Ultrasonic Waves Assisted Synthesis of Curcuminoids Based on 3- Methylacetylacetone and in Situ Synthesis of Gold Nanoparticles Capped with Curcuminoids

Ultrasonic irradiation was used to induce the Knuevenagle reaction between aromatic aldehydes and 3methylacetylacetone to synthesize curcumin analogues with moderate to good yields. The structures of the compounds were established by elemental analysis and from their mass and 1 HNMR spectra. In situ curcumin-gold nanoparticles were synthesized. The solutions of the prepared nanoparticles have purple to deep-red colors and their UV-vis spectra were characterized by the Surface Plasmon Resonance bands within the range 538-554 nanometer.


Introduction
Due to its practical benefits compared to conventional methods large numbers of compounds have been synthesized by ultrasound waves irradiation of the reactants. The benefits include higher yields, shorter reaction time and milder conditions. The synthesized compounds by this technique span over wide spectrum including organics [1][2][3]inorganics [4][5][6], polymers [7,8] and nanoparticles [9,10].
Curcumin is of considerable interest and is well-known compound because of its antioxidant [11][12][13], anti-inflammatory [14], antimicrobial [15] and anticarcenogenic activities [16][17][18][19]. In addition it is unique among active compounds because it is extremely safe even at very high doses. On the other hand and due to the presence of the olefinic groups in it structure this β-diketone of poor aqueous solubility rendering it of relatively low bioavailability [20]. This reason prevents curcumin to be approved as pharmaceutical agent. In order to overcome this shortage, synthesis of compounds with the same or even hopefully with better activities but with reasonable water solubility are continuously in progress. The best choice in this case is the synthetic analogues or derivatives less or more related to curcumin. Curcumin nanoparticles as pure curcumin or as adsorbed curcumin on gold surfaces were reported to enhance the solubility of curcumin in water and its biological activities [21][22][23][24][25][26][27][28].
In this work we report the synthesis of curcumin analogues via the reaction of aromatic aldehydes and 3methylacetylacetone under ultrasound irradiation (Scheme I) as well as the synthesis of the nanoparticles of some curcuminoids.

Results and discussion
The curcumin analogues were synthesized by altrasonic-assisted Knuevenagle reaction of 3-methylacetylacetone with variety of aromatic aldehydes in the presence of boric oxide and aminoethanol. The reactions were done with relatively short times (20 min) as compared to the conventional reaction. The general synthesis procedure is shown in scheme I. The synthesized compounds were confirmed by elemental analysis and by mass and 1 H NMR spectra. The infrared spectra were characterized by a strong band within the range 1618 -1625 cm -1 due to the stretching vibration of the carbonyl group which is shifted to lower frequencies due to both its conjugation with the unsaturated ethylinic system and participation in the intrahydrogen bonded chelated ring. This proved that the compounds are present mainly in the enolic form. The mass spectra showed the peak of the parent ion and a base peak results from the ion due to fragmentation at the methylene group of the chelated ring. The spectra were also characterized by a general peak due to the ion resulted by losing the Ar-CH=CH-fragment. The 1 H NMR spectra confirms the enolic structure of the compounds by two notes. First the absence of the methylene signal which must be present in the spectra of the keto form and such a signal presents at 2.34 ppm in the spectrum of the keto form of acetylacetone. Second the presence of the much more downfield peak (17.04 -17.84 ppm) which attributed to the intrahydrogen bonded chelated proton of the enolic OH group as it is the case with β-diketones [29]. Scheme 1. Synthesis of curcumin analogues, reaction conditions and prepared compounds.
The curcuminoid capped gold nanoparticles (AuNPs) were synthesized in situ by the adsorption of compounds on the gold nanoparticles surface. The formation of the nanoparticles was confirmed by their electronic spectra as follows. The electronic spectrum of the gold solution is characterized by a long and strong band at 287.9 nanometers while the electronic spectra of the curcuminoids are characterized by long bands at 419.9 -458.4 nm and accordingly has yellow colors. When the species were brought to contact their solutions changed to purple or deep-red color depending on the curcuminoid. These solutions are characterized by bands appear at longer wavelengths which are not present in the gold or the curcuminoid solutions. The resulting bands were interpreted as a Surface Plasmon Resonance (SPR) [30] that characterizes the electronic spectra of nanoparticles of organic compounds adsorbed on the gold surface and the optical properties of the nanoparticles depend strongly on their size, shape and interaction between the nanoparticles and the adsorbed species on the surface of the nanoparticles. Figs. 1-5 show the UV-vis spectra of chloroauric acid (1), the curcuminoid (2) and AuNPs (3). In all cases a new band at longer wavelength is appeared which attributed to surface Plasmon absorption maxima and situated at 554.6, 553.1, 538.4, 539.0, and nm for the curcuminoids 4, 5, 6, a, and b respectively. The difference of SPR bands is due to the varied level of size distribution of the nanoparticles in the solution and their aggregation [27]. It is worthy to note that efforts to prepare nanoparticles from curcuminoids that not have phenolic OH groups were failed with us.

General
NMR spectra were recorded on a Bruker 500 in deurated DMSO with tetramethylsilane as an internal standard. Mass spectra were determined on a Funigan instrument at 70 eV. Melting points were measured in open capillary tubes in a Thermo scientific apparatus. UV-vis spectra were measured with a CECIL CE7200 spectrophotometer in quartz matched cells of 1-cm pathlengths. Infrared spectra were recorded by Iraffinity-1 Shimadzu FTIR spectrophotometer. Elemental analyses were performed by Thermo Finnigan CHNS-O analyzer, 1112 series.

The Synthesis of curcuminoids
The compounds were synthesized according to the method described by Yingjie et al. [31]. A round-bottomed flask containing a mixture of boron oxide (0.013 mol), DMF (6 mL), monoethanolamine (0.37 mL) and trimrthylborate (2 mL) was set in an ultrasonic cleaner (40 kHz, 500 W). Aromatic aldehyde (0.025 mol) and 3-methyl-pentane-2,4-dione were added to the flask mixture and the contents were irradiated at 80 °C for 20 min. The progress of the reaction was monitored with TLC. After the completion of the reaction, the mixture was poured into 100 mL of 5% warm acetic acid. The crude product was filtered and separated by column chromatography on silica gel (200-300 mesh) using mixture of 1:3 hexane:diethylether as an eluent.
The method described by Singh et al. [27] was employed. HAuCl4 was added into 500 mL of water to make 1.5 x 10 -4 M. The mixture held at 90°C under constant sterring, followed by the addition of the curcuminoid (4 mg). The heating was stopped after the mixing of the reactants and allowed to cool to room temperature to form deep red to purple colored solutions depending on the curcuminoid used. The solution colors were purple for compounds 4 and 5 and deep red for compounds 6, a and b.

Conclusions
The synthesis of curcumin analogues could be accelerated by synthesis under ultrasonic radiation conditions. The reaction time by this method is only 20 min compared to about 3 h in the conventional reflux method. Concerning nanoparticles the presence of the phenolic OH groups in curcumin analogues may be essential for the synthesis.