CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 1624–1627 http://dx.doi.org/10.1071/CH11236
Communication
Efficient Synthesis of Ellagic Acid Salts Using Distillable Ionic Liquids Shahana A. Chowdhury,A Pamela M. Dean,A R. Vijayaraghavan,A and D. R. MacFarlaneA,B A B
School of Chemistry, Monash University, Clayton Campus, Victoria 3800, Australia. Corresponding author. Email:
[email protected]
A direct, one pot synthesis of an ellagic acid salt was achieved at room temperature by dimerization of ethyl gallate using N,N-dimethylammonium N0 ,N0 -dimethylcarbamate, a distillable ionic liquid, as solvent. Manuscript received: 9 June 2011. Manuscript accepted: 23 August 2011. Published online: 16 September 2011.
Ellagic acid (EA) is a naturally occurring plant polyphenol present in high concentrations in various fruits and nuts.[1–3] Plants produce EA and convert it to a form of tannin known as the ellagotannins. These are glucosides that are readily hydrolyzed by water to regenerate ellagic acid when the plants are eaten.[4] EA is also a primary constituent of several tanninbearing plants which produce the category of tannins known as gallotannins.[5] These, when hydrolyzed by water give rise to EA and gallic acid. Such plants include Terminalia Chebula and Terminalia belerica, two related species which are ingredients of the Ayurvedic medicine known as Triphala. EA has antiviral and antibacterial activities.[6–7] EA also has antioxidant, anti-mutagen, and anti-cancer properties. Studies have shown anti-cancer activity[8–10] on cancer cells of the breast, oesophagus, skin, colon, prostate, and pancreas. More specifically, EA is thought to prevent the destruction of the P53 gene by cancer cells. EA causes a decrease in total hepatic mucosal cytochromes and an increase in some hepatic phase II enzyme activities, thereby enhancing the ability of the target tissues to detoxify the reactive intermediates.[11] It has also shown a chemoprotective effect against various chemically induced cancers. Mandal and Stoner[12] reported inhibitory effects of ellagic acid on N-nitrosomethylbenzylamine (NMBA) tumorigenesis in the oesophagus of F-344 rats. EA inhibited the development of both preneoplastic and neoplastic lesions by 25–50 %. These results were confirmed in a subsequent experiment by Daniel and Stoner.[13] EA was also found to be an effective inhibitor of NMBA-tumorigenesis in the rat oesophagus only if administered before, during, and after the carcinogen; there was no significant inhibition of esophageal tumorigenesis when the inhibitor was administered in the post-initiation phase only.[14] The hydrolyzable tannins are based on the structural unit of gallic acid and are invariably present as multiple esters of D-glucose (gallotannins). The derivatives of hexahydroxydiphenic acid (ellagitannins) present in plants are assumed to be derived by oxidative coupling of adjacent galloyl ester groups present as a polygalloyl D-glucose ester, as shown in Scheme 1.[15] To replicate this coupling in the laboratory has Journal compilation Ó CSIRO 2011
proven difficult. Mishra and Gold [16] reported the preparation of ellagic acid by oxidation of gallic acid in a mixture of glacial acetic acid and conc. H2SO4 (20:1, v/v) using K2S2O8 and the yield was reported as only 10 %. In another process, Stoner et al.[17] synthesized ellagic acid from methyl gallate and ammonium hydroxide using a direct oxidative coupling method, and the yield reported was only 47 %. Alam and Tsuboi[18] reported the challenging unsymmetric biaryl bond formation for the synthesis of 3,30 ,4-tri-O-methylellagic acid by the intramolecular Ullmann coupling reaction from gallic acid, but with limited success. Hence a direct synthesis of EA has been a challenge due to the difficulty in carrying out this oxidative aryl–aryl coupling. In recent years, ionic liquids (ILs) have been extensively investigated for use as replacement solvents for many organic chemical reactions.[19–21] Recently our group investigated the use of N,N-dimethylammonium N0 ,N0 -dimethylcarbamate, DIMCARB (a distillable ionic liquid) to extract hydrolyzable tannins in high yield from plant materials.[22] The major advantage of this ionic liquid is its ability to dissolve a wide range of organic compounds to an appreciable extent and the ease with which it can be recovered after the reaction. These ionic liquids are less viscous than imidazolium ILs, can be distilled easily, and reused without significant loss of purity. The objective of the present study was to employ these ‘distillable’ ionic liquids as a reaction solvent-cum-catalyst for the direct synthesis of EA from ethyl gallate. OH
OH O
O
HO
OH
O HO
O
OH
⫺2H OH O
HO OH
Bisgalloyl ester (gallotannin)
O
OH O
HO
O
OH Hexahydroxydiphenoyl ester (ellagitannin)
Scheme 1. Derivation of ellagitannins by oxidative coupling.
