ORG1 – Syntheses of Acetaminophen and Aspirin
Estimated Time Required: 60 minutes
Introduction
Ethanoylation (better known as acetylation) is the introduction of an acetyl functional group onto a
suitable nucleophile. As a common moiety in many syntheses, acetyls can be used as a protecting
group, intermediate, or may be part of a final target (Figure 1b),
Me
O
a)
O
O
OH
OH
b)
O
HO
OH
O
Me
O
OH
Figure 1. a) acetyl protected glucose. b) the C and D rings of Taxol, a natural product and cancer therapeutic.
Acetylation can proceed by both acid and base catalyzed pathways as seen below (Scheme 1). The left
pathway below shows the use of a non-nucleophilic base to deprotonate the oxygen of phenol. Acetic
anhydride then undergoes a nucleophilic attack by the phenolic anion, forming a tetrahedral
intermediate before the acetate anion is eliminated. This results in formation of the phenyl acetate
product. The pathway on the right demonstrates the acid catalyzed acetylation pathway. First,
protonation of acetic anhydride activates the carbonyl carbon for a nucleophilic attack by phenol.
Following formation of a tetrahedral intermediate, proton transfer causes elimination of acetic acid,
while subsequent deprotonation forms the phenyl acetate product.
H O
O
O
B
Me
O
Me
O
Me
O
O
Me
O
Me
Me
H
tetrahedral
intermediate
Me
O
OH
O
O
O
Me
O
O
H
H+
O
tetrahedral
intermediate
Me
O
O
O
O
H
Me
O
O
H+ transfer
Me
O
H+
O
Me
HO
O
Me
H
Me
O
O
O
H
Me
O
O
O
Me
H
Scheme 1. Base (left) and acid (right) catalyzed acetylation of phenol with acetic anhydride.
In this experiment, acetic anhydride is used to acetylate different starting materials resulting in two
common analgesic compounds, acetaminophen (Tylenol) and acetylsalicylic acid (aspirin). Microwave
heating allows these reactions to be performed in only minutes while maintaining good yields.
Experimental
Draw reaction scheme below:
Reagent
CAS
MW (g/mol)
Density (g/mL)
4-aminophenol
acetic anhydride
water
Equivalents
mmol
Amount
2.75
2.89
0.55 M
Note: The concentration of the solution with respect to the limiting reagent is given under the “mmol” column for
water.
Product
CAS
MW (g/mol)
N-(4-hydroxyphenyl)acetamide
mmol
Theo. Yield
2.75
Required equipment: Discover® microwave synthesizer
10-mL glass microwave reaction vessel
small stir bar
microwave vessel cap
25-mL Erlenmeyer flask
ice bath
glass stirring rod
vacuum filtration assembly
Procedure:
1) Weigh 0.300 g of 4-aminophenol and place it into a 10-mL microwave reaction vessel with stir bar.
2) Add 5.00 mL of deionized water to the reaction vial, washing down any 4-aminophenol stuck to the sides of the
vessel.
3) To this solution, add 0.273 mL of acetic anhydride and seal the vessel with a cap.
4) Place the sealed vessel into the microwave cavity and heat the reaction mixture using a “standard” method to
110 °C with 300 W for a one-minute hold time.
5) After the reaction is complete, transfer the solution to a small flask then place it in an ice bath until crystals
form. Scratch the sides of the flask to promote crystallization, allowing it to sit in an ice bath for at least 15
minutes after crystals form.
6) Vacuum filter the resultant crystals and wash them with cold water. Let the crystals dry thoroughly before
recording the mass of acetaminophen product. Calculate the percent yield of product and perform a melting
point (lit: 169-172 °C) analysis to confirm purity; NMR (DMSO-d6) and IR analysis can be performed, if
available.
Experimental
Draw reaction scheme below:
Reagent
CAS
MW (g/mol)
Density (g/mL)
2-hydroxybenzoic acid
acetic anhydride
Product
Equivalents
mmol
Amount
3.62
5.43
CAS
MW (g/mol)
2-acetoxybenzoic acid
mmol
Theo. Yield
3.62
Required equipment: Discover® microwave synthesizer
10-mL glass microwave reaction vessel
small stir bar
microwave vessel cap
25-mL Erlenmeyer flask
ice bath
glass stirring rod
vacuum filtration assembly
Procedure:
1) Weigh 0.500 g of salicylic acid and place it into a 10-mL microwave reaction vessel with stir bar.
2) Add 1.00 mL of acetic anhydride to the reaction vial and seal the vessel with a cap.
3) Place the sealed vessel into the microwave cavity and heat the reaction mixture using a “standard” two-stage
method to 80 °C for 10 seconds and 130 °C for a one minute hold time using 200W of power.
4) After the reaction is complete, transfer the solution to a small flask and dilute it with 2 mL of ice water.
Transfer the flask to an ice bath and scratch the sides of the beaker to promote crystallization, allowing it to sit
in an ice bath for at least 15 minutes after crystals form.
5) Vacuum filter the resultant white aspirin crystals washing with cold water.
6) Recrystallize the aspirin from hot deionized water, adding a few drops of ethanol if the aspirin product does not
go into solution. Collect the recrystallized aspirin by vacuum filtration, allowing the crystals to dry over vacuum
before recording the mass. Calculate the percent yield of product and perform a melting point (lit: 134-136 °C)
analysis to confirm purity; NMR (CDCl3) and IR analysis can be performed, if available.
Qualitative analysis for salicylic acid: In a test tube, dissolve a few crystals of your final product in some ethanol. Add a
couple of drops of aqueous 1% iron(III) chloride solution (or a few grains of iron(III) chloride hexahydrate) to your sample
and note the color of the solution. Add a few grains of salicylic acid to the same test tube and note any changes to the
color of the solution.
Results and Discussion
1) In the above experiment, why does acetylation NOT take place at the positions indicated? Explain.
NH2
O
OH
HO
OH
2) The following NMR spectra show the acetaminophen product and an unwanted by-product. What is the byproduct and how did it form?
Acetaminophen
X : parts per million : 1H
By-product
X : parts per million : 1H
3) Water is not used in the acetylation of salicylic acid. Why not?
Conclusions
1) How would you make the compound below?
NH2
O
Me
O
2) What would you do to prevent the formation of the by-product in 2) above?