Synthesis of aspirin

November 2, 2022 by J.A Dobado

Written by J.A Dobado | Last Updated on May 2, 2024

Objective

The purpose of this experiment is to familiarize the students with the reaction of esterification getting aspirin (acetyl
salicylic acid) from the salicylic acid and acetic anhydride.

Background

Acetylsalicylic acid is marketed under the name of aspirin for the home Bayer being one of the drugs most consumed
in the world. It was synthesized at the end of the last century by the German chemist Felix Hofmann.

It uses a reaction of esterification catalyzed acid (H2SO4 or H3PO4 ), where the salicylic acid treated with acetic
anhydride gives acetylsalicylic acid (aspirin). In this reaction, it becomes a hydroxyl group to an ester, obtained as a
by-product acetic acid.

It is a drug that is found in the list of essential medicines of the WHO. Acts as antipyretic, and mainly as an analgesic.
As antipyretic exerts its effect on two levels: it increases the heat dissipation by Vaso-dilation (action not significant),
and acts on the thermostat hypothalamic, which is the central regulator of the body’s temperature.

Their administration route is oral, as it is well absorbed from the gastrointestinal tract. The acetylsalicylic acid may be
partially hydrolysed; this, in addition to noticed easily by the smell of acetic acid, it can be recognized by a trial with
FeCl3 and seeing if it produces violet colour.

Reaction mechanism

The reaction is catalysed by acid (phosphoric acid, H3PO4). In a first step occurs the protonation of acetic anhydride as
shown in the figure.
This is going to promote the reactivity of acetic anhydride, which is positively charged at one of the
carbons. It is a reaction of esterification of phenol involves the breaking of a link O–H, and is carried out
with acetic anhydride.
In a second step, there is an addition: the electron pair of the phenol attacks the carbon positively charged
acetic anhydride.

In a third step happens a removal: producing acetic acid and acetyl salicylic acid protonated. The fourth and
last step it is a deprotonation by the effect of the water that is added at the end of the reaction.
Experimental procedure

Place 3 g (0.022 mol) of salicylic acid in a flask of 100 ml. Then, add 6 ml of acetic anhydride and then 6 to 8 drops
of phosphoric acid (H3PO4) of 85 %. Subsequently, stir gently to mix the layers and dipped the flask connected to a
reflux equipment in a bath of hot water (70-80 °C) for 15 min.

DANGER! “The acetic anhydride reacts violently with water and the mixture may splatter.”

Moves the flask from the bath and, while still hot, is added drop by drop to about 1 ml of water, stirring after each
addition. Once you have added the first ml of water, can already added quickly, another 20 ml of the same.

The flask is cooled in an ice bath, with what the product should begin to crystallize. Vacuum filter and calculate the
performance of the dry product (performance estimated 70 % and melting point 134-136 ° C).

Physio-chemical properties

This table collects data for the molecular weight (Mw), melting point (M.P.) boiling point (B.p.) and density of the
reactive and compounds used in this laboratory experiment.

Mw Density
Name M.P. (ºC) B.p. (ºC)
(g/mol) (g/ml)

Acetic acid 60.05 16.2 118 1.049

Acetylsalicylic acid 180.16 134-136 - -

H3PO4 98.00 40 158 1.685

Acetic anhydride 102.09 -73.1 139.8 1.080

Experiment 614: Synthesis of Aspirin

Section 1: Purpose and Summary

 Conduct a chemical reaction to produce aspirin.

 Separate the aspirin from the reaction by-products using vacuum filtration.

 Analyze the aspirin and estimate its purity.

Acetylsalicylic acid, commonly known as aspirin, is the most widely used drug in the world today. Its analgesic,
antipyretic, and anti-inflammatory properties make it a powerful and effective drug to relive symptoms of pain, fever,
and inflammation. Salicylic acid, whose name comes from Salix, the willow family of plants, was derived from willow
bark extracts. Hippocrates the ancient Greek physician, as well as Native Americans before Columbus’ time, prepared
willow bark teas as headache remedies and other tonics. In modern times, salicylic acid is administered in the form
of aspirin which is less irritating to the stomach than salicylic 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 quenched (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.

The aspirin should be analyzed for the presence of any contaminating salicylic acid. In the final part of today’s lab,
you will take a small amount of your aspirin and test it with iron(III) chloride (FeCl3). FeCl3 reacts with
phenols (alcohol groups attached to aromatic rings) to produce colored complexes. Notice that salicylic acid contains
the phenol functional group but aspirin does not. Therefore, the more salicylic acid that contaminates your
aspirin, the darker the color will be with FeCl3.
Section 2: Safety Precautions and Waste Disposal

Safety Precautions:

Use of eye protection is recommended for all experimental procedures.

