Laboratory 10 Williamson Ether Synthesis Preparation of Phenacetin from Acetaminophen (1) PDF

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Laboratory 10: Williamson Ether Synthesis: Preparation of Phenacetin from Acetaminophen Claudia Rys (Partner: David Rafacz) August 1, 2019 Methods and Backgrounds

Figure 1.  Williamson ether synthesis of phenacetin (right) from acetaminophen (left). Phenacetin is prepared via a Williamson ether synthesis of acetaminophen and iodoethane in the presence of base, as seen in figure 1. The product is then purified by recrystallization and characterized by thin-layer chromatography (TLC), melting point analysis, IR and NMR spectroscopies. Ethers are chemical compounds that have two side chains bound to an oxygen atom. Acetaminophen possesses an alcohol group which means that it participates in hydrogen bonding, resulting in the bond interactions being very strong. The high strength of bonds results in them being difficult to break, requiring high temperatures when boiling in order to accomplish this. Ethers, on the other hand, exhibit significantly lower boiling points as they possess weaker associations such as dipole-dipole interactions. A very common way to synthesise these compounds is through the Williamson ether synthesis, which proceeds through a deprotonation of an alcohol group on a compound which, in our procedure is acetaminophen, by a strong base. This mechanism results in the formation of an alkoxide ion. An SN2 substitution takes place, and this mechanism is depicted in figure 2 below. The hydroxide ion deprotonates the alcohol on the acetaminophen, then a nucleophile attacks an alkyl halide forming an ether. A limitation of the williamson ether synthesis is sterically hindered alkyl halides, while synthesis functions most efficiently with primary alkyl halides. Secondary alkyl halides are not very effective, because elimination mechanisms take precedence over substitution in that situation. Tertiary alkyl halides cannot be used in the williamson ether synthesis because they are way too sterically hindered. In our reaction, acetaminophen is converted to phenacetin with ethyl iodide being used which is a primary alkyl halide. There exists constant competition between substitution and elimination in this mechanism. The likelihood of elimination occurring increases with the increase in substitution of alkyl halides, and due to the alkoxides being powerful bases, they may cause the alkyl halide to change to

an alkene. Therefore, for the williamson ether synthesis using a secondary alkyl halide is not favorable, and a tertiary will most likely undergo elimination.

Figure 2. deprotonation (top) and substitution (bottom) involved in Williamson ether synthesis. Thin layer chromatography (TLC) is utilized in the laboratory to monitor the progress and completion of the ether synthesis. Three lanes are created by dotting the TLC plate. The first spot contains acetaminophen, the middle lane contains a co-spot of acetaminophen with the reaction mixture, and the third one is solely the reaction mixture. The Rf value of acetaminophen and phenacetin is calculated to determine the polarity of each compound. The more polar compound will be more attracted to the polar stationary plate. Between the two compounds, acetaminophen is the more polar compound and will travel slower and therefore have the lower Rf value. Phenacetin, on the other hand, is the less polar compound and will travel faster up the plate, and will have the higher Rf value. TLC confirms the purity of the resulting product, and if impurities do exist, there may be several unwarranted spots observed. The melting point is a physical property utilized in this laboratory, as is a beneficial method of figuring out the purity of the product. Upon testing, the melting point should fall in between the range of the theoretical melting point. Depressed or higher than expected results indicate impurities in the product. IR spectroscopy can be analyzed to see what functional groups are present or absent in the spectrum. If the Williamson ether synthesis is carried out appropriately, the -OH stretch should not be visible. Instead, a peak should appear between 1060-1150 cm-1 for an alkyl ether (phenacetin). Likewise, the NMR spectroscopy should not display any chemical shift for an -OH hydrogen. A chemical shift between 3.2-4.2 ppm should be observed to help in confirming synthesis of phenacetin from acetaminophen. Experimental Procedure Williamson Ether Synthesis Weigh out 1.3g of acetaminophen. If in tablet form, crush four 325mg strength tablets using a mortar and pestle. Transfer the powder to a 50-mL round bottom flask and add a boiling stone to

the flask, along with 2.5  g of potassium carbonate (K2CO3) and 15 mL of 2-butanone. In the fume hood, add 1mL of iodoethane to the mixture. Proceed to assemble an apparatus for heating under reflux, connect the round bottom flask to the reflux condenser and heat for one hour. After the reflux, cool the reaction mixture at room temperature to below its boiling point. Filter the solids using vacuum filtration, and wash it twice with 5 mL portions of ethyl acetate. A TLC plate is set up, and three lanes are formed on the plate. Three dots are drawn on the bottom of the plate in a row. One is for pure acetaminophen, the middle is for the co-spot of the reaction mixture with acetaminophen, and the last one is for the pure reaction mixture. The plate is then placed in a beaker, and a mixture of 4:1 ethyl acetate:methylene chloride is used as the eluent. The beaker is covered with a watch glass and solvent travels up the stationary phase. After the solvent finishes traveling up the TLC plate, the solvent line is marked. The TLC plate is then inspected under UV light. The spots observed are circled, and the retention factor (Rf) of the substances present is calculated. The TLC is a verification test for completion of the reaction. Once confirmed, proceed to carry out the rest of the procedure. Transfer the filtrate from the vacuum filtration to the separatory funnel and extract with 20 mL of 5% NaOH followed by 20mL of water. The organic layer will be the top layer in both extractions, because it is the less dense layer. Transfer the organic layer to a clean Erlenmeyer flask, and dry using anhydrous sodium sulfate until the solid no longer clumps. The cloudy solution should become clear as the Na2SO4 is added. Decant the phenacetin solution to a 50mL round bottom flask. A rotary evaporator is then utilized to remove solvent from the solution. The resulting solid is recrystallized with hot ethanol while swirling vigorously. Ensure that only the minimal amount of Ethanol is used. The saturated solution is removed from heat once the solid is completely dissolved. Cool the solution at room temperature, and then in an ice and water back. The solid is then vacuum filtered, dried, and weighed. The percent yield is then calculated and noted. The melting point is taken by placing 0.3 cm of solid product into a capillary and placing into a MEL-TEMP apparatus. The melting point is observed via a magnifying lens and temperature is recorded as soon as the solid begins to melt. Set up TLC again, prepare a solution of the solid product in ethyl acetate, and use a mixture of 4:1 ethyl acetate:methylene chloride as the eluent. Run the TLC again and calculate R  f values. Prepare NMR by dissolving about 100mg in about 0.5 mL of CDCl3 and place solution into an NMR tube. Provide the TA with product to perform the IR and NMR. Characterize the product. Data Acquisition/Calculations

