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Williamson Ether Synthesis of Phenacetin from Acetaminophen And Electrophilic Bromination of Phenacetin

Lontsie Tedonzong CHEM 3412 Dr. Shaobin Miao July 21, 2021

Line Reaction (Lab 1)

Line Reaction (Lab 3)

[10]Formula:C10H13NO2 [10]MWt: 179.22

Formula: C10H12BrNO2 [10] MWt:94.96

Formula:C10H12BrNO2 [10]MWt: 258.11

Introduction In lab 1, acetaminophen was converted to phenacetin by a Williamson ether synthesis, with Diethyl sulfate serving as the ethyl source, and potassium carbonate used as the base to form the phenoxide ion. Acetaminophen and phenacetin are nonopioid analgesics. It is the most widely used, non-anti-inflammatory medication for mild to moderate pain relief and fever reduction. The FDA banned the use of phenacetin in 1983, as its prolonged use led to kidney toxicity. In lab 3, an electrophilic aromatic substitution of bromine was performed, so the phenacetin was brominated. In this experiment, there is a possibility to get any of the two Regioisomers above but only one was made. In an Electrophilic substitution reaction, electrophile displaces a functional group in a compound.

Safety Information for both Lab 1 and 3 [1] Acetaminophen- irritates of skin and eyes. Harmful if swallowed. [2] Diethyl sulfate- possible carcinogen, causes severe skin burns and eye damage May cause respiratory irritation May cause genetic defects. [3] Potassium bromate- Strong Oxidizer, irritant of skin and eyes. Causes eyes redness, skin burns, itching if overexposed. [4] Hydrobromic acid- Strong Acid, avoid contact with skin and eyes. [5] Phenacetin- A carcinogen, Harmful if swallowed.

[6] Methanol- Vapor harmful. Flammable liquid and vapor. Harmful if swallowed, inhaled, or absorbed through the skin. Causes eye, skin, and respiratory tract irritation. May cause central nervous system depression.

Experimental Section Lab 1 To a mixture of acetaminophen (1.891g) and potassium carbonate (3.040g) in a 50 mL round-bottom flask was added 16mL of acetone. Diethyl sulfate (2.00 mL) was then dispensed in hood by the instructor and the mixture was heated at reflux for 40minutes. The mixture was then poured into an excess of water, and the resulting solid once fully formed was filtered by suction and rinsed with water. The product was stored in a labeled vial for 2 days. Then, its mass and melting point were obtained. The product had an appearance of a fine white crystalline solid, it had a melting point of 132°C -135.2°C, a mass of 1.065g and a percent yield of 56.63%

Lab 3 In a small Erlenmeyer flask with a stirring bar in, was added 0.536g of the phenacetin and 5.0 mL of acetic acid. To this was added potassium bromate (0.179 g) and 0.60 mL of hydrobromic acid. The mixture was allowed to stir for 20 minutes. The mixture changed from light brown, to yellow then orange when hydrobromic acid was added. Then the mixture became thicker, and with time it became dark orange and turned back to a lighter liquid form. When the mixture was poured in 50 mL of water, it turned cloudy white. The mixture was stirred until the solid became nicely suspended. The solid was collected by vacuum filtration and rinsed with water. Then, it was recrystallized by dissolving it in a 5ml of hot MeOH. After hot filtration, the solution was dropwise added water till a slight cloudiness just lingered, then the mixture was chilled on ice to complete the crystallization. The solid was collected by vacuum filtration and allowed to dry under suction. Melting point of the recrystallized product was taken and compared to that of phenacetin and to that of the two mono-bromo regioisomers. The product had an appearance of a white solid, it had a melting point of 112°C 113.5°C, a mass of 0.561g and a percent yield of 18.45%

[7] Figure 1 (Reflux)

[8] Figure 2 (Vacuum filtration)

[9] Figure 3 (Mel-temp apparatus)

[9] Figure 4 (hot filtration)

