Chemistry Experiment: Synthesis of Aspirin

Chem. 111, Fall 2003

Experiment 11

Objectives

1. Making aspirin from a common chemical called salicylic acid.

2. Obtain practice with handling chemicals and with techniques (recrystallization) for the
isolation of a pure chemical compound.
3. Making oil of wintergreen.

Background information

Organic chemistry can be defined as chemical reactions between molecules that contain
carbon in a large part of their structure. Often these organic molecules contain many covalent
bonds, which are the type of bonds found between two non-metal atoms. If you look on the
periodic table you will see that only a small portion of the elements are considered to be non-
metals, including C, N, O, S, Cl, and F. This small number of elements can be bonded together
in different amounts, bonding types (single, double triple bonds), and structural patterns to form
over 10 million known molecules! The billions of dollars generated by the pharmaceutical
industry is a prime example of how important organic chemistry is to our modern day society.
In this experiment you will perform an organic synthesis to make aspirin. Aspirin is the
trade name for the molecule acetylsalicylic acid (aren’t you glad we don’t have to use “that”
name when you have a headache). The earliest known use of this molecule has been traced back
to the fifth century B.C. The Greek physician Hippocrates described an extract of willow tree
bark, a bitter powder that could be used to reduce fevers. In 1829, Salicin was isolated from
willow bark and used as a pain reliever. Unfortunately Salicin was not very popular since it was
found to be very acidic and a stomach irritant. In 1897 a German chemist named Felix Hoffman
was working for the Bayer chemical company. Hoffman was looking for a less acidic pain
reliever that his father could take for his arthritis. His research led to the synthesis of
acetylsalicylic acid (ASA) or aspirin. Bayer patented the name and commenced to market the
product in 1899. It was a huge success and sales grew rapidly. In fact, the company set up by
Friedrich Bayer & Company is generally reckoned to have been the first
pharmaceutical company, and the production of aspirin is generally accepted to
have laid the foundation of the modern pharmaceutical industry.
Interestingly enough it wasn’t until the 1970’s that scientists began to
understand how aspirin actually worked as a pain reliever. Today 80 billion
aspirin tablets are consumed every year across the globe to reduce fevers,
relieve pain, and even help prevent heart attacks.

Bayer
 In commercial aspirin products, a small amount of ASA (300 to 400 mg) is bound
together with a starch binder and sometimes caffeine and buffers to make an aspirin tablet. The
basic conditions in the small intestine break down the ASA to yield salicylic acid, which is
absorbed into the bloodstream. The addition of a buffer reduces the irritation caused by the
carboxylic acid group of the aspirin molecule.
Aspirin can be produced in a one step chemical process by reacting salicylic acid with
acetyl chloride, according to the reaction:
O O
C OH Cl OH
+ H3C C + HCl

OH O O C CH3
O

Salicylic acid acetyl chloride acetylsalicylic acid hydrochloric acid

aspirin

Aspirin is a white solid that is almost completely insoluble in water. We will use this
physical property of our product to separate it from the final solution.
If time allows, we will synthesize methyl salicylate, which is another ester of salicylic
acid. It occurs in a wide range of plants and is known as ‘oil of wintergreen’. It is still used in
candies and in ointments for joint and muscle pains.

O O
+
C OH H O CH3
+ H3C OH
OH OH

Salicylic acid methanol Methyl salicylate (wintergreen)

Thin layer chromatography (TLC) is used to separate and identify aspirin. Small amounts of the
synthesized product, starting material (salicylic acid) and commercial aspirin are placed along
one edge of a chromatography plate. The plate is then placed in a container with solvent. With
the plate acting like a wick, the solvent flows up the chromatogram, carrying the samples with it.
Molecules that are more soluble in the solvent will move higher on the paper; the molecules that
are more attracted to the plate will remain closer to the original line. After removing the plate,
the samples can be detected wit UV light.

