Synthesis of Aspirin (Acetylsalicylic Acid)

Synthesis of Aspirin(Acetylsalicylic acid)
Theoretical Background
Aspirin is a member of the salicylic acid structural class of non steroidal anti-inflammatory
drugs (NSAID). Like other NSAIDs aspirin is commonly prescribed for its antipyretic,
analgesic, and anti-inflammatory effects.
There are stories dating back to ancient Greece regarding the use of willow leaves and
meadow sweet to treat fever. These plants were later found to contain salicin, a precursor to
salicylic acid, which was used to treat arthritis by the early 1800s. However, it was not well
tolerated by patients due to its unpleasant taste and strong gastric side effects.
Bur in 1899, a chemist named Felix Hoffman at Bayer Pharmaceuticals synthesized aspirin
from salicylic acid. The important alteration Hoffman made was the addition of an acetyl
group to salicylic acid, generating acetylsalicylic acid, which is the chemical name for
aspirin.
The preparation of Aspirin 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.
To prepare aspirin, salicylic acid is reacted with an excess of acetic anhydride. A small
amount of a strong acid is used as a catalyst which speeds up the reaction. In this experiment,
sulfuric acid will be used as the catalyst. The excess acetic anhydride will be reacted with the
addition of water. Overall, the reaction takes place between a carboxylic acid and an acid
anhydride to form an ester.
Aspirin is not very soluble in water so the aspirin product will precipitate when water is
added. Some of the other compounds, acetic anhydride and acetic acid, dissolve in water, but
salicylic acid is only slightly soluble in cold water. Vacuum filtration will separate the
crystalline aspirin away from everything else in the reaction mixture except for any salicylic
acid that did not react.
This modification makes aspirin unlike other NSAID because it irreversibly inhibits
cyclooxyrgenase enzyme, or COX, enzymes by acetylation. Other NSAIDs inhibit
cyclooxyrgenase enzymes by competing with the enzyme’s substrates for access to the active
site. In such cases, when the drug has been cleared from the active site, the effect of the drug
ceases. Aspirin, however, transfers its dactyl group to one of the amino acid residues in the
active site of the enzyme. To be specific, aspirin acetylates serine 529 in COX-1, and serine
516 in COX-2. These are homologous serine residues, meaning that they are in the same
relative position in the active site and perform the same function, with discrepancy in number
being due to the fact that amino acid sequence of these two enzymes is slightly different. This
oxygen atom attacks the carbonyl on aspirin and there by acetylated, covering aspirin into
salicylic acid in the process.
The hydroxyl group in the serine residue is critical in carrying out enzymatic function, and its
nucleophilicity is nullified once acetylated. So by altering the structure of the active site,
aspirin renders the enzymes permanently. This means that new enzymes must be made within
the body before the effect of aspirin wears off.
Method
Materials Required:
→ Apparatus: 500mL beaker,125mL erlenmeyer flask, hot plate, filter paper, funnel and
watch glass
→ Chemicals: Salicylic acid, acetic anhydride, concentrated sulfuric ac
Procedure:
1. Put water in a 500mL beaker and start heating it on a hot plate
2. While that heats, prepare our reaction: put about 2 grams of salicylic acid in a 125mL
Erlenmeyer flask.
3. Add 5mL of acetic anhydride to the powder.
4. Add 5 drops of concentrated sulfuric acid and swirl the mixture to make sure that
everything is well mixed.
5. To get even heating, dip the flask in the hot water beaker, instead of putting it directly
on a hot plate.
6. Heat the water until it reaches around 80 or 90 degrees celsius, and then leave the
reaction flask partially submerged in the hot water for about 10 minutes.
7. After taking it out of the water let the solution to cool down to room temperature.
Aspirin crystals should start to form as the solution cools down.
8. Use a glass rod to scratch the slides of the flask to initiate crystallization if necessary.
9. If no crystals are formed, add about 10mL of cold water to the reaction mixture. This
will halt the reaction.
10. To make sure all the crystals have been formed, dip the flask in an ice water bath.
Leave it there for 10 minutes.
11. After the aspirin crystals are formed, collect them by filtration.
12. Even though the product is collected, it is not totally pure. So recrystallization must be
done to further purify the product:
i. Start by dissolving the impure aspirin in 5mL of ethanol.
ii. Then add 50mL of hot water to the crude sample
iii. Add the vessel to the hot plate and start adding more solvent.
iv. After all is dissolved, take the vessel off the hot plate and place it at room
temperature. Over time, the crystals start to form.
v. After the crystals are formed, collect them by filtration.
13. Put the filter paper with the product on the watch glass and leave it at room temperature
to air dry.
Synthesis of Aspirin from Plants
Aspirin

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Synthesis of Aspirin(Acetylsalicylic acid)

The preparation of Aspirin is an example of an organic synthesis called esterification.

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