Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-Enamine

J.
of Advanced Engineering and Technology

Vol. 2, No. 2 (2009) pp. 281-283
Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-enamine

Eun-SunYoo
Department of Oriental Medicine Industry, Honam University, Korea
(Received : May. 20, 2009, Revised : Jun. 02, 2009, Accepted : Jun. 12, 2009)
Abstract : 2-Acetylcyclohexanone was synthesized by acylation reaction of acidic anhydride using enamine
as organiocatalyst instead of a strong base, NaOH, resulting in milder reaction conditions. The reaction was
conducted in toluene and direct distillation of the reaction mixture before hydrolysis was leaded to a high
yield of the pyrrolidine enamine. This condition was leaded good yields (73.6%) without side reactions.
Acylation gave an enol form (71.7%) and a keto form (28.3%) of 2-acetylcyclohexanone mixture, the
composition of which was determined by 1H-NMR spectroscopy.
Key words : pyrrolidine, enamine, mild condition, NMR
1. Introduction
a higher reaction rate than the more weakly basic morpholine, while
cyclic amines generally produce enamines faster than open-chain
ones [5].
In this study, an enamine as organocatalyst is reacted with acetic
anhydride to synthesize 2-acetylcyclohexanone by acylation from
acetic anhydride as carbonyl compound. The purpose of this study
is to see if an pyrrolidone enamine can increase the product yield by
avoiding side reactions (Figure 1) with short time.
The formation reactions of carbon-carbon bonds are important in

organic synthesis [1-5]. In general, acylation reaction is one of the
important carbon-carbon forming reactions. It belongs to the
reactions of the enolate derived from a carbonyl group with an
electrophilic carbon such as Aldol, Claisen, Michael reaction and
alkylation of metal enolates [6-9].The acylation reaction as well as
above other reactions of enolates has serious limitations to be
overcome. In these reactions, a strong base NaOH is needed to
transform the carbonyl compounds into their anion forms.
Generally, the carbonyl compounds such as ketone and aldehyde
have high pKa values (pKa ~
20) [1]. It is difficult to make their
anion forms of carbonyl compounds by removing the hydrogens on
the -carbons because of their weakly acidic characteristics.
Therefore, the product yields of acylation, alkylation, and an aldol
condensation are low and unwanted side reactions occur (Figure 1).
In order to avoid side reactions, a good nucleophile needs to be
produced under mild reaction conditions. The rationale for selecting
an enamine to satisfy the above condition is that it is easily alkylated,
especially more C-alkylated than N-alkylated as shown in Figure 2.
The amines found most generally useful are pyrrolidine (reaction
of ketone enamines with alkyl halides and electrophilic olefins),
morpholine (acylation reactions, electrophilic olefins with ketone
and aldehyde enamines) and piperidine (electrophilic olefins with
aldehyde enamines) [3,4]. The rates of formation of enamines are
affected by two factors, the basicity and steric environment of the
secondary amino group and the nature and environment of the
carbonyl group [3]. Of the secondary amines used, pyrrolidine gives
Figure 1. The side reactions shown in the acylation using base.
Corresponding Author
Tel : 062-940-5564
E-mail : [email protected]
Figure 2. Nucleophilicities on nitrogen (I) and carbon (II) due