Safety Notes

1. The acetyl chloride and pyridine should only be dispensed in a hood.

2. Always wear appropriate eye protection and gloves while handling the chemicals.
Procedure

Part A- Preparation of Aspirin

(adapted from Journal of Chemical Education • Vol. 75 No. 6 June 1998 • "An Efficient
Microscale Procedure for the Synthesis of Aspirin", Sangeeta Pandita and Samta Goyal)

1. Place 150 mg (0.001 mol) of salicylic acid in a 10 mL test tube and add 0.1 mL of
pyridine (just sufficient to dissolve it) while the tube rests in a ice-cold water bath. Keep
the test tube in a hood while you are doing this! Pyridine smells very bad, and you may
want to wear latex gloves to avoid getting it on your skin.

2. For the next step, be sure that the open end of the tube is not pointing toward you or
anybody else. Occasionally the reaction goes quickly and shoots material out of the tube!
Add one-tenth milliliter of acetyl chloride (slight excess over 0.001 mol )in one portion to
the test tube. Again, keep the mixture in a hood!

3. The mixture becomes viscous at this stage. Let the mixture sit in a beaker of cold water
bath for 15 min. – it does not need to be in the hood. While waiting, set up a vacuum
filter flask with a Büchner funnel and a piece of filter paper which just fits the bottom of
the funnel, as shown in the figure below. Attach a thick rubber tube to an aspirator
mounted on a water faucet

4. Now add 5 mL of cold water to the test tube and cap it with a rubber stopper. Shake the
mixture. Do this cautiously at first until you are sure that no violent reaction is occurring.
The mixture should turn cloudy. Shaking is continued until a white product appears (it
may takes several minutes, be patient!)
 5. Turn on the water faucet all the way and check to be sure you have good suction. Break
the suction by disconnecting the tube from the flask (leave the water running). Pour the
mixture into the funnel, trying to get as much of the solid transferred as possible.
Connect the hose and apply full suction for at least 30 seconds. Wash the crystals with
cold water. Break the suction. Do not just turn off the water; this may create a back-flow
of the water into your filter flask. Dry them on the filter paper for about 5 min.

Part B- Recrystallization

6. Carefully scrape off most of your crystals into a 50 mL beaker. SAVE THE FILTER
PAPER! Add about 3 mL of cold water and place the mixture on a hot plate in a hood.
Heat until all of the crystals dissolve (check with the instructor if complete solution does
not seem to be happening.) When the crystals are completely dissolved in the hot
solution, remove the beaker and allow it to cool. You should see nice crystals of aspirin
beginning to form! When the recrystallization is complete, filter again, and dry. SAVE
THE FILTER PAPER for the next step!

Part C- Oil of Wintergreen

1. Place 1.00 gram of salicylic acid in a test tube. (record the actual mass used)
2. Add 5 ml of methyl alcohol and 3 drops of concentrated sulfuric acid.
3. Heat this mixture in a boiling water bath for 15 min.
4. Note the odor of the liquid in your tube, remember to WAFT.

Results

Calculate the theoretical yield of aspirin in grams. Use this to calculate the % yield for this
experiment.

% yield = actual yield (grams) x 100

theoretical yield (grams)
Questions
1. Why is aspirin said to be gentler on the stomach than previous pain relievers?
2. Draw the complete Lewis structure of aspirin (include all lone pairs of electrons).
3. Methyl salicylate (Oil of wintergreen) is an irritant that acts as a counterirritant to aches
and pains. The irritant action of the wintergreen stimulates blood flow. What do you
experience when eating a wintergreen life saver? How does your experience explain the
effects oil of wintergreen has on your sore muscles?
4. The LD50 of aspirin is 1.5 g/kg. Calculated the lethal dosage to a 22 lb (10 kg) child.
5. Extra strength aspirin tablets contain 500 mg of aspirin, how many tablets correspond
with your answer from question 4?
6. In your own words, explain what is happening in the first reaction we carried out, for the
synthesis of aspirin.
7. In your own words, explain what is happing in the reaction for the synthesis of oil of
winter green.
8. What mass of salicylic acid is needed to produce one extra strength tablet (500 mg of
aspirin) if the reaction has a 60% yield?