www.publish.csiro.au/journals/ajc
One Pot Synthesis of an Ellagic Acid Salt
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Thus in the present study we have employed N,Ndimethylammonium N0 ,N0 -dimethylcarbamate (DIMCARB) ionic liquid for the synthesis of EA from ethyl gallate. The synthesis of the DIMCARB ionic liquid followed the literature procedure.[23] Typically 0.66 g (3.3 mmol) of ethyl gallate was
2.694 A
2.763 A
2.788 A 2.738 A
Fig. 1. Crystal structure of bis[3,8 dimethylammonium]2,7-dihydroxychromeno[5,4,3-cde]chromene-5,10-dione dehydrate.
added to 4.43 g (33.1 mmol) of DIMCARB along with 0.12 g of water in a 100 mL round bottom flask and the homogenous mixture was stirred at room temperature for 5 h. Then 2.30 g of water was added to the reaction mixture and the mixture was left overnight. A light yellow coloured crystalline solid precipitated. The solid was filtered, washed with hot water and dried at 808C for 1–2 days. An unoptimized yield of 70 % was obtained. Electrospray ionisation mass spectroscopy showed the ellagate anion at m/z: 301.1 ([M1] and the dimethylammonium cation at m/z: 46.1 [Mþ1]. The melting point was found to be .3508C. 1H NMR (300 MHz, [D6]-DMSO) d 7.2 (2H, s, ArH), 2.6 (6H, s, N(CH3)2), 4.4 (4H, broad peak, OH/H2O) data and the crystal structure obtained indicate that the product obtained is the bis(dimethylammonium) salt of ellagic acid. The 13C NMR data pertaining to the title compound has been given in the supplementary information (Table 3 in the Accessory Publication). A crystal structure analysis was performed on a crystal cut from large needle shaped crystals that formed slowly from the reaction mixture after further addition of water (Fig. 1). The structure is that of a bis (dimethylammonium) salt hydrate of ellagic acid, bis[3,8-dimethylammonium]2,7-dihydroxychromeno[5,4,3-cde]chromene-5,10-dione dihydrate, 1 (Fig. 1 and Fig. A1 in the Accessory Publication). The packing of 1 (Fig. 1) consists of infinite 1D chains of cations, anions and water molecules, lying parallel to the a axis, each chain supported by a hydrogen bonded network (Table 1 in the Accessory Publication). The individual chains are periodically linked by a four membered O—H O—H O—H cooperative ring involving the anion of neighbouring chains to the water and a subsequent anion of the studied chain (Fig. 2). Each anion is hydrogen bonded to four cations and four waters. Each cation is hydrogen bonded to two anions which are stacked above each other, thus resulting in a cooperative C—O H—N—H O-C chain. The orientation of this ionically intercalating chain results in p p ring interactions between the aromatic rings of the anion (Table 2 in the Accessory
3.37 A
2.74 A
2.79 A
2.76 A 2.70 A
Fig. 2. A section of the extended packing of bis[3,8 dimethylammonium]2,7-dihydroxychromeno[5,4,3-cde]chromene-5,10-dione dihydrate displaying the O–H O (labels in red) and N–H O (labels in blue) hydrogen bonding.
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S. A. Chowdhury et al.
