SYNTHESIS OF ASPIRIN

Silverio, A.
1
, Soriano, R.
1
, Tan, J.
1
, Tequillo, H.
1
, Tolentino, M.
1

University of Santo Tomas, Faculty of Pharmacy
1


ABSTRACT
The experiment is performed to explore the chemical process in the synthesis of a common organic product called
acetylsalicylic acid (aspirin) and to become familiar with the optimum conditions needed for successful yields.
Aspirin, produced from the acid catalyzed esterification of salicylic acid and acetic anhydride, is synthesized and
purified by recrystallization. Ferric chloride test was performed to detect the presence of enol in the salicylic acid,
commercially available aspirin, prepared aspirin, benzoic acid, benzyl alcohol, and a control group, which is water.
The color of the resulting mixture, whether purple or yellow, determines the presence of enol. Salicylic acid and
prepared aspirin produced a purple coloration and therefore tested positive (contains enol) while commercially
available aspirin, benzoic acid, benzyl alcohol and water produced a yellow coloration and tested negative (contains
no enol). Starch test was likewise performed to detect the presence of starch in prepared aspirin, commercially
available aspirin, and a control group, which is water. A blue or blue-black color indicates the presence of starch.
The commercially available aspirin produced a yellow coloration, therefore testing positive while prepared aspirin
and water tested clear. Melting point determination was performed as the last confirmatory test with test values of
136-138
o
C and 137-139
o
C.
INTRODUCTION
Aspirin, also known as acetylsalicylic acid,
is a derivative of salicylic acid. It is the most widely
used medicine in the world. It has the ability to
reduce fever (antipyretic), reduce pain (analgesic),
relieve swelling and pain associated with rheumatism
and arthritis (anti-inflammatory), enhance the
elimination of uric acid (uricosuric), and interfere
with the bodys production of prostaglandins and
their products (thromboxanes), which are associated
with headaches, platelet aggregation and
vasoconstriction.
[1]

Aspirin is a part of a group of medications
called nonsteroidal anti-inflammatory drugs
(NSAIDs), but differs from most other NSAIDs in
the mechanism of action. Aspirins ability to suppress
the production of prostaglandins and thromboxanes is
due to its irreversible inactivation of the
cyclooxygenase (COX) enzyme. Aspirin acts as an
acetylating agent where an acetyl group is covalently
attached to a serine residue in the active site of the
COX enzyme. This makes aspirin different from
other NSAIDs (such as diclofenac and ibuprofen),
which are reversible inhibitors.


The main side effects of aspirin are
gastrointestinal ulcers, stomach bleeding, and ringing
in the ears, especially with higher doses. In children
and adolescents, aspirin is not recommended for flu-
like symptoms or viral illnesses, because of the risk
of Reyes syndrome.
The synthesis of aspirin is classified as an
esterification reaction. Salicylic acid is treated with
acetic anhydride, an acid derivative, causing a
chemical reaction that turns salicylic acids hydroxyl
group into an ester group. This process yields aspirin
and acetic acid, which is considered a byproduct of
this reaction. Small amounts of sulfuric acid are used
as acid catalysts.
[2]


Figure 1. Esterification of salicylic acid and acetic
anhydride to produce acetylsalicylic acid and acetic
acid.
EXPERIMENTAL
A. Compounds Tested
Salicylic Acid is a monohydroxybenzoic acid, a type
of phenolic acid and a beta hydroxyl acid. This
colorless crystalline organic acid is widely used in
organic synthesis and functions as a plant hormone. It
is derived from the metabolism of salicin. It is
probably best known as a key ingredient in topical
anti-acne products.
[3]

Acetic anhydride has a chemical formula
(CH
3
CO)
2
O. It is commonly abbreviated Ac
2
O.
Acetic anhydride is the simplest isolatable acid
anhydride and is a widely used reagent in organic
synthesis. It is a colorless liquid that smells strongly
of acetic acid.
[4]


Benzoic acid has the chemical formula C
7
H
6
O
2
(or
C
6
H
5
COOH), is a colorless crystalline solid and a
simple aromatic carboxylic acid. It occurs naturally
in many plants and it serves as an intermediate in the
biosynthesis of many secondary metabolites. Salts of
benzoic acid are used as food preservatives and
benzoic acid is an important precursor for the
industrial synthesis of many other organic substances.

[5]



Figure 3. Structure of Benzoic Acid.

Benzyl alcohol is an aromatic alcohol with the
formula C5H6CH2OH. It is a colorless liquid with a
mild pleasant aromatic odor. It is a useful solvent due
to its polarity, low toxicity, and low vapor pressure.

[6]

Figure 4. Structure of Benzyl Alcohol.
B. Procedure
1. Reaction of Salicylic Acid and Acetic
Anhydride
Weigh 2 grams of salicylic acid and transfer to a hard
glass test tube. Add exactly 5 mL of acetic anhydride.
Carefully add 5 drops of concentrated sulfuric acid
and stir until salicylic acid is completely dissolved.
Place on a water bath with a temperature of 70-80
o
C
for 20-30 minutes with occasional stirring. Add
dropwise of room temperature water until the
solution becomes cloudy. Remove the solution from
water bath. Scratch the inner wall of the test tube and
rinse with ice cold water. Place the rinsings on a
beaker. Add 20 mL of ice cold water to the beaker
and stir. Place the beaker on an ice bath for 10
minutes to allow aspirin to crystallize. Filter the
solution in a pre-weighed filter paper and allow to
dry. Weigh the aspirin.

