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.

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.

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 drug 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.

Salicylic acid reacts with acetic anhydride according to the following reaction:

MW = 138.12       MW = 102.09                  MW = l80.16           MW = 60.05

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 phosphoric acid.

Acetylsalicylic acid is the "generic" name for the compound that is commonly called "aspirin".  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.

Procedure:

Synthesis of Aspirin:

1. Obtain a 125 mL Erlenmeyer flask and clean it thoroughly with soap and water.  Rinse it with dionized water and use a paper towel to remove as much of the excess water as possible.  Use your Bunsen burner to flame dry the Erlenmeyer flask.  BE CAREFUL NOT TO BURN YOURSELF.   Be sure to let the flask cool to room temperature and record its mass to the nearest 0.001 g.
2. Add approximately 200 mL of water to a 600 mL beaker and heat it ~85^oC.  While it is heating, you can proceed with the experiment.
   
3. Weigh out approximately 1.5 g of salicylic acid (to the nearest 0.001 g) directly into a 125 mL Erlenmeyer flask.  It is important that no solid remains on the sides of the flask, since any solid that is not in solution does not react and will decrease your yield.
4. Measure out 3 mL of acetic anhydride (~0.027 mole) in a 5 mL graduated cylinder. DANGER:  ACETIC ANHYDRIDE IS EXTREMELY CAUSTIC.  WEAR GLOVES WHEN POURING IT AND BE VERY SURE THAT IT DOES NOT GET ON YOUR HANDS.  IF ACETIC ANHYDRIDE SHOULD COME IN CONTACT WITH THE  SKIN, WASH IMMEDIATELY WITH PLENTY OF WATER FOR AT LEAST 5 (FIVE) MINUTES.  DO NOT BREATHE THE VAPOR.
5. Add the acetic anhydride to the salicylic acid in the Erlenmeyer flask in such a way that any salicylic acid clinging to the inside of the flask is rinsed down into the bottom.  Swirl the flask gently.
6. After all the acetic anhydride has been added, add 10 drops of 85% phosphoric acid (H₃PO₄ - serves as a catalyst) and gently swirl the mixture.
7. Place the flask in the hot water bath for approximately 5 minutes, swirling occasionally.  All of the solid salicylic acid should have reacted by this time, leaving a clear colorless solution of the final product and any excess acetic anhydride.
8. While the reaction mixture is still hot, add 3 mL of distilled water.  CAUTION:  THE DECOMPOSITION OF THE EXCESS ACETIC ANHYDRIDE IS EXOTHERMIC.  HOT VAPOR COULD BE EVOLVED AND SPATTERING MAY OCCUR.  STAND BACK.
9. When the decomposition is complete, add an additional 25 mL of distilled water.  Use some of it to rinse down the inside of the flask.  Swirl the flask to achieve thorough mixing. 
   
10. Place the flask in an ice water bath and stir until crystallization begins.  Allow the flask to stand in the ice bath until crystallization is complete (about 15 minutes).
11. Construct a second ice bath to cool the distilled water you will need to wash the crude aspirin.  Place a 100 mL beaker with approximately 50-60 mL of distilled water into the bath.  It is important that this distilled water is cold since aspirin is soluble in warmer water.
    
12. Filter the crude product using suction and wash three times with 15 mL portions of cold water (this will remove any impurities).  After washing, pull air through the product to remove excess moisture.  The longer you allow the product to air dry with the suction on, the better your yield will be.
13. Put a distinguishing mark on a clean watch glass and weigh it.
14. Transfer your damp product to your weighed watch glass and place in the oven (at less than 90°C) for 10-15 minutes.  Remove your watch glass from the oven and let it cool to room temperature.  Weigh the watch glass and product. 
    
15. Carefully break up any clumps to facilitate drying and put the watch glass back in the oven for another 10 minutes.  Remove it, let it cool, and weigh again.  If the two weights agree to 0.01g or less, then your product is dry.  If the two weights to not agree to 0.01g, then you will need to continue the heating, cooling, and weighing cycle until two consecutive weights are within 0.01g.
16. Thoroughly clean your largest test tube with soap and water.  Rinse it with dionized water and use a paper towel to remove as much of the excess water as possible.  Use your Bunsen burner to flame dry the test tube.  BE CAREFUL NOT TO BURN YOURSELF.   Be sure to let the test tube cool to room temperature before you weigh it.
17. Once your product is dry, quantitatively transfer it to your freshly cleaned test tube and use a cork to close the test tube.
    
18. Create a label with the following information:: Your Name, Date, Product Name, Actual Weight of Product, Theoretical Yield, and % Yield.
19. Affix the label to the corked test tube and turn it in to your instructor.  You will be testing the purity of this product in next week's lab.
    

The calculation of theoretical yield is a stoichiometry problem of the "limiting reagent" type.  It is possible to calculate a theoretical yield if the number of moles of one of the reactants is known and if the number of moles of the other reactant is in sufficient excess to insure that the first reactant (the limiting reagent) is completely used up.  Many reversible reactions which would ordinarily give a complex mixture of reactants and products may be forced to completion by using one of the reactants in excess.  This displacement of a reversible reaction in one direction by manipulating reaction conditions is a practical example of LeChatelier's Principle (more on this next Semester!). The reason for using an excess of acetic anhydride (which is decomposed to acetic acid in a vigorous reaction with water) is that the salicylic acid is a solid which would be mixed in with the filtered product if it were not all used up.  Assuming that all the salicylic acid was converted to aspirin, calculate the actual yield of crude aspirin, the theoretical yield, and the percent yield:

(Updated 8/8/09 by C.R. Snelling)