous stirring for five hours. The end of the reaction was determined by the end of the evolution of hydrogen bromide (poorly soluble in the solvent system). The endpoint was also recognized by the change in color from the the black of copper(II) bromide to a gray/white color of copper (I) bromide. The copper (I) bromide was removed by filtration and the HBr by decantation. The solvent mixture was removed by rotary evaporation to give a yield of 1.63 g of product.
Synthesis of 2-isopropenyl-6-hydroxy-5-dodecylthio acetyl-2,3-dihydrobenzofuran . 1.5 g (0.01 mol) of  and 1.16 g (0.01 mol) of sodium 1-dodecanethiolate dissolved in 30 ml de tetrahydrofuran in a 100 ml round-bottom flask were refluxed for one hour. The solution was then cooled and vacuum filtered, and the solvent removed by rotary evaporation, yielding a dark brown solid which was then dissolved in 40 ml of carbon tetrachloride. This fraction was washed with successive fractions of distilled water and then dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, yielding 1.6 g of product.
Synthesis of 2-isopropenyl-6-hydroxy-5 dodecylthioacetyloxime-2,3-dihydrobenzofuran . 1.5 g of  , 2.70 g of hydroxylamine and 11.32 g of NaOH (mass ratio of hydroxyketone: hydroxylamine hydrochloride:sodium hydroxide = 1:1.8:8.8) were dissolved in 30 ml of distilled water in a 100 ml round-bottom flask. The solution was stirred vigorously for 30 min and adjusted to pH 5 with glacial acetic acid. The light brown precipitate obtained was extracted with successive portions of benzene which were then dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, yielding 0.8 g of product.
Synthesis of 2-isopropenyl-6-hydroxy-5-acetyloxime-2,3-dihydrobenzofuran .
1.43 g of DHEU, 2.62 g of hydroxylamine and 12.80 g NaOH (mass ratio of hydroxyketone: hydroxylamine hydrochloride: sodium hydroxide = 1:1.8:8.8) were dissolved in 30 ml of distilled water in a 100 ml round-bottom flask. The solution was stirred vigorously for 30 min and adjusted to pH 5 with glacial acetic acid. The light brown precipitate obtained was extracted with successive fractions of benzene which were then dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, yielding 0.78 g of product. Melting point 71-78 °C
Solubilities. Tests were carried out on the solubilities of the products obtained as well as on their copper salts, using pure solvents (Escaid).
RESULTS AND DISCUSSION
All the syntheses were followed using IR spectroscopy immediately after their completion. Also, 1H-NMR and 13C-NMR spectra were made of DHEU and compounds  and . Table 1 shows the distribution of substituents in the compounds. Scheme 3 shows the numbering of the protons and carbon atoms in the molecules. Tables 2 and 3 give the spectroscopic results for the compounds.
The chemical structure of dihydroeuparin is typical of all plant species 20) of the genus Senecio. The two modifications made to the DHEU molecule included addition of a hydrocarbon branch and transformation of the ketone group into an E oxime. In the first case two specific points of the structure of the dihydroeuparin were changed: the double bond of the isopropenyl group (precursor of  ), and the a-methyl group of the carbonyl 19) (precursor of 6).
In general, the synthetic procedures are simple and well described in the literature 21), with the exception of the use of CuBr2 for the introduction of bromine into the a-methyl group on the carbonyl, and the use of thiourea 18) in the synthesis of dodecanethiol. The yields are quite close to those reported, with a difference of +15%, and with adequate purity according to the spectra. These reactions did not present risks as long as adequate precautions were taken. The overall yields obtained, taking DHEU as a reference, were h(3) = 28%; h(6) = 29%; h(7) = 49%.
Scheme 3. Numbering system of protons and carbon atoms
The characterization of products 3, 6 and 7 carried out by IR, 1H-NMR and 13C-NMR were consistent when analyzing the changes produced in the DHEU. Also, the spectroscopic changes caused by the different structural modifications were compared with similar products in the SDBS, 22) a spectroscopic data base of Japanese origin.
The probable structures of the 3 and 6 derivatives in isotropic solvents include a rigid portion and a hydrocarbon branch having different spatial distributions and folding. The association of these structures as dimers is known, but their degree of association will depend on the concentration and the solvent. In anisotropic solvents (e.g., paraffin) the structure appears better ordered, with the hydrocarbon branch aligned with the solvent chains. 23) Therefore, it is estimated that the spatial orientation of the rigid portion with respect to the hydrocarbon branch shown by 3 would be different from that shown by 6, and thus the interaction of the oxime group with the interface would also be different. Product 7 could be used for comparing the effect of the hydrocarbon branch. Both the derivatives and their copper salts are soluble within the range of application of the extractants. This agrees with previous studies1 on DHEU
The synthesis of DHEU derivatives is described in detail. Spectroscopic analyses (Tables 2 and 3) of derivatives 3, 6, and 7 confirm that these molecules can be obtained in high purity. The overall yield of 3 and 6 from leaves of Senecio graveolans is low. About 100 kg of leaves are required to obtain 0.84 kg of product. In spite of that, since it is possible to introduce hydrocarbon chains on DHEU which increase the insolubility of the complexes in water at the same time that their solubility in organic solvents is increased, the study of the extraction properties of the derivatives appears interesting.
It should be noted that the particular position of the hydrocarbon branch with respect to the oxime group allows prediction of a different interaction between 3 and the interface when compared with that of 6 and the interface. It is expected that these differences in interaction with the interface will make possible the observation of differences in the effect of the nitrate ion on the stability of its ligands.
Due to the specific conditions related to each extraction, which depends on the ore to be processed, practical use of these materials is not possible at present.
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