Lab 2. What a Pain! Phenacetin Synthesis from Acetaminophen
What reaction conditions converts acetaminophen to phenacetin? Which functional group reacts? What conditions makes
this reaction occur in the reverse direction?
Prelab Activity
Spend 5 minutes on the following activity. Assign a notetaker. Report to the class.
1. Take a look at an Acetaminophen tablet. Is it pure Acetaminophen? If not, what other substances are in the tablet?
2. a. Using Lewis structures, write a chemical equation that represents the synthesis of phenacetin from acetaminophen.
b. Identify the functional group(s) in each reactant and product.
c. Which reactant is chiral? Identify the chirality center(s).
d. Which reactant is an acid? Identify the acidic H. State the pKa of this acid.
e. Which reactant is a base? Identify the basic atom. Draw the conjugate acid of this base. State the pKa of this acid.
f. Identify the nucleophile(s) and electrophile(s). If there is more than one nucleophile or electrophile, identify the best
nucleophile/electrophile. Use curved arrows to show how the nucleophile reacts with the electrophile.
g. This reaction is a ____ reaction.
o
o
o
i. Identify the alpha carbon. Is this carbon 1 , 2 , or 3 ?
h. Identify the leaving group. Is this leaving group a good or poor leaving group?
i. Identify the beta carbon. Is there a H bonded to this C?
j. Calculate the moles of each reactant in each reaction. Identify the limiting reactant. Calculate the theoretical yield of
product.
k. What property of the product distinguishes it from the reactant? How will you characterize the product?
Table 1. Chemical Properties of Lab 2 Compounds.
Compound
Structure
Functional
Acid/Base/
Group(s)
pKa
-
Nu: /E
+
Molar
mass
density
m.p.,
o
C
Polar
or nonpolar?
Objectives
1. convert an alcohol to an ether by substitution reaction
2. synthesize phenacetin from Acetaminophen
3. analyze your sample by HPLC
4. propose a reaction mechanism
Reference: 1. B.D. Williams, B. Williams, and L. Rodino, “Synthesis of the Sweetener Dulcin from the Analgesic
Acetaminophen”, J. Chem. Educ., 2000, 77, 357-359.
Introduction
If you have a headache, you take a pain reliever, such as acetaminophen (Tylenol). In this lab, you will take
acetaminophen and convert it into phenacetin, another pain reliever. Phenacetin was banned by the Food and Drug
Admininstration (FDA) in 1983 due to adverse side effects including increased risk of certain cancers and kidney damage.
Phenacetin is metabolized to acetaminophen. Interestingly, acetaminophen replaced phenacetin in some over-the-counter
medications following the ban.
Once you make phenacetin, you will identify the reaction conditions to convert the phenacetin back to acetaminophen and
do your experiment. In other words, reverse the reaction.
While you are doing this experiment, try to determine the purpose of each step in the procedure, e.g.,
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Is this reagent reacting with one of the acid, base, or neutral? If so, write a chemical equation that represents the
reaction. Is this reagent the limiting reactant or excess reactant?
• If the solvent I just added formed two layers, is the solvent extracting something? Which substance is being
extracted?
• What is the reason for heating or cooling?
Record the purpose of each step in your notes.
•
Materials
Tylenol tablets
1 M NaOH in ethanol
HPLC
ethyl iodide
1 M HCl (aq)
IR
NMR
Procedure
Caution: The acids and bases in this experiment are corrosive. Be careful handling these substances.
Part 1. Synthesize phenacetin from acetaminophen.
1. Synthesis
a. Grind 2 tablets of Tylenol (350 mg of acetaminophen per tablet or an equivalent amount) using a mortar and pestle.
Place the powder in a 50-mL round bottom flask with a magnetic stir bar.
b. Add 5.25-mL of 1M ethanolic NaOH solution to the Tylenol.
What does the ethanol or NaOH do?
c. Attach a condenser to the RB flask and bring to a vigorous reflux. Maintain reflux for 15 minutes. Then, remove the
flask from its heat source.
