Synthesis of 2-Acetylcyclohexanone by Enamine Reaction Gabby Sysavath TA: Meng Wang Monday 11:30am-2:20pm

ABSTRACT: The lab experiment was executed to produce an enamine where it would react with acetic anhydride and water to synthesize the desired product, 2-acetylcyclohexanone. 0.809g of cyclohexanone reacted with 0.54ml of pyrrolidine in p-toluenesulfonic acid where an enamine was created. The enamine was further reacted with acetic anhydride where an acetyl group added to the alpha-carbon this is known as alkylation.Then hydrolysis occurred to give the desired product of 2-acetylcyclohexanone. The reaction underwent distillation where the heat initiated the reaction. Two purification techniques were used to isolate the product. The first consisted of extraction of the organic layer. The second purified the mixture even more through column chromatography. Evaporation was utilized to further isolate the desired product. The percent yield attained was 99.4% with the final product weighed at 0.905g. The IR spectrum analysis displayed peaks at 1712cm-1 indicating C=O (ketone) bond, 2863cm-1 representing sp3 CH bond, 2934cm-1 also showing sp3 CH bond, and 3026cm-1 portraying sp2 CH bond.

 

Sysavath  2  

INTRODUCTION: The purpose of this two-week lab experiment is to create an enamine from cyclohexanone and pyrrolidine, which will react with acetic anhydride and water to synthesize 2acetylcyclohexanone. This multi-step reaction involves a two-week process where week one focuses on preparing and reacting the enamine and then, week two consists of hydrolyzing and purifying the desired product, 2-acetylcyclohexanone. An azeotrope forms as a byproduct during the formation of the enamine. The azeotrope is a mixture of water and toluene and will be removed during distillation. This will cause the equilibrium of the reaction to shift towards the enamine production because the water and toluene are taken out of the reaction. This azeotrope distillation portrays Le Chatelier’s Principle that if a system at equilibrium is disturbed, the system will move in such a way as to counteract the disturbance. So increasing the amount of one of the reactions and/or removing the products as they are formed will increase the products such as the enamine that is desired. Because the azeotrope has a lower boiling point than the enamine that is wanted, the distillation will be performed with the use of heat. The distillation process is crucial for the formation of the desired product, 2-acetylcylohexanone, because without it, the reaction would have little enamine product, which is needed to produce 2acetylcyclohexanone. Below is an image of the distillation apparatus that will achieve the first part of the experiment, the formation of the enamine.

 

Sysavath  3  

The image above portrays the glassware that will be used in distillation. This set up is very important in order to collect the distillate, which is the azeotrope, in the Hickman head. The water condenser helps the evaporating chemicals to be cooled as they are moved up through the apparatus. The drying tube serves as protection for the students from vapors that are dangerous. After the enamine is formed, it reacts with acetic anhydride where it produces an enamine cation and an acetate ion. This is where part one of the experiment as well as week one of the experiment was stopped and put aside for the following lab class. The second part of the experiment consists of hydrolyzing the enamine cation, which synthesizes 2-acetylcyclohexanone, and then purifying the product. So it is vital that water is returned to the reaction, in order to form the desired product. This is achieved by refluxing the reaction.

 

Sysavath  4  

The image above displays the essential glassware to form the apparatus that will be used in the reflux process of the experiment. The 10mL round-bottom flask will be heated on the aluminum block. It is also attached to a water condenser that will help cool the dispersing chemicals as well as keep the reaction cool. During this process, the pyrrolidine ion portion of the enamine will be replaced with a ketone and another molecule of the pyrrolidine catalyst is also created. The formation of the enamine is shown below as well as the overall synthesis of 2acetylcyclohexanone.

 

Sysavath  5  

The first week/first part of the experiment demonstrates that cyclohexanone reacts with pyrrolidine in p-toluenesulfonic acid to create the enamine as well as water. The ptoluenesulfonic acid is a mild acid that acts as a catalyst. The enamine then reacts with acetic anhydride to produce the enamine cation as well as acetate ion, this is also alkylation of the enamine. The enamine cation reacts with water to produce the desired product, 2acetylcyclohexanone, as well as amine and hydronium. The mechanism of the formation and reaction of the enamine to synthesize 2-acetylcyclohexanone is shown below.