Compound

Molecular Weight

acetaminophen 151.17 g/mol

Density/Mol arity

Reaction Weight or Volume

mmol

Equivalents

N/a

1.3 g

8.60

1.0

Potassium carbonate

138.21 g/mol

N/a

2.5 g

18.1

2.1

iodoethane

155.97 g/mol

1.94 g/mL

1.0 mL

12.4

1.44

2-butanone

72.06 g/mol

0.805 g/mL

15 mL

167.6

19.4

Table 1. Reaction Table Calculations performed in laboratory notebook _________________________________________________________ Percent Yield Formula: Percent Yield = [(Actual Yield) / (Theoretical Yield)] ᐧ 100 Actual Yield (g): 0.50  Phenacetin molar mass(g/mol): 179.2  Theoretical yield(g): (8.60 ᐧ 10-3  mol acetaminophen) ᐧ (1 mol phenacetin) / (1 mol acetaminophen)  ᐧ (179.2 g phenacetin) / (1 mol phenacetin) = 1.54  Percent yield: [(0.50 g) / (1.54 g)] ᐧ 100 = 32.47% _________________________________________________________ Retention Factor (Rf ) Formula: (Rf )=(distance travelled by solute/distance travelled by solvent) Phenacetin Product: distance traveled by phenacetin product: 3.2  cm distance traveled by solvent: 4.50 cm Rf =  (3.2 cm) / (4.50 cm) = 0.71 Pure Acetaminophen: distance traveled by acetaminophen: 2.0  cm distance traveled by solvent: 4.50 cm Rf = (2.0 cm) / (4.50 cm) = 0.44 _________________________________________________________ Melting Point

Phenacetin actual melting point: 134°C Phenacetin observed melting point: 123°C - 128.5°C _________________________________________________________ IR Analysis Inspect the spectrum and determine key functional groups present on the graph Range (cm-1)

Observed Functional Group N-H Stretch

3280.05 cm-1

alkyl ether

1130.82 cm-1

aromatic

3073.01-3252.73 cm-1

Table 2. IR functional groups with respective frequencies. _________________________________________________________

NMR Analysis Inspect the spectrum and analyze the chemical shift, multiplicity, and integration Chemical Shift

Multiplicity

Integration

Function Group

1.29, 1.45, 1.61 ppm

triplet

3H

no electron withdrawing groups on carbon

6.76, 6.97 ppm

triplet

2H

aromatic

7.38, 7.59 ppm

triplet

2H

aromatic

3.98 ppm

quartet

2H

CH2 group

Table 3. NMR data _________________________________________________________ Conclusion The objective of this laboratory was to successfully yield pure phenacetin through Williamson ether synthesis. A rotovap was used to remove a solvent, the remaining crude solid was

purified by ethanol. Various characterization tests of the product were then performed, and the percent yield was calculated at the conclusion of the lab. The theoretical yield was calculated using the limiting reagent, acetaminophen. The limiting reaction is the chemical in the reaction that limits the amount of product that is able to form. The acetaminophen is the limiting reagent is because it contains the least amount of moles out of all of the other reagents(as seen in table 1). The percent yield of the reaction was calculated to be 32.47%. This is extremely low, and there are several reasons for this poor result. One of the things that we attributed to the low percentage yield is that we added too much of the ethanol solvent during the recrystallization procedure. When separating the organic and aqueous layers in the separatory funnel, we incorrectly determined which was the organic layer and disposed of the needed layer. This led us to not being able to perform the rotary evaporator part of the procedure, and obtain the data needed. We mended this by joining another laboratory group and conducting the rest of the experiment with their materials. In regards to the TLC segment of the procedure, the Rf values demonstrated that acetaminophen is more polar than phenacetin. The value could have been higher, however due to some impurities in the product the value was quite low. The experimental melting point was relatively accurate, so there weren't many impurities present in our product. The IR and NMR spectroscopies were overall successful. The chemical shift near ether at 3.98 ppm shows that ether was successfully synthesized during the reaction process. The IR spectroscopy indicated a relevant stretch at 1130.82 cm^-1. This stretch shows that there are other functional groups in the williamson synthesis reaction. The lack of an -OH stretch is a positive result because this shows that the reaction went to completion. Overall, the experiment was very insightful and introduced us to the rotary evaporation device. This technique is important to understand for future experiments. The identity of phenacetin product was successfully confirmed using the TLC plate analysis, melting point analysis, and IR and NMR spectroscopy.

References ● Gilbert J.C., and Martin, S.M., Experimental Organic Chemistry, 4th Edition, Cengage Learning, Boston, MA, 2011. ● Landrie, C.L., and McQuade, L.E., Organic Chemistry: Lab Manual and Course Materials, 8th edition, Hayden-McNeil, LLC, Plymouth, MI, 2018...