While you are refluxing, go to Step 4.
d. To the hot solution, add 0.7 mL of ethyl iodide.
Is the ethyl iodide the limiting reactant?
Reflux for an additional 15 minutes.
2. Workup
a. Filter the hot solution under vacuum through a Buchner funnel and into a filter flask containing a mixture of ice and
water. The insoluble starches should be collected on the filter paper.
b. The phenacetin precipitates from the filtrate as a white solid upon contact with the cold water.
c. While still cold, collect the solid phenacetin by vacuum filtration.
Wash with ______ water.
d. Dry the solid in the oven at 100 °C for 5 to 10 minutes or by place the sample on a watch glass over a heat source not
exceeding 100 °C.
e. The phenacetin prepared by this method is generally pure.
If necessary, you can further purify the phenacetin by recrystallization from hot water. Use decolorizing charcoal if the
impure phenacetin is ____.
Waste Disposal: solids – in solid waste.
Ethanolic NaOH – neutralize with acid and dispose in sink.
Any solution containing iodide – in halogenated waste.
3. a. Determine the % yield.
b. Characterize the product by:
(i) melting point.
(ii) IR.
(iii) HPLC.
(iv) NMR
c. Summarize your data and results in Table 3.
Table 3. Phenacetin synthesis data and results.
Run 1
Run 2
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Method
Mass of acetaminophen
Moles of acetaminophen
Volume of 1 M NaOH
Moles of NaOH
Limiting reactant
Moles of Phenacetin
Theoretical yield of Phenacetin, g
Actual yield of Phenacetin, g
% yield of Phenacetin
o
Experimental melting point range, C
o
True melting point, C
reflux
microwave
4. Repeat the experiment except this time use the microwave oven to heat your reaction mixture instead of doing a reflux.
Part 2. Synthesize acetaminophen from phenacetin. (Phenacetin is metabolized to acetaminophen.)
1. Identify the reaction conditions to convert phenacetin to acetaminophen. Explain the purpose of each step.
Use the mass of phenacetin you made in Part 1.
2. a. Do your experiment.
b. Characterize your product.
c. Summarize your data and results in a table.
Waste Disposal:
Questions
1. For each reaction, report the following:
a. % yield,
b. characterization data and results. Did you make your desired product?
2. In the synthesis of phenacetin from acetaminophen, an alcohol is converted to an ether.
a. Is the –OH in acetaminophen a nucleophile or electrophile?
b. What is the function of the ethanol/NaOH?
c. What is the function of the CH3CH2I?
d. Describe the mechanism of this reaction. Identify the nucleophile in each step. Use curved arrows to show bonds
breaking and forming. What is the leaving group?
e. Would you get phenacetin by treating acetaminophen with sulfuric acid followed by ethanol? Give reasons.
3. In the synthesis of acetaminophen from phenacetin, an ether is converted to an alcohol.
a. Explain the purpose of each reaction step in your procedure.
b. Describe the mechanism of the synthesis of phenacetin from acetaminophen. Identify the nucleophile in each step. Use
curved arrows to show bonds breaking and forming. What is the leaving group?
c. Is there another nucleophile or electrophile that can react with the reagent(s) you chose that could interfere with your
desired reaction? In other words, is there another atom in phenacetin that could react with your chosen reagent so
acetaminophen was not produced? If so, which atom in phenacetin reacted with your reagent and what compound was
produced?
d. How is the phenacetin to acetaminophen related to the sucrose hydrolysis to glucose and fructose reaction? (Hint: think
functional group conversion.)
e. In theory, can sucrose be hydrolyzed (see Lab 1) under the same reaction conditions as the conditions you used for the
phenacetin to acetaminophen reaction? Give reasons.
4. Is there a common intermediate in each mechanism? In so, what makes the reaction go in one direction or the other
once this intermediate forms? (Remember, many organic reactions are reversible.
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