Sulfuric acid (H2SO4) is highly corrosive. Avoid contact with your eyes, skin, and clothing. In case of contact, rinse with
plenty of water. Ask instructor to assist with the cleaning of any spills.

Acetic anhydride is a lachrymator (its vapor irritates the eyes causing tears to flow). Keep it in the fume hood.

Waste Disposal:

The reaction mixtures used in this experiment may be safely disposed of in the sink, followed by copious amount of
running water.

Solids, aspirin and salicylic acid, should be disposed of in the regular trash container.

Section 3: Procedure

Part 1: Synthesis of Aspirin

1. Prepare a boiling-water bath by filling a 600-mL beaker with about 400 mL of tap
water. Put the beaker on the hot plate.

2. Weigh out about 2.1 grams of salicylic acid on a piece of weighing paper. To do
this, first tare a piece of weighing paper (This means to put a piece of paper on
the balance and press the zero or tare button. Fig.1) Add some salicylic acid a 1. Mass of Salicylic
little at a time onto the weighing paper until you have about 2.1 gram of it on the Acid:
paper. It is OK to weigh a little extra mass (do not return excess salicylic acid to
its container as this might contaminate the entire amount if your spatula is not
perfectly clean). Record the mass of the solid. Place this solid into a 125- ______________ grams
mL Erlenmeyer flask (other sizes may be acceptable).

3. In the fume hood, measure out 4 mL of acetic anhydride in a

small graduated cylinder and add it to the flask. From this point on, keep your
flask under the hood, because it now contains acetic anhydride (the vapors of
acetic anhydride are very irritating).

4. Add about 5 drops of concentrated sulfuric acid. This will be the catalyst for the
 reaction.

5. Place the flask in the boiling water bath and clamp it in place. (Fig.2)

6. Heat the reaction for at least 15 minutes. 2. Volume of Acetic

Anhydride:
7. Put at least 60 mL of laboratory water into a 150mL beaker (or similar size).
Then put this beaker in an ice-water bath. Use this cold water in
steps 9, 12, 13, and 14 below.
______________ mL
8. After the reaction has heated for at least 15 minutes, remove it from the boiling
water bath.

9. In 1- or 2-mL portions, add about 10mL cold water to the reaction, swirl the
reaction between each 1-2mL portions. This water will react and destroy any
remaining acetic anhydride. (Fig3.)

10. Put the flask with the reaction into an ice water bath (Fig.4). Crystals of aspirin
should form. Chill for at least 10 minutes in order to obtain the maximum
amount of crystalline product.

3. Mass of filter
paper:
 ______________ grams

4. Mass of crystals
11. Collect the aspirin crystals by vacuum filtration. and filter paper:
To prepare a vacuum filtration set up:

a) You will need a Buchner funnel, a clean 250-mL vacuum filter flask, a filter adaptor ______________ grams
(often a one-hole stopper), a pre-cut filter paper and Beaker #2. WEIGH the dry filter
paper.

b) Place the filter paper on the Buchner funnel. The filter paper should fit snugly and
cover all the small holes in the funnel.

c) Using the filter adaptor, place the Buchner funnel on top of a vacuum filter flask. You
might need to use a clamp and a ring-stand to keep the setup intact and upright.

d) Connect a vacuum tubing hose to the vacuum filter flask and to the vacuum supply.
 e) Wet the filter
paper with a little laboratory water. Turn the vacuum on and confirm that there are no
leaks.(Fig.5)

12. Add about 25 mL cold water to the reaction and mix well.

13. Filter the crystals. Use a few milliliters of cold water to transfer as much solid as
possible.

14. Disconnect the vacuum temporarily and add 15 mL of cold water to the crystals
in order to rinse them. After the crystals have soaked in the cold water for a few
seconds, reconnect the vacuum to filter once more. Leave the vacuum on for
several minutes to air dry the crystals.

15. With the vacuum on, stir the crystals carefully to help dry them. Do this for about
15 minutes.

16. Turn off the vacuum and weigh just the filter paper with the crystals. If you use a
watch glass to carry the filter paper and crystals to the balance, be sure to tare
the weight of the watch glass (in other words, don’t include the weight of the
watch glass with your filter paper and crystals.)

