FeCl 3-catalyzed Synthesis of Dehydrodiisoeugenol

Dehydrodiisoeugenol (DDIE) synthesis has been performed by modifying a method recommended by Leopold with a different ratio of isoeugenol and FeCl3 (1.9:1). FeCl3 was chosen as catalyst due to its efficiency and environment-friendly property. This modification yielded 22.93 % of product. The product, a white crystalline form, was characterized using thin layer chromatography, melting point, UV, IR, HRMS, and NMR spectroscopy, as well as HPLC, employing pure DDIE as the standard. TLC chromatogram showed Rf 0.32 using n-hexane/ethyl acetate (8:2). The crystals melted at 138-139 C, while its UV maximum was detected at  273 nm. IR spectrum showed a specific broad O-H stretch at 3437.15 cm, C-H aromatic and C-H alkene at 3163.26 and 3024.38 cm, C-H alkyl stretch at 2951.09 and 2927.94 cm. An overtone peak of aromatic was detected at 2100 to 1700 cm. C-O peak was detected at 1126.43 cm. HPLC showed that this compound was eluted at 11.886 minutes after it was injected to a C18 column 250 x 4 mm using a mixture of methanol and double distilled water (73:27) for mobile phase. HRMS spectra predicted that the molecular structure is C20H22O4 as showed by abundance peak at m/z 327.1595 of [M+H]. H-NMR and C-NMR indicated that the synthesized compound contains 13 types of proton and 20 types of carbon. Herein we reported that white needle-like crystals of DDIE using FeCl3 as catalyst had been synthesized, moreover the decreasing of the catalyst reduced the yield of the product.

Previous study determined that the level of DDIE, myristicin, and safrole in the ethanol extract of nutmeg seeds was 4.662 %, 17.226 %, and 10.979 %, respectively using RP-HPLC (Saputri, 2014).Isolation of bioactive compounds from plants is a wholesome-work therefore this research was aimed to synthesize DDIE by employing FeCl 3 as catalyst.
The coupling of two phenoxy radicals leads to new asymmetric stereo-centers.The reaction can lead to pure enantiomers or mixtures if stereo-control exists due to a catalyst and/or matrix and/or chiral auxiliarities in the starting compound.The coupling will form a very reactive quinone methide intermediate, which could react quickly with a suitable nucleophile and leads finally to a stable dimeric structure called lignin or dilignol (Setälä, 2008).
Leopold categorized eight groups of lignin compound with different elements, whereas DDIE was categorized in group VII.Leopold method in which 50 g of isoeugenol, as the starting material, was reacted with a few crystals of DDIE, had successfully yielded 30 % of the product.This reaction was catalyzed by FeCl 3 with ratio of isoeugenol-FeCl 3 1.4:1 (Leopold, 1950).In his paper, Leopold did not provide detailed information, either of the amount of DDIE that he had used for the reaction or the characterization analysis of the product.
FeCl 3 was chosen in this reaction, due to its efficiency and green catalyst property in modern organic synthesis (Diaz et al, 2006).The use of FeCl 3 as catalyst were reported for arylation of benzyl alcohols and benzyl carboxylates (Zhan and Liu, 2006), benzylation of 1,3-dicarbonyl compounds (Komeyama et al, 2007) and the synthesis of 1-substituted-1H-1,2,3,4-tetrazoles.The latter mentioned that an excess of FeCl 3 , as catalyst, did not lead to a substantial improvement in the yield while decreasing the catalyst reduced it (Darvish and Khazraee, 2015).

Synthesis of DDIE
This compound was synthesized by modifying a method recommended by Leopold (Leopold, 1950): 1 mL of isoeugenol 99.0 % oily solution was slowly added by stirring, into a mixture of 12.06 mL ethanol 95% and 5.36 mL of double-distilled water, until the two immiscible liquids dissolved.Into this mixture, 5 mL of FeCl 3 35% (isoeugenol: FeCl 3 = 1.9 : 1) was added and stirred until a yellowish-green precipitate formed (Fig. 2a).Then, 230 µL of 500 μg/mL DDIE standard was poured into the solution.The mixture was kept at 5 o C for 24 hours.The white crystalline formed (Fig. 2b) was vacuum-filtered and washed with 45% ethanol.

Thin Layer Chromatography
A few mg of the white crystalline product was dissolved in methanol and eluted on silica gel F 254 (Merck) using a mixture of n-hexane-ethyl acetate (8:2) as eluent.Both isoeugenol 99.0 % and DDIE standard were used as comparison.

UV Spectroscopy
2 mg of the white crystalline product was dissolved in 100 ml of double-distilled water to get 20μg/ml.This solution was measured its absorbance against water in UV-1700 Pharma (Shimadzu) spectrophotometer.

IR Spectroscopy
2 mg of the white crystalline product was dispersed in 198 mg of previously dried KBr.The disc was measured its %T using FTIR IRAffinity-1 (Shimadzu).

HPLC
20 μl of 20 μg/ml solution was injected to C18 column, 250 mm x 4 mm of HPLC 1525 Binary HPLC Pump (Waters) instrument, using a mixture of methanol and double-distilled water (73:27) as mobile phase.Flow rate was set at 1 ml/min.The UV detector was set at 282 nm.

HRMS
A few mg of the white crystalline product was dissolved in a mixture of acetone and 0.1 % formic acid in acetonitrile-water (1:1).The solution was ionized by heating it at 300 o C after it was injected to a capillary column of HRMS (Waters LCT Premier XE).TOF was used as detector.

NMR
10 mg of the white crystalline product was dissolved in CDCl 3 and injected in 1 H-NMR (Agilent), 13 C-NMR (Agilent).Spectrum was recorded at 500 MHz and 125 MHz Agilent, respectively, and analyzed using VnmrJ 3.2 software.

Result and
Leopold, who isoeugenol-Fe this paper.
In our project yellowish-gre 230 μl of DDI