Synthesis of Aspirin

Introduction: Aspirin, or acetylsalicylic acid, is one of the most widely produced drugs in the world. In the U.S. alone, over 25 billion tablets are made each year. It is the most widely used analgesic, and is much preferred over morphine because it does not involve physiological dependence. Aspirin is also very effective as an antipyretic, or fever-lowering agent and also as an anti-inflammation agent. It finds wide applications from rheumatism and arthritis to hangover and the common cold. In spite of extensive research to clarify the mechanism of the action of aspirin, much of the mystery of its operation still remains. A London doctor, Thomas Sydenham (1624-1689), is generally given credit for the initial investigations that led to aspirin. He became impressed with the reports of Jesuit missionaries of the medicinal properties of the bark of the cinchona tree, extracts of which were used successfully by certain Indians in South America in treatment of malaria. Sydenham then investigated bark of various trees and found that extracts of the barks of the willow and poplar were effective in reducing fever. In 1826 the active principle of willow bark was isolated and called salicyn (Latin for willow tree). Around 1835 a chemical called salicylic acid was obtained from willow extracts. In 1852 salicylic acid was made without using any natural willow materials. In 1874 a process suited for large scale production was developed. There were, of course, side effects with salicylic acid as there usually are with all drugs, especially when they are first introduced. One of these was irritation to the stomach. Some chemists suggested neutralizing the acid with sodium hydroxide. This was found to be a considerable improvement, and sodium salicylate became the major drug for rheumatic fever. However, sodium salicylate had a rather unpleasant taste and still caused stomach irritation in some cases. Attempts were made to alter the structure of the molecule while still retaining the medicinal value and without contributing further side effects. Eventually, Felix Hofmann prepared a derivative called acetylsalicylic acid that proved very effective and produced much less gastric irritation. In 1899, the new drug was produced commercially by the Bayer chemical plant where Hofmann worked and was given the trade name Aspirin, which indicated it is from the spirea willow, the source of the original salicylic acid. The basic srtructure of acetylsalicylic acid is the benzene ring of six carbon atoms. This compound is produced by the esterification reaction of salicylic acid with acetic anhydride as shown on the next page.

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CH3 COOH + OH O C CH3
Salicylic acid MW = 138.1 Acetic anhydride MW = 102.1

C O

H2SO4

COOH + O O C CH3
Acetic acid MW = 60.06

CH3COOH

Acetyl salicylic acid MW = 180.2

There are many brands of aspirin on store shelves, but most of these are about the same, the major difference being the purity of the product. It costs more to remove the unreacted salicylic acid and acetic anhydride and the acetic acid by washes and recrystallizations. However, the drug laws require conformity here, so aspirin is aspirin regardless of the source. You may be wondering why you are using acetic anhydride in this lab and not the more abundant and less costly acetic acid. The reason is that salicylic acid has both a phenolic group and a carboxylic group. The phenolic group of one salicylic acid molecule could react with the carboxylic acid group of another salicylic acid molecule to produce a dimer side-product and not the desired aspirin product. To minimize the production of the dimer side-product, acetic anhydride is used because it is more reactive than acetic acid and minimizes the amount of dimer side-product by quickly consuming the salicylic acid before much can react with itself.
HOOC OH + COOH HO O C
dimer

HOOC

OH + O H2O

Procedure: Fill a 400 mL beaker about half full with tap water and place the beaker on a hot plate. Put a thermometer in the bath and heat the water until the temperature reaches 90C. Maintain the temperature of the water bath between 80C and 90C. Do not let the temperature go above 90C. While the water bath is heating, measure 3.0 grams of salicylic acid into a 125 mL Erlenmeyer flask. Using a dry graduated cylinder, measure out 6 mL of acetic anhydride and add it to the flask. Add 5 drops of concentrated H2SO4 and swirl to mix. Clamp the flask onto a ring stand and lower it into the hot water bath. Leave the flask in the bath for 15 minutes, then remove it and without cooling, carefully add,

3 drop by drop, 20 drops of cold water from a medicine dropper to destroy the excess acetic anhydride (watch for splattering). Add 20 mL of distilled water to the flask; then put it in an ice bath to cool the reaction mixture for about 20 min. At the end of this time, a precipitate should have formed. If not, scratch the inner wall of the flask with a glass stirring rod to induce crystallization. Set up a suction filtration apparatus, using a Buchner funnel, filter paper circle, and suction flask (see below), and collect the crystals on the filter. Wash the precipitate three times with 10 mL portions of ice-cold distilled water by pouring the water through the filtration set-up. Allow the final washing to drain thoroughly then scrape the moist crystals into a 150 mL beaker. Add 10 mL of 95% ethyl alcohol to dissolve the crystals. When all of the crystals have dissolved, add 25 mL of distilled water to the beaker. Stir the beaker until precipitation begins, then cool the beaker in an ice bath until precipitation is complete, about 10 min. Using the suction filtration apparatus, collect the re-crystallized product on the filter paper and wash three times with 10 mL portions of ice-cold distilled water. Leave the suction on after the last washing has drained so that air is drawn past the crystals to dry them as much as possible. Transfer the dry crystals to a clean watch glass. Let the aspirin finish drying by storing in your lab drawer for at least one day (or until your next lab period). Weigh the watch glass and aspirin to determine the weight of the product. Determine the melting point of your dried aspirin crystals by using a melting point apparatus and compare the melting point with that given in chemical literature (135C).

Suction filtration apparatus

4 Name Date

Report for Experiment: Aspirin

Percentage yield of aspirin 1. 2. 3. Weight of salicylic acid used Weight of aspirin crystals collected Weight of aspirin theoretically obtainable from salicylic acid used. Show work!

4.

Percentage yield of aspirin. Show work!

Melting point 1. 2. Melting point range of your aspirin Chemical literature melting point

5 Questions: 1. Write the chemical equation showing how you could make aspirin from acetyl chloride.

2.

Could aspirin be made by the method used in this experiment from the compounds shown below? Explain.
COOH and OH CH3 O C O O C CH3

3.

Aspirin is insoluble in water. Why then, is it soluble in sodium hydroxide solution?

4.

What is an analgesic?

5.

What is an antipyretic?