Project 5 Procedure

Generic synthesis of chalcone epoxides.

In a 250 mL Erlenmeyer flask, benzaldehyde (2.2 mL, 22 mmol) and acetophenone (2.6 mL, 22 mmol) were dissolved in methanol (44 mL). Aqueous sodium hydroxide (30% m/v, 4.4 mL) was added dropwise over approximately 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then heated to a gentle reflux for 3-5 minutes. The flask was then cooled to room temperature. Aqueous hydrogen peroxide (30% m/v, 5.0 mL) was then added dropwise over a period of 3-5 minutes. The mixture was stirred in an ice-water bath for 1 hour, and then ice-cold water (50 mL) was added. The mixture was vacuum filtered, and the solid product was washed with cold water. Recrystallization from 95% ethanol gave the chalcone epoxide (4.144 g, 84%).

NOTE: If the reaction generates a solid pellet after the brief refluxing period, you may add 5-10 mL methanol and break the solid to achieve a more slurry-like consistency before adding the hydrogen peroxide.

UPDATE (11/8/21): Examine your Week 1 results carefully. Some groups may have isolated chalcone rather than the epoxide. Others may not have successfully isolated either product. If your group did not successfully produce the epoxide, you should spend Week 2 attempting to make it by other methods. Among the possible reasons for a failed reaction, two are especially likely in this case:

1) The insolubility of the initial chalcone product in methanol may have hindered its transformation to the epoxide.

2) Hydrogen peroxide solutions are unstable, and the concentration may change significantly over time. Since you did not titrate your hydrogen peroxide, its concentration was unknown. It is possible the quantity of peroxide added to your reaction was insufficient.

The two procedures below address both of these possibilities. Depending upon the quantity and quality of material you have in hand, you may choose to retry the one-pot chalcone epoxide synthesis under the modified conditions OR you may choose to epoxidize the chalcone sample you isolated.

ALTERNATIVE ONE-POT CHALCONE EPOXIDE SYNTHESIS. In a 50 mL Erlenmeyer flask, acetophenone (408 µL, 3.5 mmol) and benzaldehyde (357 µL, 3.5 mmol) were dissolved in methanol (7 mL). Aqueous sodium hydroxide (30%, 933 µL) was added, and the reaction was stirred at room temperature for 30 min. The mixture was heated briefly (2-3 min) on a hot plate to ensure complete reaction. (Additional precipitation was observed upon heating and the mixture was a thick slurry after heating was complete). After cooling the mixture to room temperature, enough acetone was added to completely dissolve the solids (~26 mL). Methanol (7 mL) was added to the solution, which was then chilled in an ice bath. Aqueous hydrogen peroxide (30%, 4 mL) was added dropwise over 3-5 minutes. The mixture was stirred for 30 minutes, then poured into ice cold water (50 mL). The resulting precipitate was collected by vacuum filtration. Recrystallization from 95% ethanol gave the chalcone epoxide.

CHALCONE EPOXIDATION PROTOCOL. In a 50 mL Erlenmeyer flask, chalcone (0.229 g, 1.1 mmol) was dissolved in acetone (~14 mL). Methanol (4 mL) was added to the solution followed by aqueous sodium hydroxide (30%, 293 µL). While the mixture was stirred at room temperature, aqueous hydrogen peroxide (30%, 1.2 mL) was added dropwise over 3-5 minutes. After 20 minutes, the reaction mixture was poured into ice cold water (20 mL), and the precipitate was collected by vacuum filtration. Recrystallization from 95% ethanol gave the chalcone epoxide. NOTE: The reaction may be monitored by TLC (6:4 hexane:ethyl acetate), and additional aliquots of hydrogen peroxide may be added if the reactant is not consumed after 20 minutes.

Generic synthesis of isoxazoles.

In a 25 mL round bottom flask, copper (II) triflate (0.044 g, 0.12 mmol) was added to a solution of chalcone epoxide (0.514 g, 2.29 mmol) in dichloromethane (5 mL). The reaction was monitored by TLC (8:2 hexane:ethyl acetate). After 30 minutes, the epoxide had been consumed. Hydroxylamine hydrochloride (0.180 g, 2.59 mmol) and 95% ethanol (5 mL) were added to the reaction mixture. The solution was refluxed for 45 minutes, then the solvent was removed by rotary evaporation. The resulting residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The product was obtained as a yellow oil (0.486 g, 98%).