Synthesis of Aspirin

Learning Goals
1. To synthesize aspirin from salicylic acid and acetic anhydride.
2. To purify the crude product by Recrystallization.

Introduction
Most drugs are chemical compounds which are described as “organic compounds” because they are comprised primarily of the elements carbon, hydrogen and oxygen. The present experiment will be the synthesis of a familiar organic compound called aspirin. The common chemical name is acetylsalicylic acid. Aspirin, the most widely used drug in the world, has an interesting history. Nearly 2500 years ago, Greeks reported that extracts of willow and poplar bark could be used to relieve pain and symptoms of illness. There are reports that American Indians, before the time of Columbus, used special teas made from the bark of willow trees to reduce fever.

In 1763, the Reverend Edward Stone introduced these extracts and teas to the Europeans and in the early 1800’s the active ingredient in willow bark (and in the flowers of the meadow sweet plant which had similar therapeutic characteristics) was isolated and identified as salicylic acid (from salix, the Latin name for the willow tree). Although salicylic acid could be synthesized in the laboratory and large quantities became available for therapeutic use in the mid 1800s, the compound’s acidic properties caused irritation in the moist membranes of the mouth, throat and stomach. In 1875, the sodium salt was introduced and although the salt was less sour to the taste (actually it had an objectionable sweetish taste), it did not alleviate the gastric discomfort problems.

salicylic acid sodium salicylate
In 1893, Felix Hoffman Jr., a chemist working for the Bayer Laboratories in Germany, discovered a practical route for synthesizing an ester derivative of salicylic acid, acetylsalicylic acid.

Acetyl Salicylic Acid
Aspirin, ASA
Acetylsalicylic acid, a weaker acid than salicylic acid, was found to have the medicinal properties of salicylic acid without having the objectionable taste or producing the stomach problems. The acetyl group effectively masks the acidity of the drug during its ingestion and after it passes into the small intestine, it is converted back to salicylic acid where it can enter the bloodstream and do its pain relieving action. Bayer called its new product “aspirin,” the name being derived from “a” for acetyl, and the root “-spir”, from the Latin name Spiraea ulmaria, the meadow sweet flower, from which salicylic acid had been isolated. It was patented by Bayer in 1899, and in 1915 Bayer Aspirin tablets became commercially available as a non- prescription drug.

The trademark is still owned by the Bayer A.G. company in Germany. Today, aspirin is one of the most widely used, commercially available pharmaceutical drugs in the world. Its properties make it a powerful analgesic (pain reliever), antipyretic (fever reducer) and anti-inflammatory (reduces swelling) drug. Aspirin is not without its faults. It still causes some stomach irritation in some individuals, and it has been estimated that about 1 mL of blood is lost from the stomach lining for each gram of aspirin consumed. Aspirin is known to interfere with normal blood clotting (which actually may be a benefit in preventing heart problems). Reye syndrome, a rare but serious illness has been associated with aspirin, and children and teenagers should not use aspirin for flu like symptoms before consulting a doctor. Synthesis

The salicylate ion forms the therapeutic part of the aspirin. Aspirin passes through the acidic stomach contents ad does not ionize and form the salicylate ion until it reaches the alkaline conditions in the intestines. Here it is hydrolyzed to form the acetate and salicylate ion. The latter ion is absorbed through the intestinal wall. The equation depicting this reaction is given below.

The final step in the commercial synthesis of aspirin involves the reverse of this reaction. The salicylic acid is treated with acetic anhydride, which is a more reactive compound than the acetate ion. Catalytic amounts of sulfuric acid make the reaction proceed very rapidly. This is the synthesis step you will perform in this assignment.

H2SO4

The above reaction is an example of an organic synthesis called esterification. Esterification is the acid catalyzed reaction of a carboxyl (-COOH) group and an -OH group of an alcohol or phenol to form a carboxylate ester. In the synthesis of aspirin the -OH group is the phenolic -OH group attached to ring of the salicylic acid. The acetyl group, -COCH3 comes form acetic anhydride, and the reaction is catalyzed by sulfuric acid. This reaction is quite simple and gives a good yield of the product. Aspirin, although it is soluble in hot alcohol, is not soluble in water. Consequently, the final product will be filtered from an aqueous solution, and washed with cold water, then air dried.

A Special Summary (Song)
“How to Make Aspirin Today”
Achey day, headache please, go away.
And I’m getting a fever, Oy vey!
Can you tell me how to make, how to make aspirin today?
These you take, when aspirin you make.
Salicylic acid’s on the list

And acetic anhydride and an acid catalyst.
Sulfuric to be exact. Mix them all and they react,
And an ester is formed. You esterify. You esterify.
On phenol, acetyl finds its goal.
And from water, white crystals arise.
And to make them pure, from alcohol recrystallize.
by Thomas Ott
Oakland University, Rochester MI

Experimental
( Preparation of Aspirin:
1- Place 3.0 g (0.02 mol) of salicylic acid in a 100 mL Erlenmeyer flask. 2- Add, with continuous stirring, 6 mL of acetic anhydride (fume hood) followed by 1 mL of concentrated sulfuric acid. 3- Stir the mixture gently observing the rise in temperature to 70-80 °C while the salicylic acid dissolves. Heat in a water bath if needed. 4- After 15 minutes the solution cools by itself to 35-45 °C and a solid mass of aspirin forms. 5- Pour 35 mL of ice-cold water over the contents of the flask to hydrolyze excess acetic anhydride and to complete the precipitation of aspirin. 6- Chill the Erlenmeyer flask in an ice bath with occasional swirling to cause precipitation of the product.

If no precipitate forms, scratching the side of the flask with a glass stirring rod may help initiate crystallization. While the flask is chilling, prepare a vacuum filtration apparatus
as shown at the right.

7- Collect the crude aspirin using a Buchner funnel and wash with ice-cold water. 8- Air-dry the product, weigh, and calculate the yield.
( Recrystallization of Crude Aspirin:
To purify your synthesized aspirin, transfer it to a small erlenmeyer flask and add a small amount of ethanol using a plastic pipet. Warm the solution to 60 ºC. Cover the solution and allow it to cool undisturbed to room temperature. Then set the beaker in an ice bath and once again scratch the inside of the flask with a glass rod to induce recrystallization.

Collect the purified aspirin by vacuum filtration and wash them with ice-cold water. Let the crystals dry for a few minutes before weighing them. Determine the mass of your dry purified aspirin.

Synthesis and Analysis of Aspirin
Report Sheet
( Give a balanced equation for the synthesis of aspirin from salicylic acid and acetic anhydride.

( Determine the limiting reagent in the synthesis reaction (show calculations).

( Preparation of Aspirin:
Theoretical yield of aspirin (Show calculations).

Actual yield=
Percentage yield (show calculations).

( Recrystallization of Aspirin:
Mass of crude aspirin=
Mass of recrystallized aspirin=
Percentage yield=

( Give the mechanism of the reaction in your experiment.