Lab 10 Williamson Ether Synthesis Preparation of Phenacetin from Acetaminophen PDF

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Lab 10: Williamson Ether Synthesis: Preparation of Phenacetin from Acetaminophen Katja Gonzalez Lab Partner: Kyle Leonida 2018/04/23 Methods and Background K2CO3 2-butanone

Figure 1: Acetaminophen to Phenacetin Reaction

The goal of this lab was to produce phenacetin by using Williamson ether synthesis by utilizing the starting components of acetaminophen, iodomethane and potassium carbonate as shown in figure one. The reason potassium carbonate is used is to be able to deprotonate the phenols hydrogen. In order to purify phenacetin and use the TLC method the product needs to be recrystallized. To finally verify the correct compound was found melting point analysis and IR spectroscopy were used. To produce molecules that can have a variety of uses, ethers should be used. Ethers are compounds with one oxygen that is attached with two “R” groups. The first use of the Williamson ether synthesis was seen mainly used for precursors such as alcohol and alkyl halide. This mechanism which was also used in lab ten is a two-step process. The first step when the alcohol is deprotonated by the use of a base in order to form an alkoxide ion. The second step of the synthesis is S 2 substitution which occurs when a alkoxide ion functions as a nucleophile and the alkyl halide functions as the N

electrophile. However, there are some limiting factors that should be considered when utilizing this synthesis. When looking at the first step a strong base is needed to be used to be able to deprotonate the oxygen because alcohols are very acidic. If you remove the strong base, the alcohol is not nucleophilic enough to move onto the next step. During the second step, there is constant competition between elimination and substitution reactions and which alkyl halide you use is important. To assure a nice and easy success of the S 2 reaction a sterically unhindered alkyl halide is best used in this reaction. In N

order create a fast reaction methyl and primary alkyl halides will be favored. When using alkoxide ions (good base) they will be in favor of an elimination reaction using a secondary alkyl halide. As for the Williamson ether synthesis, it will favor the

substitution reaction using a primary alkyl halide and an alkoxide ion. The reaction rate in the second step S 2 reaction will depend on the total strength of the nucleophile. This is due to the carbon-oxygen bond that has formed. The reaction rate can also have a N

dependency on the leaving group. If there is a better leaving group present such as an alkyl iodide it will for an easier breakage between a carbon-hydrogen bond. In order to help push the reaction to proceed rapidly it best to use the preferred solvent known as a polar aprotic solvent. A reflux apparatus was used during the lab procedure. When thinking of the term heating under reflux it relates to the mixture created to be heated to its boiling point utilizing a reflux condenser. This will then allow for a continuous return of the volatile materials back into the flask. The reflux apparatus is best utilized in order to prevent the solvent or reactant used in the lab to evaporate out or lost. Using this apparatus means that there will a lesser time requirement for completion due to the reaction being able to be conducted at much higher temperatures.

Figure 2: Reflux Apparatus

Once the reflux apparatus is complete, Thin-Layer Chromatography can be completed. TLC is used to view the progress of the reaction by looking at a comparison between a pure sample of acetaminophen to the mixture we have, which should be phenacetin. For the plate three spots were created. First spot known as a co-spot contained both the mixture created and pure acetaminophen, second spot was just pure acetaminophen and the third spot was just the mixture created. Upon completion of the TLC plate a UV light was used to circle our spots in order to analyze and calculate the R values achieved. This entire process was then again completed was the experimental process f

was over and we had out final product.

Once TLC plate was completed it is time to move into the extraction part of the procedure. The extraction is involved in the selective removal of one or more components of a liquid. The substances that are divided should be immiscible phases that come into contact with one another. The different layers and separation are dependent upon the density of each substance.

Figure 3: Liquid liquid Extraction

After the extraction, a rotary evaporator was used in order to remove any solids that can be formed at room temperature. This is achieved by reducing the pressure of the solvents without bumping in order to quickly evaporate the solvents you have obtained. For this lab the solvents we are trying to evaporate are 2-butanone and ethyl acetate One advantage when comparing this mechanism against simple distillation is that the friction force and centrifugal will cause the solution to spread which will increase the surface and allows for an easier evaporation.

Figure 4: Set-up for the Rotary Evaporator

Experimental Procedure Before the procedure can take place, a reaction table needed to be completed for us to be able to calculate the percent yield at the end of the experiment. There was the option of using either powder or crushing up tablets. For this experimental procedure the powder method was utilized. 1.30 g of powdered was weighed and placed into a 50 mL round bottom flask. 15 mL of 2 butanone and 1 boiling stone are next added into this flask. Due to the dangers of iodoethane, 1 mL is measured under the hood and placed into the flask. The reflux apparatus should be setup at this time. The flask is then placed on the apparatus and run for exactly one hour. Once the hour is complete the reaction was then cooled and placed into a vacuum filtration to filter out any solids. These solids are then washed through a Buchner funnel twice using 5 mL of ethyl acetate each time. Taking the liquid from the filtration flask a TLC plate can be completed on the reaction mixture. On the TLC plate three dots are created pencil. On one dot pure acetaminophen is placed, on the second dot the reaction mixture is placed and only third and final dot a combination of acetaminophen and your reaction mixture is placed. The elute for the plat is 4:1 ethyl acetate: methylene chloride. Once the plate has completed it will be examined under a UV light from which R can be easily calculated. The liquid from the filtration flask should now be added into a f

separatory funnel and extracted with first 20 mL of 5% NaOH and then 20 mL of H O. When separating, the organic layer should be located on top for both NaOH and H O. The organic layer left after these separations will then be placed into an Erlenmeyer 2

2

flask with Na SO in order to dry any excess water. The amount needed is based on when clumping is no longer visible. The solution is then decanted into a 50 mL round 2

4

bottom flask and taken to the rotary evaporator in order to remove the ethyl acetate and 2-butanone. In order to dissolve the phenacetin achieved a minimal amount of hot ethanol should be used. Both the phenacetin and ethanol should be kept on the heating mantle. Once the phenacetin is dissolved it is then removed from heat and cooled to room temperature and finally placed in an ice bath. The solid formed is then placed onto a vacuum in order to filter and dry the solid. Once the product has fully dried it is weighed and this weight is used to calculate the percent yield. Another TLC should be taken as this point utilizing the same procedure as above. To verify the product obtained is truly phenacetin melting point analysis, IR and NMR were completed.

