CH 2280

GREEN CHEMISTRY: SYNTHESIS OF DISUBSTITUTED CHALCONES – THE ALDOL REACTION (Adapted from a procedure by J. R. Mohrig, C. N. Hammond, and P. F. Schatz.)

Materials From the Chemicals Hood: Nothing from the Stockroom 4-Methylbenzaldehyde 4-Methoxyacetophenone 4-Methoxybenzaldehyde 4-Fluoroacetophenone 4-Chlorobenzaldehyde 30% Sodium hydroxide aqueous 4-Benzyloxybenzaldehyde solution 4-Methylacetophenone Ethanol

Scenario: You will synthesize a disubstituted chalcone and use a variety of analytical techniques to discover which of its functional groups are reduced by catalytic hydrogenation. Most research in organic chemistry involves multifunctional molecules. Indeed, most organic compounds found in nature, as well as modern pharmaceutical agents, are multifunctional molecules. Determining which functional groups react in a chemical reaction is critical to the success of synthetic organic chemistry. Another goal of organic synthesis is to discover environmentally friendly reactions, called green chemistry, where a minimum of waste is produced and the reactions have high atom economy. One of the goals of green chemistry is the use of less hazardous solvents. The synthesis of chalcones can even be done with no solvent. However, the use of water as a solvent leads to a more uniform product. This straightforward synthesis demonstrates the important chemistry of the aldol condensation followed by dehydration to form a conjugated ketone. Chalcones are an important class of naturally occurring compounds of interest to the pharmaceutical industry for their potential antitumor, antibacterial, antifungal, and anti-inflammatory activity. A set of chalcones will be synthesized in this project, using a variety of para-substituted benzaldehydes and acetophenones. After purification by recrystallization and characterization by melting point, infrared and NMR spectroscopy, the chalcones will be readily identifiable.

SAFETY INFORMATION Wear gloves while conducting this experiment. The aldehydes and ketones used in this project are skin and eye irritants. The concentrated aqueous sodium hydroxide solution is corrosive. Contact with it can cause burns.

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R1 Name R2 Name Chalcone mp, °C

CH3 4-Methylbenzaldehyde CH3 4-Methylacetophenone 1 126-127.5

OCH3 4-Methoxybenzaldehyde OCH3 4-Methoxyacetophenone 2 100-101.5

CH3 4-Methylbenzaldehyde OCH3 4-Methoxyacetophenone 3 127-127.5

CH3 4-Methylbenzaldehyde F 4-Fluoroacetophenone 4 146-147.5

Cl 4-Chlorobenzaldehyde CH3 4-Methylacetophenone 5 146-147.5

Cl 4-Chlorobenzaldehyde OCH3 4-Methoxyacetophenone 6 127-128.5 Cl 4-Chlorobenzaldehyde F 4-Fluoroacetophenone 7 136-137

C6H5CH2O 4-Benzyloxybenzaldehyde CH3 4-Methylacetophenone 8 108-109

C6H5CH2O 4-Benzyloxybenzaldehyde OCH3 4-Methoxyacetophenone 9 116-117

Techniques: Recrystallization Melting Point Infrared Spectroscopy NMR Spectroscopy

Procedure: Your group will be assigned an aldehyde and a ketone to use in your chalcone synthesis. Combine 14.0 mmol of your aldehyde and 14.0 mmol of your ketone in a 50-mL Erlenmeyer flask. Stir the mixture with a glass rod until a homogeneous liquid forms. Add 4 mL of 30% aqueous NaOH to the Erlenmeyer flask. The best way to do this is to pour a very small amount of this solution into a beaker, then use a plastic disposable pipet to transfer 1 mL at a time into the Erlenmeyer flask containing the aldehyde/ketone mixture. Pour any left over NaOH solution into the “Base Waste” 5-gallon waste container in the hood. Stir the contents of the Erlenmeyer flask occasionally with a stirring rod for 10 min or until the mixture solidifies. Next, heat the mixture on a steam bath for 15 min. The mixture may liquefy upon heating. Cool the reaction mixture to room temperature. If the product does not solidify in 5 min, stir the mixture while cooling it in an ice-water bath. If solidification does not occur by cooling and stirring, add 1 mL of ethanol to the crude product and stir to induce crystallization. If solidification still does not occur, heat the product on the steam bath. If the reaction mixture is completely solidified, add 5 mL of water and stir it with a stirring rod until a suspension forms. Collect the product by vacuum filtration, and while the vacuum is still connected wash the product with 20 mL of water. Transfer the solid into a 125 mL Erlenmeyer flask and recrystallize the crude product from ethanol. Allow the product to dry until the next lab period, and then obtain its mass and melting point. Compare the melting point with the literature value listed above. Calculate your percent yield. Obtain an infrared spectrum and NMR spectrum of the purified chalcone. Save the remainder of your product for next week’s hydrogenation.

Cleanup: Discard the filtrate from the reaction mixture in the container labeled “Base Waste.” If your chalcone does not contain chlorine or fluorine, place the recrystallization filtrate in the container for flammable organic waste; use the container for halogenated organic waste if your chalcone contains chlorine or fluorine. 2