Publication). The anionic O2A hydrogen bond distance is marginally shorter than those for O3A, as expected for a charged interaction. The direct synthesis of bis(dimethylammonium) ellagate, 1, from ethyl gallate involves the formation of a new aryl-aryl C-C bond by oxidative coupling (Scheme 2) as well as the formation of two intramolecular ester linkages. A plausible mechanism for this reaction, that is DIMCARB mediated, is shown in Scheme 3. DIMCARB is formed by the condensation reaction of CO2 and HN(CH3)2. These two species exist in equilibrium in the liquid with the dimethylcarbamate anion. The mixture is distinctly basic in nature and therefore acts as a good medium for the ester interchange and deprotonation reactions in Scheme 3. It also provides a source of dissolved CO2 for the abstraction of H to form HCOO in the oxidative coupling step. There was evidence of formation of the formate ion in the mass spectral analysis of the crude reaction mixture. It is also possible that dissolved O2 gas could serve as the oxidant in this reaction. However, in the reaction system involved there would be insufficient oxygen present to produce the yield obtained in the reaction.
In conclusion, EA salts can be synthesized in one step at room temperature using DIMCARB ionic liquid and the subsequent EA can be easily obtained after washing the derivative with hot water. The reaction involves an unusual oxidative coupling reaction that appears to be mediated by the DIMCARB solvent, in which CO2 is readily available to act as a Lewis acid in the oxidative coupling step. Methods Crystallography Crystallization of bis[3,8-dimethylammonium]2,7-dihydroxychromeno[5,4,3-cde]chromene-5,10-dione dihydrate (1) was achieved via recrystallization of the resultant light yellow crystalline product using 2.30 g of water at 298 K. Crystals resulted after one day. The reflection intensity data were measured on a Bruker X8 APEX KAPPA CCD single crystal X-ray diffractometer, using graphite-monochromated MoKa radiation ˚ ). Crystals were coated with Paratone N oil (l ¼ 0.71073 A (Exxon Chemical Co., Houston, TX) immediately after isolation and cooled in a stream of nitrogen vapour on the diffractometer. O O⫺
O O
HO
O
2
HO
i) DIMCARB at r.t.
HO
OH
2 C2H5OH ⫹
ii) H2O
CH3
O
⫺
O
OH
CH3
⫹ H2N
O bis-dimethylammonium ellagate
Ethyl gallate
Scheme 2. Synthetic pathway of bis-dimethylammonium ellagate.
O HO
O O
2
HO trans-esterification
2 C2H5OH
HO
⫹
DIMCARB
OH
O OH
HO O
OH
Ethyl gallate O “Diester” DIMCARB ⫺H⫹ CO2 O
O
O
⫺
O
⫺
O H HO
O
O OH
OH
HO
⫺
O
OH
HO O
O
OH
O
O
O
O
O
O HO HCOO⫺
O HO
O
⫹
OH
OH
OH
HO O
OH
⫺2H⫹
⫺
O O⫺
O O
OH
O
O
Ellagic acid
Ellagate anion
Scheme 3. Possible mechanism for the formation of ellagate anion from ethyl gallate.
2
One Pot Synthesis of an Ellagic Acid Salt
Structures were solved by direct methods using the program SHELXS-97 and refined using SHELXL-97[24]. All non-hydrogen atoms were revealed in the E-map and subsequent difference electron density maps, and thus placed and refined anisotropically. The H atoms of C4A, O3A, C1, and C2 were observed in different syntheses, were placed in geometrically idealized positions, and constrained to ride on their parent atoms ´˚ and Uiso(H) ¼ with C—H distances in the range 0.95–1.00 A xUeq(C), where x ¼ 1.5 for methyl and 1.2 for all other C atoms. All other H atoms were located and placed. Crystal data for (I): C14H4O8 2(C2H8N1) 2(H2O), M ¼ 428.39, monoclinic, space group P21/n, a ¼ 4.7321 (6), b ¼ 11.142 (2), c ¼ 18.021 ´˚ , b ¼ 93.30 (3)8, U ¼ 948.6 (3) A ´˚ 3, Z ¼ 2, D ¼ 1.500, (2) A c 1 t ¼ 123 (2) K, m(Mo-Ka) ¼ 0.12 mm . Full-matrix least-squared refinement was based on 2134 reflection data and yielded wR2 ¼ 0.154 (all data), R1 [1679 data with F2 . 2s(F2)] ¼ 0.088, and goodness-of-fit on F2 ¼ 1.20. Accessory Publication Crystallographic information and structural identification (13C NMR spectroscopy) of the title compound is available on the Journal’s website.
Acknowledgements We thank the ARC Special Research Centre for Green Chemistry, Monash University for financial support.
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