Cyclohexanone picks up a proton in order to become a cation. Then the nitrogen in the amine/pyrrolidine attacks the carbon of the carbonyl in cyclohexanone, which pushes the electrons up to oxygen. The hydroxide needs to become a better leaving group so it attacks the hydrogen bonded to nitrogen, which then gives the electrons back to nitrogen. The electrons from nitrogen move down to form a double bond to the carbon while the newly formed water

 

Sysavath  6  

leaves. The water then attacks one of the alpha-carbon hydrogens where the bond goes back to the ring, and the electrons in the double bond move back up to nitrogen. The electrons from nitrogen move back down to form the double bond as the double bond in the ring attacks one of the carbonyl carbons in acetic anhydride. The double bond from the carbonyl carbon to the oxygen is then moved up to the oxygen. Now, acetic anhydride is bonded to the enamine. The electrons from the oxygen anion move back down to form a double bond in order for the acetate to become a leaving group. The acetate then leaves becoming an ion. Now that the acetyl is attached to enamine, water attacks the carbon bonded to nitrogen to force the electrons to move up to nitrogen. The nitrogen then grabs a hydrogen from the water that is attached to the ring as the bond moves down to the oxygen. The electrons from the oxygen move down to form a double bond as the bond to the amine moves up to nitrogen. This makes the amine/pyrrolidine a good leaving group and a byproduct of the reaction. Water then deprotonates the newly formed ketone in order to give the electrons back to oxygen. This serves as to why a hydronium is a byproduct of the reaction. Then, the desired product, 2-acetylcyclohexanone is produced. After the reflux process, the product goes under a purification technique in the experiment, which is extraction. Extraction is a good purification technique because it isolates the product by having the desired product be in the layer that will not be extracted from the tube so this technique is used frequently in organic chemistry. The way extraction works is by the different solubilities and densities and the separation of solutions. After the reflux, the first extraction occurs and 1mL of water is added to the mixture where all water-soluble components of the mixture move to the bottom aqueous layer, which is then extracted and discarded. The second extraction involves 2ml of 6M HCl, the HCl works to move any nitrogen-containing

 

Sysavath  7  

molecules from the organic layer to the bottom aqueous layer where again, it is removed and discarded. A third extraction occurs with water and the bottom layer is once again removed. The next purification technique that the product goes through is column chromatography. This works by applying the different molecules’ polarities to separate from one another. The equipment used in the apparatus involves a Pasteur pipet, solid polar stationary phase, liquid mobile phase, and Erlenmeyer flask. The pipet is loosely packed with the stationary phase where the mixture passes through with the mobile phase. Column chromatography is a good purification technique because the more polar the molecules within the solution are, they will adhere to the stationary phase and will not go through as quickly while the molecules that are non-polar will elude quicker into the flask. The stationary phase or absorbent used in the experiment is alumina while the mobile phase or eluent is methylene chloride. The contents of the flask after the column chromatography are the desired product, 2-acetylcyclohexanone, toluene and methylene chloride which are all non-polar. Evaporation must occur to remove the undesired products, toluene and methylene chloride. The evaporation occurs by heating the mixture in a warm water bath and using a stream of air to evaporate toluene and methylene chloride. The pure product should be attained after ~15 minutes of evaporation. After evaporation, the product will be characterized through a technique that is beneficial in the identification of the product. This technique is called infrared (IR) spectroscopy. IR is useful in the process of identifying the product because functional groups absorb different frequencies so the spectra will show different wavelengths that correlate to that specific functional group. Essentially, a beam of infrared light passes through the unknown sample where the light bends/vibrates the bonds within the sample. Like mentioned before, the different bonds bend at different wavelengths of light so on the spectra it will show the different bonds for the

 

Sysavath  8  

ability to characterize the unknown sample. 2-acetylcyclohexanone will show sharp peaks at ~1700cm-1 that relate to carbonyls of ketones groups, ~2900cm-1 corresponds to sp3 hybridization carbon, and peaks at ~3026cm-1 that equate sp2 CH bonds. There should also be peak(s) at ~1600cm-1 that show a C=C double bond because of the tautomerization of the product from the forms of keto to enol. So then the identification of the product, 2acetylcyclohexanone, can be made since the functional groups of it are known. The product will be weighed so that percent yield calculations could be made. The percent yield will be calculated because it can demonstrate whether or not the reaction was successful.

