Synthesis of 2-acetylcyclohexanone

Written by J.A Dobado | Last Updated on April 22, 2024

Objetives

To produce a β-dicarbonyl compound, in this case 2-acetylcyclohexanone from cyclohexanone, using an enamine as a synthetic intermediate.

Background

Organometallic compounds and carbanions are not the only species used in organic synthesis with nucleophilic carbon atoms.
The carbon in the β-position of an enamine has a nucleophilic character and can be alkylated or acylated with an appropriate electrophilic reagent.

This reactivity of enamines, which can be easily prepared from carbonyl compounds, is due to the relocation of the non-bonding electron pair of nitrogen through the carbon double bond at the β-position. Alkylation or acylation of an enamine leads to the formation of an iminium ion, which by hydrolysis regenerates the carbonyl compound.

2-acetylcyclohexanone synthesis OEKATORRSPXJHE-UHFFFAOYSA-N

In this experiment, cyclohexanone is acetylated via pyrrolidinamine. In a first step, cyclohexanone is converted to the corresponding enamine by reaction with pyrrolidine in the presence of an acid as catalyst. The reaction is carried out in toluene and refluxed using a Dean-Stark apparatus to remove water formed in the reaction.

The enamine produced is not isolated but is immediately reacted with acetic anhydride to produce the corresponding acetylation. Water treatment of the starting material leads to hydrolysis to 2-acetylcyclohexanone. In a final step, the reaction crude is purified by vacuum distillation. The compound generated exists as a mixture of keto and enol forms, and the percentage of each tautomer can be estimated by 1H-NMR.

Experimental procedure

40 ml of toluene, 5 ml of cyclohexanone, 4 ml of pyrrolidine and 0.1 g of p-toluensulfonic acid are added to a 100 ml round bottom flask. The flask is connected to a Dean-Stark apparatus and this in turn to a reflux condenser with a drying tube. The mixture is heated at reflux for 1 hour and then allowed to cool to room temperature. The setup is modified to carry out an azeotropic distillation (to remove any remaining pyrrolidine and water) to a maximum of 108-110 °C. At this point, remove the heat source and allow the flask to cool to room temperature. Remove the distillation equipment and add a 4.5 ml solution of acetic anhydride in 10 ml of toluene. Place this in the stopper of the flask and allow the mixture to stand at room temperature for at least 24 h.

Then slowly pour 5 ml of water over the reaction crude and heat the mixture at reflux for 30 min. The reaction crude is allowed to cool to room temperature and transferred to a 50 ml separating funnel with 10 ml water, separating the two phases.

The organic phase is washed successively with 3 M HCl (3 x 10 ml) and water (10 ml) and transferred to an Erlenmeyer flask. Then it is dried over anhydrous sodium sulfate. Finally, the solvent is removed at a rotary evaporator, and the residue is transferred to a vacuum distillation apparatus of appropriate size and distilled under reduced pressure using a water pump (or a pump making a vacuum of about 15 mm Hg). The distillate thus obtained is weighed and the yield is calculated.

Physico-chemical properties

This table collects data for the molecular weight (Mw), melting point (M.p.) boiling point (B.p.) and density of the reactives and compounds used in this laboratory experiment.

Name Mw (g/mol) M.p. (ºC) B.p. (ºC) Density (g/ml)
2-Acetylcyclohexanone140.18 -111-1121.078
Acetic anhydride102.09-73.1139.81.080
Cyclohexanone98.14-471550.947
H2SO498.083 -1.80-1.84
HCl 36.46-30>1001.200
Na2SO4142.04884 -2.630
p-Toluenesulfonic acid172.2106-107 -1.240
Pyrrolidine71.12-6087-88 -
Toluene92.14-93110.60.867

GHS pictograms

Hazard pictograms form part of the international Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and are collected in the followinf Table for the chemical compounds used in this experiment.

Name GHS
2-Acetylcyclohexanone Non-hazardous
Acetic anhydride ghs02  Danger Warning Flammable pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Cyclohexanone ghs02  Danger Warning Flammable pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
H2SO4 ghs05  Danger Warning Corrosive cat. 1 pictogram
HCl ghs05  Danger Warning Corrosive cat. 1 pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Na2SO4 Non-hazardous
p-Toluenesulfonic acid ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram
Pyrrolidine ghs02  Danger Warning Flammable pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Toluene ghs02  Danger Warning Flammable pictogram ghs08  Danger Warning Systemic health hazards pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram

International Chemical Identifier

The IUPAC InChI key identifiers for the main compounds used in this experiment are provided to facilitate the nomenclature and formulation of chemical compounds and the search for information on the Internet for these compounds.

2-AcetylcyclohexanoneOEKATORRSPXJHE-UHFFFAOYSA-N
Acetic anhydrideWFDIJRYMOXRFFG-UHFFFAOYSA-N
CyclohexanoneJHIVVAPYMSGYDF-UHFFFAOYSA-N
H2SO4QAOWNCQODCNURD-UHFFFAOYSA-N
HCl VEXZGXHMUGYJMC-UHFFFAOYSA-N
Na2SO4PMZURENOXWZQFD-UHFFFAOYSA-L
p-Toluenesulfonic acidJOXIMZWYDAKGHI-UHFFFAOYSA-N
PyrrolidineRWRDLPDLKQPQOW-UHFFFAOYSA-N
TolueneYXFVVABEGXRONW-UHFFFAOYSA-N

Video on the synthesis of 2-acetylcyclohexanone

References

Back to the Advanced Organic Synthesis Experiments page.

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