to the hybrid structuresof an enamine.
281
282
Eun-SunYoo
2. Experimental Section
2.1. Preparation of Enamine
Enamine of cyclohexanone was prepared by the usual azeotropic
procedure [1,2]. 3.2 mL of cyclohexanone (MW=91.1), 15 mL of
toluene, and 0.1 g of p-toluenesulfonic acid monohydrate, 4.0 mL
of cooled pyrrolidine (MW=71.1, d=0.85 g/mL), and a boiling
point were added to a 100-mL Erlenmeyer flask. The mixture was
heated under reflux for 30 minutes. Then it was distilled by simple
distillation with a receiving flask in an ice bath until the temperature
of mixture reached 108-110oC (bp of toluene). The product
(enamine) was cooled to room temperature [1,2].
2.2. Preparation of 2-Acetylcyclohexanone
3.2 mL of acetic anhydride (MW=102.1, d=1.08 g/mL) in 0.5
mL of toluene was added to the flask with the enamine product.
The flask with the mixture was capped with a stopper and then
placed in a dark place for 12 hours. After that, 5.0 mL of water was
added to this mixture, and it was heated under reflux for 30 minutes.
After the mixture was transferred to a separatory funnel, the toluene
layer was washed with 10 mL of 6 M hydrochloric acid. Then the
organic layer was extracted after it was washed with 5.0 mL of
water and dried by adding 1.0 g of magnesium sulfate. The most of
toluene in the organic layer was removed by simple distillation and
evaporated in a water bath (70oC) using a stream of dry air. 2.5 mL
of liquid was remained [1,2,10].
2.3. Column Chromatography
The crude product (liquid) was dissolved in 2.5 mL of methylene
chloride and purified by column chromatography using methylene
chloride as a mobile phase and alumina as a stationary phase. Then
the purified product was evaporated in a warm water bath (50oC)
using dry air until the volume was about 3.0 mL. After evaporation,
a yellow liquid was obtained and then was weighed [12]. This was
determined to be 2-acetylcyclohexanone. The percentage yield of
product (MW=140.2) was calculated. The product was analyzed by
1
H-NMR spectroscopy (400 MHz, CDCl3).
means to prepare the product of asymmetric carbon-carbon bond

formation reactions, such as acylation of carbonyl compounds. The
difficulty of this experiment was to pick at the exact temperature for
boiling of toluene (b.p. 110oC) because the temperature above
100oC was increased sharplyduring distillation. The evaporation of
toluene in the distillate was also difficult that reaction product as
well as toluene might evaporate simultaneously due to the
characteristics of azeotrope.
The actual and theoretical yields of 2-acetylcyclohexanone were
3.189 g and 4.33 g, respectively. The percentage yield of the
experiment was 73.6 % and this value was more than Stork's result
[2]. In the case of Stork et al.[2], acetic anhydride gave a 42 % yield
of 2-acetylcyclohexanone with the enamine of cyclohexanone using
dioxane solvent. Toluene was used as a solvent and 73.6 % yield of
2-acetylcyclohexanone was obtained. The reason for obtaining a
large amount of product using toluene might be explained that the
rate of bimolecular reaction was increased in the higher b.p. solvent
such as (toluene ; b.p.=110oC) because of the higher temperature
than dioxane (b.p.=101.1oC). Therefore, more product could be
obtained in a shorter period of reaction time.
3.1. 1H-NMR Spectroscopy Study

The product was isolated by simple distillation and identified by
1
H-NMR spectroscopy (400 MHz, CDCl3). In 1H-NMR spectroscopy,
2-acetylcyclohexanone was nearly 71.7 % enol form in aqueous
acid medium (Figure 3).
The percentage of enol- and keto- structure of product was
calculated as follows. The offset peak was assigned to the enolic
hydrogen at 15.9 ppm (integral height = 0.3 cm). The remaining
absorptions at 1.7-2.4 ppm (integral height = 5.5 cm) was
assigned to the 3 protons (from methyl hydrogen), the 11 protons
(from enol structure), and the 12 protons (from keto structure).
Thus, the 4.6 cm integral height (5.5 cm - (0.3 3) = 4.6 cm)
corresponded to the protons from enol and keto forms. Therefore,
2.4. 1H-NMR Spectroscopy

1
H-NMR spectroscopy (Bruker model AV-400 spectrophotometer,
400 MHz, CDCl3) was used to determine the percentage of enol
content for 2-acetylcyclohexanone. The offset peak was assigned to
the enolic hydrogen at 15.9 ppm. The remaining absorptions at 1.72.4 ppm were assigned to the 3 protons (from methyl hydrogen),
the 11 protons (from enol structure) and the 12 protons (from keto
structure).
3. Results and Discussion

