Synthesis of 2-Acetylcyclohexanone via Enamine Intermediate Formation

Heston Allred & Kelly SchaichSuchetan PalThursday 11:30-2:20 pmLab 10&11

Abstract2-Acetylcyclohexanone, was synthesized from cyclohexanone and the secondary amine, pyrrolidine, using an enamine as an intermediate product. First, the enamine was formed using p-toluenesulfonic acid as a reagent. The reagent reacted with cyclohexanone and pyrrolidine via an acid catalyzed addition-elimination reaction. After enamine formation, acetic anhydride and water were used to form the final product of 2-acetylcyclohexanone via an acylation reaction. The percent yield was determined to be xxxxxx and the IR spectra was consistent with the product formed.

IntroductionThe purpose of this experiment was to synthesize 2-acetylcyclohexanone from cyclohexanone and pyrrolidine. Therefore, a new carbon-to-carbon bond needed to be formed in order to get the desired product. This can be achieved through acylation or alkylation reactions, which remove the hydrogens of the -carbon of carbonyl compounds. Acylation reactions, however, can often produce unwanted side products because the equilibrium for carbonyl compounds, which are reacted with aqueous sodium hydroxide, is unfavorable toward product formation. This is because of the high pKA of carbonyl compounds and thus the concentration of the nucleophilic conjugate base is low compared to the concentration of the OH- nucleophile. This causes other side reactions to occur more favorably and results in low product yield. In order to synthesize the product more effectively an intermediate enamine product was formed first, from the carbonyl compound of cyclohexanone and the secondary amine, pyrrolidine, through an acid catalyzed addition-elimination reaction. This produced the necessary enamine, which acted as a strong nucleophile under mild reaction conditions, allowing the acylation reaction equilibrium to be pushed to the right and thus be more effective in producing the desired product.Acid catalyzed addition-elimination reaction:

Acylation reaction:

Mechanism:

Procedure0.40 mL toluene was added to 0.64 mL cyclohexanone. 20 mg p-toluenosulfonic acid monohydrate was then added to this mixture followed by 0.54 mL of pyrrolidine. The mixture was then distilled, with stirring, for about 30 minutes maintaining a temperature of no less than 140C. Two mL of distillate was removed as the distillation process was occurring. The reaction mixture was then cooled to room temperature. 0.64 mL acetic anhydride previously dissolved in 1.0 mL toluene was added to the enamine. The mixture was swirled and allowed to stand for one week. 1.0 ml water was added, followed by boiling with stirring for 30 minutes at roughly 120C, after which it was cooled to room temperature. Another portion of 1.0 mL water was added, the mixture shaken, and then extracted. 2 mL of 6M hydrochloric acid was added to the toluene layer containing the product, shaken, and extracted, followed by 1.0 mL water, reshaken, and then extracted again. Four microspatulas of granular anhydrous sodium sulfate, added and the organic phase, were placed in a water bath at 70C with a stream of dry air until the volume was between 0.3 and 0.5 mL in a 5-mL conical vial. The resulting product and residue was retained for purification via column chromatography. 1.0 g of alumina was used as the absorbent. 0.5 mL methylene chloride was added to the crude product, which was percolated in the column after 1.0 mL of methylene chloride was added. After the mixture had passed through, doses of methylene chloride were added totaling 5 mL until all of the product had gone through. Half of the resulting product was then placed in a water bath at 50C with light air until the volume was 0.5 mL in a 5-mL conical vial followed by the remaining product with the same procedure being followed. The percent yield was determined and an infrared spectrum taken.