 

Sysavath  9  

PROCEDURE: 0.64mL (0.809g) of cyclohexanone was transferred into a preweighed 10mL roundbottom flask. 4.0 mL of toluene, ~20mg (0.024g) of p-toluenesulfonic acid monohydrate, 0.54mL of pyrrolidine and a spin vane were added. A Hickman head, a water-cooled condenser, and a drying tube containing moist cotton were attached to the flask. Distillation occurred for ~30 minutes at about 140°C where the distillate (~2mL) started to collect in the Hickman head. The distillate (azeotrope) was removed and discarded as it produced. 0.64mL of acetic anhydride dissolved in 1.0mL of toluene was transferred to the cooled flask containing the enamine where the color turned from bright yellow to an orange. Finally, it was allowed to sit until the next lab class. 1.0mL of distilled water was added to the flask. A water condenser was attached to start the boiling of the mixture. It boiled and stirred for ~30 minutes (~120°). The mixture cooled and was transferred to a centrifuge tube for extraction. 1ml of water was added and the bottom layer was removed. 2mL of 6M HCl was added to the tube and bottom layer was removed. 1mL of water was added and bottom layer discarded. The organic layer was transferred into a vial with ~4 microspatulas of anhydrous sodium sulfate. The remaining toluene was evaporated in water bath at ~70°C with stream of dry air. Then the solution was purified by column chromatography. !

A 5!-inch pipet was packed with 1g of alumina (stationary phase) and set up above a collection flask. The crude product dissolved in 0.5mL of methylene chloride (mobile phase) while 1mL of methylene chloride was added to the column. The crude product was added and passed through the column to the collection flask. Then the solution from the flask was heated in a 50°C water bath while the methylene chloride evaporated with stream of air. After evaporation, the final product was weighed for percent yield calculations and characterized by infrared spectroscopy.

 

Sysavath  10  

DATA and CALCULATIONS: Raw Data: •

Starting weight of pyrrolidine: 0.459g

•

Starting weight of cyclohexanone: 0.809g

•

Starting weight of p-toluenesulfonic acid: 0.200g

•

Theoretical yield of product, 2-actelycylohexanone: 0.905g

•

Actual yield of product, 2-acetylcyclohexanone: 0.900g

•

% Yield of 2-acetylcyclohexanone: 99.4% Limiting Reagent Calculation

0.809𝑔  𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑥𝑎𝑛𝑜𝑛𝑒  ×  

0.54𝑚𝑙  𝑝𝑦𝑟𝑟𝑜𝑙𝑖𝑑𝑖𝑛𝑒  ×  

1  𝑚𝑜𝑙 = 0.008  𝑚𝑜𝑙𝑒𝑠  𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑥𝑎𝑛𝑜𝑛𝑒 98.15𝑔

0.85𝑔 1  𝑚𝑜𝑙 × = 0.0065  𝑚𝑜𝑙𝑒𝑠  𝑝𝑦𝑟𝑟𝑜𝑙𝑖𝑑𝑖𝑛𝑒 1  𝑚𝑙 71.1𝑔

**Pyrrolidine = limiting reagent because contained fewest moles** Percent Yield Calculation Theoretical Yield Calculation: 𝑚𝑜𝑙  𝑜𝑓  𝑙𝑖𝑚𝑖𝑡𝑖𝑛𝑔  𝑟𝑒𝑎𝑔𝑒𝑛𝑡  ×  𝑟𝑎𝑡𝑖𝑜  𝑜𝑓  𝑠𝑡𝑎𝑟𝑡𝑖𝑛𝑔  𝑚𝑎𝑡𝑒𝑟𝑖𝑎𝑙𝑠  𝑡𝑜  𝑝𝑟𝑜𝑑𝑢𝑐𝑡   ×  𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟  𝑤𝑒𝑖𝑔ℎ𝑡  𝑜𝑓  𝑝𝑟𝑜𝑑𝑢𝑐𝑡 = 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙  𝑦𝑖𝑒𝑙𝑑 0.0065  𝑚𝑜𝑙𝑒𝑠  𝑏𝑒𝑛𝑧𝑜𝑝ℎ𝑒𝑛𝑜𝑛𝑒    ×  

140.2𝑔  2 − 𝐴𝑐𝑒𝑡𝑦𝑙𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑎𝑛𝑜𝑛𝑒 1  𝑚𝑜𝑙