The reaction of an enamine with acetic anhydride yielded 73.6 %
of 2-acetylcyclohexanone in a mild reaction condition without side
reactions. This result indicated that an enamine was a successful
2 2 (2009)
Figure 3. 1 H-NMR spectrum of the synthesized 2acetylcyclohexanone using enamine as organocatalyst.
Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-enamine
283
without side reactions. Acylation gave an enol form (71.7%) and a

keto form (28.3%) of 2-acetylcyclohexanone mixture.
In the future, this study will be enlarged to obtain the high
enantio- and diastereo-selectivities as well as to increase the product
yield using various enamines and solvents under the mild reaction
conditions.
Figure 4. The keto and enol forms of 2-acetylcyclohexanone.
3.3 cm (0.311 protons) of the 4.6 cm intergral height was assigned

to the enol structure. Enol % = 3.3/4.6 100 = 71.7%, Keto % =
(4.6-3.3)/4.6 100 = 28.3%. The enol structure was the major form
of 2-acetylcyclohexanone, same as the Pavia et al [1] and
Igiesias [11].
The reason for obtaining more enol form (71.7 %) than keto form
(28.3 %) of 2-acetylcyclohexanone can be explained that the enol
form is stabilized by conjugation and intramolecular hydrogen
bonding as shown in Figure 4. The C = C bond of the enol form
decreases the electron density of bonds through conjugation. The
H O hydrogen bond also stabilizes the enol form by forming a
ring.
4. Conclusion
In conclusion, using an enamine, 2-acetylcyclohexanone was
synthesized by acylation reaction of acidic anhydride. This reaction
carried out mild reaction conditions using an enamine instead of
NaOH in order to bond to the ketone with good yields (73.6%)
References
(1) Pavia, D,L., Lampman, G. M., Kriz, G.S. and Engel, R.G.
Intoduction to Organic Laboratory Techniques: A Small Scale
Approach, 2nd ed. Thomson Brooks/Cole: Canada, 330-339
(2005).
(2) Stork, G., Brizzolara, H., Landesman, H., Szmuszkovicz, J. and
Terrell, R. J. Am Chem. Soc., 85 (2), 207-222 (1963).
(3) Cook, A.G., Absi, M.L. and Bowden, V.K. J. Org. Chem., 60(10),
3169-3171 (1995).
(4) Cao, C., Sun, X., Zhou, J. and Tang, Y. J. Org. Chem., 72(11),
4073-4076 (2007).
(5) Meyer, W.L., Bramon, M. J., Burgos, C, Goodwin, T. and
Howard, R.W. J. Org. Chem., 50(4), 438-447 (1985).
(6) Luo, S., Xu, H., Mi, X., Li, J., Zheng, X. and Cheng, J. J. Org.
Chem., 71, 9244-9247 (2006).
(7) Curphey, T.J., Hung, J.C. and Chu, C.C. J. Org. Chem., 40, 607614 (1975).
(8) Bruson, H.A. and Riener, T.W. J. Am. Chem. Soc., 64, 2850-2856
(1942).
(9) Curphey, T., Hung, C.Y. and Chu, C.C. J. Org. Chem., 40(5),
607-614 (1975).
(10) Chiba, T., Okimoto, M., Nagai, H. and Takata, Y. J. Org. Chem.,
44(20), 3519-3523 (1979).
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J. of Adv. Eng. and Tech., Vol. 2, No. 2 (2009)

Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-Enamine

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J.

of Advanced Engineering and Technology

Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-enamine

The formation reactions of carbon-carbon bonds are important in

Figure 1. The side reactions shown in the acylation using base.

Figure 2. Nucleophilicities on nitrogen (I) and carbon (II) due

means to prepare the product of asymmetric carbon-carbon bond

3.1. 1H-NMR Spectroscopy Study

2.4. 1H-NMR Spectroscopy

3. Results and Discussion

Figure 3. 1 H-NMR spectrum of the synthesized 2acetylcyclohexanone using enamine as organocatalyst.

Synthesis of 2-Acetylcyclohexanone Using Pyrrolidine-enamine

without side reactions. Acylation gave an enol form (71.7%) and a

3.3 cm (0.311 protons) of the 4.6 cm intergral height was assigned

J. of Adv. Eng. and Tech., Vol. 2, No. 2 (2009)

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