Jamie Brown, Chem 213Synthetic #2 FFRSynthesis of DibenzalactetoneIntroductionIn this experiment dibenzalacetone was purified by recrystallization after it was produced by a Claisen-Schmidt reaction with benzaldehyde and acetone. The Claisen-Schmidt is an aldol condensation reaction, which takes place between an aromatic aldehyde and a ketone to result in an enone. An enone is a conjugated ketone product such as dibenzalacetone, which can be used as a good way to make C-C bonds (1) due to the positive charge that can be produced at the unsaturated carbon and is susceptible to nucleophilic attack. Condensation reactions like the Claisen-Schmidt reaction are useful due to the reactive nature of its intermediate enolate ions, which when produced leave the possible nucleophilic carbon site through the movement of electrons or deprotonating the carbon (1). The result of a condensation reaction is the loss of water and production of a , unsaturated ketone or aldehyde.Dibenzalacetone is an organic compound, which in this case was yellow solid after recrystallization. Dibenzalacetone is a known component of sunscreen or as a metallic ligand in biological chemistry (1). Also recent research is implicating that dibenzalacetone may also have antibiotic behavior to pathogens such as tuberculosis and be associated with anti-cancer activity such as apoptosis (2). The most prevalent evidence with this finding is related to that of throat cancer in, which dibenzalacetone is found to cause apoptosis to the mucoepidermoid carcinoma cells. Evidence of dibenzalacetone as an antibiotic for pathogens entails that it is not directly dibenzalacetone, which is an antibiotic but rather a derivative of it , such as in this case a 2-chlorodibenzalacetone.

In this mechanism the hydroxide group of the NaOH dissociates from the sodium and attacks a proton on the carbon of acetone. The departure of the proton from acetone then makes the site of the carbon nucleophilic. Then the nucleophile attacks the carbon of the carbonyl in benzaldehyde to create a ketone connected to an aryl enolate ion. The charge of the enolate is concentrated on the oxygen atom, which then attacks a proton from the newly created water to create a hydroxide group in place of the enolate ion. An carbon shared between the two oxygen bonded carbons then is deprotonated by attack of a hydroxide, which leaves a negative charge at the site of the carbon. The electrons creating the negative charge on the carbon then bond between the carbon of the hydroxide group and the in this step the hydroxide detaches from the carbon as well due to the creating of a double C=C bond at the and positions of the compound. Hydroxide then attacks an proton on the carbon terminal to the ketone group. This attack results in a negative charge on the terminal carbon, which then attacks the carbonyl of another benzaldehyde from the carbon and creating an enolate ion connected to a enone but pushing the electrons to the oxygen atom. The oxygen atom then attacks a proton on the newly formed water to create a hydroxide group on the carbon of the enolate. Hydroxide then comes and attacks an proton on the carbon between the ketone group and the hydroxide group. At this point water is loss from the reaction. Then electrons on the negatively charged carbon create a C=C double bond between the and carbon. As the double bond is formed the hydroxide group detaches from the carbon resulting in the product dibenzalacetone.Experimental:Dibenzalacetone. Benzaldehyde (.4248g, 4mmol), 95% ethanol (3mL, 2.367mmol), and 3M sodium hydroxide (4mL, 8.52mmol) were added to an Erlenmeyer flask (10mL) and stirred for 1 hour. Acetone (.146ml, 2mmol) added using calibrated pipette (1mL) after reaction mixing had started. Reaction monitored by TLC (30% ether/ 70 hexane but then changed to 30% ethyl acetate/70% hexane due to poor results). After running reaction to completion cooled in ice bath to start recrystallization. Water (1mL) added to flask, then decanted into Hirsch funnel for vacuum filtration and washed with water (3mL). After drying crystals, recrystallized dibenzalacetone (.206g, .88mmol) in solvent (70% ethanol/30% water) and decanted into Hirsch funnel for vacuum filtration to be dried. Product was trans, trans-dibenzalacetone (.162g, .69mmol, 78.6%) mp 103-110 o C; IR (ATR) max (cm-1) 3330.2, 2820, 1685, 1675; 1H NMR (40 MHz, CDCl3) (ppm) 1.8 (d, 2H), 4.7 (d, 2H), 7.3-8 (t,10H); 1H NMR (400 MHz, CDCl3) (ppm) 1.7( d, 2H), 4.7(d, 2H), 7.1 (d, 2H), 7.3-7.5 (t, 6H), 7.6-7.7 (q, 4H), 7.7-7.9 (d, 2H); UV/Vis (ethanol) 328nm, 34,300.Results, Discussion, & Conclusion: In this reaction dibenzalacetone was made by a Claisen-Schmidt condensation using benzaldehyde and acetone with sodium hydroxide. To purify the product the dibenzalacetone was recrystallized and dried so it could be identified by its use as one of the three possible dibenzalacetone isomers. The synthesis of dibenzalacetone was run 15 minutes longer then recommended because when a TLC plate was analyzed at the 45-minute mark the observed results showed that some starting material still remained. In analysis through IR the results picked up the aldehyde group stretch from the starting material so the reaction actually could have been run longer because it was clearly not run to completion with no starting material. The purification process was a success because crystals were formed rather easily since seeding or scratching did not need to be done for crystals to form. During the dissolving process though the solvent was switched to a 80% ethanol/ 20% water mix because there was a slight difficulty getting all the product to dissolve in order to supersaturate the solution. The percent yield of product obtained was 78.6% compared to the expected yield of 90-94% from the theoretical yield of this dibenzalacetone isomer (3). The percent recovery was also low because it was not about 44%, which means that the process of had a number of possible issues that could have affected the yield. A possible issue could be from the reaction not running to completion as seen from the IR data picking up the aldehyde group stretch. Another could have depended on the process of recrystallization, because the solvent proportions were changed from 70% ethanol/ 30% water to 80% ethanol/ 20% water to help with dissolving due to time restraints, which could have affected the amount of dibenzalacetone that recrystallized back out of solution since dibenzalacetone is highly soluble in ethanol.