= 0.905𝑔  2 − 𝐴𝑐𝑒𝑡𝑦𝑙𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑥𝑎𝑛𝑜𝑛𝑒 Percent Yield Calculation: 𝐴𝑐𝑡𝑢𝑎𝑙  𝑦𝑖𝑒𝑙𝑑  (𝑔𝑟𝑎𝑚𝑠)  ×  100% = 𝑝𝑒𝑟𝑐𝑒𝑛𝑡  𝑦𝑖𝑒𝑙𝑑 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙  𝑦𝑖𝑒𝑙𝑑    (𝑔𝑟𝑎𝑚𝑠)

 

Sysavath  11   0.900𝑔  2 − 𝐴𝑐𝑒𝑡𝑦𝑙𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑥𝑎𝑛𝑜𝑛𝑒  ×  100% = 99.4% 0.905𝑔  2 − 𝐴𝑐𝑒𝑡𝑦𝑙𝑐𝑦𝑐𝑙𝑜ℎ𝑒𝑥𝑎𝑛𝑜𝑛𝑒

IR Spectra Analysis Wavelength Indicated Bonds 3026cm1

Sp2 CH

2860cm-1

Sp3 CH

2935cm-1

Sp3 CH

1712cm-1

C=O (ketone)

 

Sysavath  12  

DISCUSSION and CONCLUSION The objective of the lab was to react an enamine, which is formed from cyclohexanone and pyrrolidine in solution of p-toluenesulfonic acid, with acetic anhydride and water to synthesize 2-acetylcyclohexanone. The experiment can be considered fairly successful. According to the IR spectra, the desired product was created and even though, the percent yield attained was ideal, it was not realistic. 2-acetylcyclohexanone was synthesized as sustained by the IR spectra. Although, there were some peaks that demonstrated that the product was not completely pure. The impurity was that of toluene because of the weak peak at 1592cm-1 showed that is indicative of an aromatic ring that of which toluene contains. However, the IR spectra showed peaks at ~2860-2935cm-1 which is indicative of sp3 hybridized bonds from cyclic carbons, peaks at 3026cm-1 which demonstrate sp2 CH bond, and a peak at 1712cm-1 which portray C=O ketone group, all of which are indicative to the desired product, 2acetylcyclohexanone. Although, 2-acetylcyclohexanone contains two ketone groups, only one C=O bond is visible because of keto-enol tautomerization where the most stable is the enol form.

 

Sysavath  13  

Also, it is conclusive that the desired product was formed because of the lack of the peak that would have been indicative of an amine peak where it would have been broad around 3300cm-1. The theoretical yield that was found for the experiment was calculated as 0.905g. In order to calculate the theoretical yield, the limiting reagent was needed. The limiting reagent in this experiment was pyrrolidine because it had the fewer moles compared to the other reagent, cyclohexanone. The percent yield was then calculated using the theoretical and the actual yield. The percent yield was calculated to be 99.4% and was extremely high for what is expected. This could have occurred because of not evaporating the product long enough. With a percent yield of 99.4% and a weak peak at 1592cm-1, it can be concluded that there was an error that was made during the experiment. During the evaporation step of the experiment, the toluene along with methylene chloride was evaporated but looking at the percent yield and IR spectrum that is not completely true even though the product was allowed almost 15 minutes to evaporate in a warm water bath and a light air stream. With that being said, toluene was not completely evaporate which most likely led to the inaccurate percent yield. In order to avoid this error and to improve the accuracy and the IR spectrum, the product should be allowed more time for evaporation. In order to produce an enamine, cyclohexanone reacted with pyrrolidine in p-toluenesulfonic acid. The enamine was then reacted with acetic anhydride to form an enamine cation that further reacted with water to synthesize the desired product, 2acetylcyclohexanone. It also created hydronium and pyrrolidine as byproducts. The desired product was synthesized which is supported by the IR spectroscopy. While the percent yield, 99.4%, is ideal it is highly unrealistic which can be attributed to not evaporating the product long enough. Overall, the experiment was successful in synthesizing 2-acetylcyclohexanone from the

 

Sysavath  14  

formation of enamine although, there were some impurities in the final product, which led to an extra peak on the IR spectra, and inaccurate percent yield.

REFERENCES CHM 234. N.p., n.d. Web. 17 Mar. 2015. . Source used for the IR peak table.   Pavia,  Donald.  CHM  238  Organic  Chemistry  Lab  Manual:  Arizona  State  University.  Cengage   Learning:  2011.  54-­‐61.  04/05/15. Trakanrungroj,  Pichaya.  CHM  238  General  Organic  Chemistry  Recitation     Presentations:  Enamine  Week  One  and  Enamine  Week  Two.  04/05/15.