Data Acquisition i. Reaction Table Mol.

D (g/mol)

Weight

or M

(g/mol

(mmol/mL

)

)

151.17

n/a

138.21

Iodoethane

155.97

2-Butanone

72.06

ii.

Compound

Acetaminophen Potassium carbonate

iii.

mmo

Equivalent

l

s

1.3 g

8.6

1.0

n/a

2.5 g

18.1

2.1

1.94 g/mL

1.0 mL

12.4

1.45

15 mL

167.6

19.5

Weight/Volume (g/mL)

0.805 g/mL

Related Equations actual value Percent yield = theoretical value ×100 % Rf value =

iv.

Rxn

distance travelled by compound distancetravelled by eluant

Calculations -

Reaction Tables Calculations mmol Acetaminophen =

1000 mmol 1.3 g × 1 mol 151.17 g /mol

= 8.6

mmol 1000 mmol 2.5 g mmol K2CO3 = 138.21 g/mol × 1 mol mmol Iodoethane =

1.0 mL ×

= 18.1

1000 mmol 1mol 1.94 g × × 1 mol 155.97 g mL

=

12.4 mmol mmol 2-Butanone = = 167.6 mmol

15 mL ×

0.805 g 1 mol 1000 mmol × × 1 mol 72.06 g mL

Equivalent Acetaminophen = limiting reagent = 1.0 18.1 mmol K 2 CO 3 Equivalent K2CO3 = 8.6 mmolacetaminophen = 2.1 12.4 mmol Iodoethane Equivalent Iodoethane = 8.6 mmolacetaminophen Equivalent 2-Butanone =

-

167.6 mmol 2−Butanone 8.6 mmol acetaminophen

= 26.9% yield

Rf Values Rf of TLC plate before work-up 2.6 cm Acetaminophen = 4.0 cm = 0.65 Reaction Mixture =

2.9 cm 4.0 cm

= 0.73

Rf of TLC plate for final product 2.4 cm Acetaminophen = 3.7 cm = 0.65 2.7 cm Phenacetin = 3.7 cm v.

= 0.73

IR Spectroscopy Wavenumbers (cm-1)

vi.

Functional group

~3300

N-H

~1700

C-O

NMR Spectroscopy Ppm 11.48-9.64

= 19.5

Percent Yield Mass of final product = 0.35 g phenacetin 0.35 g phenacetin Percent yield = 1.3 g acetaminophen ×100 %

-

= 1.45

Functional group Aromatic ring

7.95-7.02

Amine

5.83-5.34  O-CH3

vii.

TLC Plates

Figure 5: TLC plate before reaction mixture work-up (left) and TLC plate after recrystallization of phenacetin (right)

Conclusion The main purpose of lab ten was to utilize Williamson ether synthesis in order to create phenacetin containing acetaminophen, iodoethane, and potassium carbonate. A base of potassium carbonate was used in order to deprotonate the phenolic hydrogen which will allow for the reaction to occur. The correct melting point of phenacetin is 134 degrees Celsius. The observed melting point for our group was between 134.6 and 136.2. The melting point was almost spot on, the slight elevation could be due to presence of impurities, but our melting point would not be enough to determine this as it is so minute. When looking at the IR spectroscopy two peaks were seen. The first peak was located around 3300 cm which is characterized as the amine stretch. The second peak was -1

located around 1700 which demonstrates the carbonyl stretch. The IR spectroscopy graph is correct as both of these functional groups should be present in the structure of phenacetin.

When looking at the NMR graph three peaks were noted. The first peak located between 11.48-9.64 shows an indication of an aromatic ring. The second peak between 7.95-7.02 show an indication of the presence of an amine. Finally, the third peak can be located between 5.83-5.34 which shows the clear presence of OCH3. All of these peaks present are indicators that the correct product has formed and further proves our success. The calculated percent yield of the compound achieved was only 40.26 percent. The yield obtained was the small amount of 0.62g in comparison to the 1.54g that should have been achieved. The best bet as to where some mixture was lost was when the reflux apparatus was in use which means some of the mixture may have boiled into the hempel column which ultimately ends in its loss. There was two different R values that resulted from the TLC that took place one after f

the reflux and the other at the end of the experiment. The first TLC plate had R values of 0.65 for pure acetaminophen and 0.73 for the reaction mixture. This clearly shows that because of a lower R value, pure acetaminophen, is more polar than our reaction f

f

mixture. The second TLC plate had similar values of 0.65 for pure acetaminophen and 0.73 of the reaction mixture. This also demonstrate that with a higher R values there is f

likely to be less polarity as shown in the phenacetin. The reaction shows the correct data of pure acetaminophen being more polar than phenacetin. References Gilbert, J.C., and Martin, S.M., Experimental Organic Chemistry, 5th Edition, Cengage Learning, Boston, MA, 2011. Landrie, C.L., and McQuade, L.E., Organic Chemistry: Lab Manual and Course Materials, 3rd Edition, Hayden-McNeil, LLC, Plymouth, MI, 2013....