Synthesis of 2-Acetylcyclohexanone via Enamine Intermediate

Formation

Heston Allred & Kelly Schaich

Suchetan Pal
Thursday 11:30-2:20 pm
Lab 10&11

Abstract
2-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 2acetylcyclohexanone via an acylation reaction. The percent yield was determined to be
xxxxxx and the IR spectra was consistent with the product formed.

Introduction
The 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:

Procedure
0.40 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.