17. Clean up: Be sure to keep the aspirin for Parts 2 & 3. Throw away the filter paper
in the trash. Dispose of the filtrate (the aqueous solution in the vacuum filtration
flask) down the drain with plenty of water. In the fume hood, rinse with water all
pipets and glassware in contact with acetic anhydride and pour the rinse water
down the drain in the fume hood.

Part 2: Analysis of Aspirin (How pure is it?)

 1. Obtain 3 test tubes and about 1 mL of ethanol (CH3CH2OH) to all 3 test tubes. Also
add 1-2 drops of 1% FeCl3 solution to each test tube. Be sure all 3 test tubes have
the same amounts of reagents.

2. Label the first test tube “Aspirin” and add to this test tube a few of your aspirin
Describe the Color:
crystals that you made today. Stir well.

3. Label the second test tube “Salicylic Acid” and add a few crystals of Salicylic Acid to
this second test tube. Stir well. This is your Positive Control. The positive control
Describe the Color:
shows you what to look for when a test is positive: in today’s analysis, the positive
control shows you a dark color because it contains unreacted salicylic acid.

4. The third test tube is your Negative Control. Do not add any crystals to this test
tube! The negative control shows you what to look for when a test is negative: in
Describe the Color:
today’s analysis, the negative control shows you a color when no contaminating
salicylic acid is present.

Compare the colors among the 3 test tubes and describe their similarities and differences.

Describe the similarities

and differences in color:

(You can use the empty

space to the left also).

Part 3: Analysis of Aspirin (How stable is it?)

1. Obtain a dry test tube and add about a pea-sized amount of your aspirin crystals
(borrow some relatively pure crystals from a classmate if your aspirin was highly
contaminated with salicylic acid).
 2. Tap the crystals to the bottom of the test tube. Use a test tube clamp to hold the test
tube.

3. Ignite a Bunsen burner.

4. Pointing the open end of the test tube away from you, GENTLY heat the bottom of the
test tube until the crystals melt. DON”T burn the aspirin.(Fig.5)

5. Remove the test tube from the flame and carefully WAFT any odors from the open end
of the test tube towards you. Do you smell anything? (To waft the odors means to Describe
“fan” the odors towards you, mixing in plenty of air to dilute the fumes.) If you don’t the Odor:
smell anything, try “pouring” the vapors out of the test tube by holding the test tube
horizontally.

6. Any odor detected may indicate that aspirin has decomposed with excessive heat.
Aspirin may also decompose slowly upon long-term storage in a humid environment.

7. After the test tube cools, wash the test tube in the sink with soap and water.

Section 4: Calculations

1. Mass of salicylic acid (g)

2. Calculate the number of moles of salicylic acid (mol)

(Molar mass = 138 g/mol)

3. Volume of acetic anhydride (mL)

4. Calculate the number of grams of acetic anhydride (g)

(Density = 1.08 g/mL)

5. Calculate the number of moles of acetic anhydride (mol)

(Molar mass = 102 g/mol)

6. Identify the Limiting Reagent (Name of compound)

 7. Theoretical Yield of Aspirin (g)

(Molar mass = 180 g/mol)

8. Mass of filter paper and aspirin (g)

9. Mass of filter paper (g)

10. Calculate the mass of aspirin (g)

11. Percent Yield of Aspirin (%)

Post Lab Questions:

1. Aspirin is slightly soluble in water: the solubility of aspirin in water is 0.33 grams per 100 mL water at room
temperature. In today’s experiment, you rinsed your aspirin with at least 50 mL of water. If the water was at
room temperature, how many grams of your aspirin would have dissolved by rinsing it today?

2. Suggest a reason why you were instructed to rinse the aspirin even though it is known that this will cause
some of the aspirin to dissolve and be lost.

3. Suppose that another student performed today’s experiment, but they forgot to air dry the aspirin during
vacuum filtration. If they weigh the aspirin when it is still damp, how will this affect the percent yield?

4. Suggest a scientific reason why we did not dry the aspirin in an oven today.
5. A desiccant, or drying agent, is often added to a container with medications to prolong the shelf life. Cotton
is sometimes used as a desiccant which is often found inside a package of aspirin. Moisture in the air
(humidity) can cause aspirin to slowly decompose through a reaction called hydrolysis. The cotton absorbs
moisture and delays hydrolysis. Suggest an easy and quick way to determine if your aspirin at home has
begun to hydrolyze.

6. Suppose two groups of students performed today’s experiment and obtained different results. One group
obtained aspirin in 88% yield which turned dark in the FeCl3 test. The other group obtained aspirin in 65%
yield which produced no color change in the FeCl3 test. Explain which group was more successful in lab.