After a number of analyses the product was identified to be the trans, trans-dibenzalacetone isomer. The product was first identified as being a dibenzalacetone isomer from IR, 40 MHz, and 400MHz 1H NMR. The IR identified. The 40 MHz 1H NMR identified the aromatic hydrogen atoms in region of 6.8-8 ppm, the region of the vinyl hydrogen atoms at 4.7ppm, and the region representing the ketone hydrogens right under 2 ppm and the 400 MHz 1H NMR gave additional incite to the aromatic hydrogen region of 6.5-8 ppm by showing the individual distinguishable hydrogen atoms of each of trans, trans-dibenzalacetones two aromatic rings. The analysis that assured that the product was indeed trans, trans-dibenzalacetone was the UV/Vis (ethanol), which picked up an absorbance at 328nm eliminating the isomers because the three isomers of dibenzalacetone show absorbance at different wavelengths as well as different IR, NMR and melting point results. The melting point confirmed the previous analyses because the experimental melting point was 103-110oC, which corresponded to the theoretical melting point in the range of 110-111o C (3). To conclude in this purification process dibenzalacetone was produced with a yield of 78.6% of the trans, trans isomer. The process of recrystallization is thus an effective method of purification as long as the appropriate solvent is used because in this process this along with not running the reaction long enough caused problems in the recovery and yield of the product. Future exploration into the synthesis of dibenzalacetone will need to keep in mind solvent effects on the process to increase the yield. Also exploration is necessary in testing the anti-cancer activity of dibenzalacetone so it can be utilized for treatment if appropriate given that dibenzalacetone is acutely toxic.

Reference:1. Azerang, P.; Sardan, S.; Sedighi, V. Synthesis of Dibenzalacetone Derivatives and Evaluation of their Antimycobacterial Property. Inter. Conf. on Advances in Biological and Pharmaceutical Sci. 2012. 215-2172. Cho, S.D.; Choi, E.S.; Jung, J.Y.; Lee, H.E.; Kim, L.H.; You, M.J. Inhibition of Specificity Protein 1 by Dibenzylideneacetone, a Curcumin Analogue, Induces Apoptosis in Mucoepidermoid Carcinomas and Tumor Xenografts through Bim and Truncated Bid. Oral Oncology.2014. 50. 189-1953. Conrad. C.R.; Dolliver. M. Dibenzalacetone. Organic Syntheses, Coll. 1943. 12. 167

Supplemental Information:IR, NMR, and UV/Vis data

Figure 1: UV/Vis (ethanol) of dibenzalacetone

Figure 2: 400 MHz 1H NMR of dibenzalacetone

Figure 3: 1H 40MHz NMR of dibenzalacetone

Figure 4: IR of trans, trans-dibenzalacetone