Mechanism

Lab 3

Results and Discussion

Williamson ether synthesis occurs by an SN2 reaction in which a metal alkoxide displaces a halide ion from an alkyl halide, and the alkoxide ion is prepared by the reaction of an alcohol with a strong base. A base of potassium carbonate was used in order to deprotonate the phenolic hydrogen which allowed for the reaction to occur. The literature melting point of phenacetin is 134-135 degrees Celsius. The observed melting point was between 132 and 135.2°C. The melting point was very close to the lit melting. The starting melting point of 132°C could have been due to presence of minimal impurities. In lab 3, the stronger directing group in this case was the ether and not the N-aryl amide as the results can show. The literature melting point of N-(3-Bromo-4-ethoxyphenyl)acetamide is 114-115°C. The observed melting point was between 122 and 113.5°C. Again, this is very close to the literature melting point. The starting melting point of 112°C could have been due to presence of minimal impurities. N-(3-Bromo-4-ethoxyphenyl)acetamide was the product because the other regioisomers lit melting point was 94-95°C. However, a yield of 56.63% in lab 1 and 18.45% in lab 3, were obtained which is quite low. These shows that some of the products was lost along the process. Some could have been lost during the hot filtration process as some product recrystallized of the filter paper, or in a flask or beaker as product were transferred from flasks to beakers.

Data Summary Table Name of reaction

Williamson Ether Synthesis of Phenacetin from Acetaminophen

Electrophilic Bromination of Phenacetin

Name of product

Phenacetine

N-(3-Bromo-4-ethoxyphenyl)acetamide

[10]Literature Melting point Melting point(lab) Appearance of product

134°C -135°C 132°C -135.2°C fine white crystalline solid

114-115°C

Moles of reactant

0.01251mole

0.00299mole

112°C -113.5°C white solid

Theoretical yield Actual yield Percent yield of product

1.891g

0.536g

1.768g 56.63%

0.599g 18.45%

Calculation

Percent yield = actual value/ theoretical value ×100

Lab 1: Moles of Acetaminophen = mass / molar mass = 1.891g / 151.16g/ mol= 0.01251mol Theoretical yield= 0.01251mol* 151.16g/mol= 1.891g Percent yield of Phenacetin = ( 1.065 g/1.891g)*100= 56.63% Lab 3: Moles of phenacetin = mass / molar mass = 0.536g/ 179.22g/ mol= 0.002991mol Moles of KBrO3= mass / molar mass = 3.040g/ 138.21g/ mol= 0.002199mol So, limiting reagent Theoretical yield= 0.002199mol* 179.22g/mol= 3.040g Percent yield of N-(3-Bromo-4-ethoxyphenyl)acetamide = (0.561g /3.040g)*100= 18.45%

Conclusion In experiment 1, acetaminophen was successfully converted to phenacetin by Williamson ether synthesis. In experiment 2, phenacetin was successfully converted to N-(3-Bromo-4-ethoxyphenyl)acetamide by an electrophilic aromatic substitution of bromine. From the observed melting point it can be said that the products were fairly pure.

References: 1) https://www.fishersci.com/store/msds?partNumber=AC102330050&productDescription=4ACETAMIDOPHENOL%2C98%25+5GR&vendorId=VN00032119&countryCode=US&language=en 2) https://www.fishersci.com/store/msds?partNumber=AC114560250&productDescription=DIETHYL+SULF ATE%2C+99%25+25ML&vendorId=VN00032119&countryCode=US&language=en

3) https://fscimage.fishersci.com/msds/19270.htm 4) https://fscimage.fishersci.com/msds/11107.htm 5) https://www.fishersci.com/store/msds?partNumber=AC216591000&productDescription=PACETOPHENETIDIDE%2C+97%25+100GR&vendorId=VN00032119&countryCode=US&language=en 6) https://fscimage.fishersci.com/msds/14280.htm 7) http://users.sa.chariot.net.au/~dna/Cooktip.html 8) https://labsociety.com/lab-equipment-category/vacuum-filtration/ 9) http://what-when-how.com/organic-chemistry-laboratory-survival-manual/recrystallization-part-1laboratory-manual/ 10) "Hazardous Substances Data Bank" data were obtained from the National Library of Medicine (US)...