Synthesis of Aspirin

Chem. 460 Dr. Ward 2019

INTRODUCTION

Compounds derived from willow bark have been in use for hundreds of years as antipyretic (fever-
reducing), analgesic (pain killing), and anti-inflammatory agents. It was eventually discovered that
salicylic acid is the portion of these molecules responsible for the therapeutic effect. Two ester
derivatives of this acid, synthesized as shown, are currently in common medicinal use: methylsalicylate
(oil of wintergreen) for external applications and acetylsalicylic acid (aspirin) for internal consumption.
These particular derivatives are chosen for their effectiveness in penetrating the intestines or the skin,
respectively.

This experiment will demonstrate the preparation of aspirin, also called acetylsalicylic acid. When
ingested, acetylsalicylic acid remains intact in the acidic stomach, but in the basic medium of the upper
intestinal tract, it hydrolyzes (one or more water molecules is removed) forming salicylate and acetate
ions (reaction shown below).

The analgesic effect of aspirin is probably due to the salicylate ion; however, its effects are still not well
understood. Someone who ingests pure salicylic acid will experience the same therapeutic effects as
aspirin, but this compound is very bitter tasting and causes more severe stomach upset. The creation of
compounds that temporarily mask a physiologically active compound, to facilitate oral ingestion or
present decomposition during transport to the site of activity within the body is a very common strategy
in drug design.

Hoffman's method for producing aspirin involves reversing the above reaction, reacting salicylic acid with
acetic acid in the presence of an acid catalyst. Instead of using acetic acid, you will use acetic anhydride, a
compound that produces acetic acid when it reacts with water. In the reaction with salicylic acid, acetic
anhydride works better than acetic acid and requires less catalyst.
After the aspirin is synthesized, it is not likely to be pure. The impurities in the crude aspirin are the acid
catalyst, ureacted acetic anhydride, acetic acid, and unreacted salicylic acid. Fortunately the first three
compounds are very soluble in water and are easily washed away from the mixture during the isolation of
the crude (unpurified) aspirin. However, both aspirin and salicylic acid are sparingly soluble in water and
any unreacted salicylic acid may be a contaminant in the crude product mixture.

PROCEDURE
Part I: Synthesis of Aspirin

1. Half-fill a large beaker with hot water and put it on a hot plate to serve as a hot water bath.
2. Weigh close to 2.1 grams of salicylic acid into a DRY 125 mL Erlenmeyer flask. Record the
appearance and exact mass of the amount you measure. (See attached data table)
NOTE: Do steps 3 through 8 in the FUME HOOD
3. Using an automatic pipet carefully measure 5 mL of acetic anhydride into the flask with the
salicyclic acid and swirl to mix the liquid with the solid.
4. Carefully add to the same flask 6 drops of sulfuric or phosphoric acid, as directed.
5. Put the flask into the hot water bath (which should be 60 to 80C). Heat for 20minutes.
During the heating process, use a clean dry glass stir rod to mix the contents of the flask. The
solid should dissolve in the liquid.
6. Remove the flask from the hot water bath. Add 2 mL of distilled water, a few drops at a time,
with continuous swirling. Do not add water all at once. The water is reacting with leftover
excess acetic anhydride. Solid crystals of aspirin may start to form at this point.
7. Add 10 grams of crushed ice to your flask and swirl. You should have a white solid product
(aspirin) at this point. If not, consult your teacher before proceeding, especially if you see an
oily liquid phase rather than a solid product.
8. Weigh and record the combined mass of a piece of filter paper and a watch glass. Wet the
filter paper and place it in a stem funnel.
9. At your lab bench, cool your flask in an ice/water bath that you construct in a large beaker.
The bath should be a 2:1 mix of ice to water. Continue to cool the flask for 5-10 minutes
with occasional swirling. You should have a white solid at this point.
10. Scrape your aspirin mixture into the filter paper and allow the liquid to drain into a waste
beaker.
11. When the filtering seems complete, rinse the reaction flask with 2-3 mL of ice cold water and
pour this into the filter paper. This is a rinsing step for both the flask and the aspirin.
12. Remove the filter paper and aspirin and place on the labeled watch glass.
13. After dry (next class meeting) weigh the watch glass, filter paper and product.
Part II: Analysis of Aspirin

1. Investigating commercially prepared aspirin

 Weigh an aspirin tablet.
 Read the label of the bottle and find out from the label how much acetyl salicylic acid it contains,
by mass.

2. Melting point
 Use a mortar and pestle to grind up a commercial aspirin tablet.
 I will explain to you how to use the melting point apparatus
 You will measure the melting point of your aspirin, pure salicyclic acid, and pure acetyl salicyclic
acid

3. Contaminants
NOTE: Because saliclylic acid is also insoluble in water, any of it that remains unreacted during the
synthesis is likely to be present in your aspirin sample. There is a phenol radical present in salicylic
acid but not in aspirin. By using a small amount of a solution of iron(III) chloride we can test for this
impurity because iron(III) chloride reacts with phenols to produce colored products.

 Obtain 4 small test tubes and add about 5 mL of water to each.

 Add a small amount (again, pea-sized) of the following to different test tubes:
o Salicylic acid
o Commercially prepared aspirin
o Acetyl salicylic acid
o Your aspirin sample
 Stopper the tubes and vortex.
 Using pH paper, determine the pH of all three samples.

 Add about 5 drops of iron(III) chloride. Mix and record your observations.
DATA TABLE:

Mass of salicylic acid= _________________

Mass of filter paper & watch glass = _________________
Mass of aspirin, watch glass and filter paper = ______________

Melting Iron(III)
Appearance pH
point chloride test

Salicylic acid

Commercially
prepared aspirin

Your aspirin

Pure acetyl salicylic

acid

CALCULATIONS

From the mass of salicylic acid you used in your experiment, calculate the maximum amount of aspirin
you could have produced. This is called the theoretical yield.

Use the mass of aspirin you actually produced (actual yield) to calculate your % yield.
Hand-In:

 Name/Date/Title/Partner’s Name
 Provide a Data Table for your synthesis and analysis work in the laboratory.
 Provide the calculations of your percent yield.

Analysis Questions
1. Pure aspirin has a published melting point of 135°C, pure salicylic acid a melting point of
159°C. Discuss your melting point results and explain any discrepancies you observe.
2. Do the results of your iron(II) chloride tests help support or refute your melting point
analysis? Explain.

Extension Questions
3. An early alternative to aspirin, salicylic acid, was corrosive to the stomach because it resembled
phenol. Draw the structure of both salicylic acid and phenol. What functional group(s) do they have
in common?
4. When aspirin tablets sit on the shelf for too long when the container is open, it often smells like
vinegar. Why might this be the case?
5. LD50 (lethal dose – 50) is the minimum dose that kills 50% of test animals in an evaluation of drug
toxicity. The LD50 for aspirin is 1.5 g/kg. Calculate the lethal dosage of aspirin to a 22-lb child.
6. Regular strength aspirin tablets contain 325 mg of aspirin.
a. How many tablets correspond with your answer from question 5?
b. Americans consume 14 billion tablets of aspirin each year.
i. If one aspirin tablet contains 325 mg, how many tons of aspirin do Americans
consume in a year?
ii. How many tablets, on average, does each American consume in a year?
c. What mass of salicylic acid is needed to produce one regular strength tablet if the reaction
has a 60% yield?
7. Aspirin can cause stomach bleeding because of its acidity.
a. Draw the structures of the alternative pain relievers, ibuprofen and acetaminophen.
b. Are either of these substances good alternatives to aspirin for the reduction of stomach
bleeding? Explain.