2. Ferric Chloride Test for Salicylic Acid
Place 1 mL of water in 6 test tubes and add the
following: a) salicylic acid, b) commercially
available aspirin, c) prepared aspirin, d) benzoic acid,
e) benzyl alcohol, and f) control group, which is
water. Shake and add 1 drop of 2% aqueous ferric
chloride. Observe the color.

3. Starch Test
Place 2mL of water in 3 test tubes and add the
following: a) prepared aspirin, b) commercially
available aspirin, and c) control group, which is
water. Add 1 drop of iodine. Observe the color.

4. Melting Point Determination
Push the open end of a capillary tube into the
prepared aspirin. Move the powder to the closed end
of the capillary tube by tapping it on the table until
the aspirin occupies 1-2 mm of the capillary tube end.
Seal the opposite end of the filled capillary tube.
Attach the capillary tube to a thermometer using
rubber bands by aligning the bulb of the thermometer
to the closed end of the capillary tube. Make an oil
bath by half filling a 100 mL beaker with warm
cooking oil. Heat the oil bath. Place the thermometer/
capillary tube assembly in an oil bath. The surface
level of the aspirin must be beneath the surface level
of the oil bath. Place the beaker on a hot plate and
frequently stir the oil to distribute heat uniformly.
Not the temperature at which the aspirin melts.
Repeat the procedure twice and average the results.
Compare the experimental result with the accepted
value.

Figure 5. An illustration of the setup used in Melting
Point Determination.

RESULTS AND DISCUSSION

Synthesized aspirin is a white crystalline solid. It is
obtained by mixing premeasured amounts of salicylic
acid, acetic anhydride and sulfuric acid. The
crystalline acid was obtained by recrystallization
process.

Ferric chloride test was performed to test for the
presence of enol. Upon adding ferric chloride to each
designated test tube, either a purple or yellow
coloration is observed. A purple color indicates the
presence of enol while a yellow color indicates the
absence of enol.

Test Tube Observation Inference
Salicylic Acid Clear purple
solution
With enol
Commercially
available
aspirin
Turbid purple
solution
With enol
Prepared
aspirin
Clear purple
solution
With enol
Benzoic acid Clear colorless
solution
Without enol
Benzyl alcohol Yellow
globules
Without enol
Control Clear colorless
solution
Without enol

Table 1. Results of Ferric Chloride Test.

In the results obtained, only salicylic acid,
commercially available aspirin and prepared aspirin
contained enol. The others did not.


Figure 6. Results of Ferric Chloride Test (L-R, T-B).
Salicylic acid, commercially available aspirin 1,
commercially available aspirin 2, prepared aspirin,
benzoic acid, benzyl alcohol and control.

Starch test was performed to test for the presence of
starch. A blue or blue-black color is the expected
result, indicating the presence of starch.

Test Tube Observation Inference
Prepared
aspirin
Clear colorless
solution
No starch
Commercially
available
aspirin
Turbid yellow
solution with
brown
precipitate
With starch
control Clear colorless
solution
No starch
Table 2. Results of Starch Test

In the results obtained, only commercially available
aspirin contained starch. The others did not.



Figure 7. Results of Starch Test (L-R). Prepared
aspirin, commercially available aspirin 1,
commercially available aspirin 2, control.

Melting point determination determines the purity of
the synthesized compound by comparing the
experimental melting point to the theoretical melting
point.

Trial Temperature
1 136-138
o
C
2 137-139
o
C
Table 3. Results of Melting Point Determination

The synthesized compound has a melting point close
if not exactly the theoretical one, which is 136
o
C.

Percentage Yield
Weight of Salicylic Acid 2.0300 g
Weight of Evaporating Dish 24.7255 g
Weight of Evaporating Dish +
aspirin
26.1339 g
Weight of aspirin 1.4084 g
Table 4. Raw data collected during the experiment

Salicylic Acid
(


) (


) (


)

Acetic Anhydride
(


) (


) (


) (


)


Salicylic Acid is the limiting reagent while acetic
anhydride is the excess reagent.











The percentage yield is 69.38%.

CONCLUSION
Aspirin is a white crystalline solid formed from the
esterification of salicylic acid and acetic anhydride in
the presence of an acid catalyst. It contains an enol
group and may contain starch when produced
commercially. It has a melting point of 136
o
C. It is
most commonly used as an NSAID.

REFERENCES
[1]
Bayquen, A., et. al. (2009). Synthesis of
Acetylsalicylic Acid (Aspirin). In Laboratory
Manual in Organic Chemistry (p. 141). Quezon City,
Philippines: C & E Publishing.
[2]
http://en.wikipedia.org/wiki/Aspirin
[3]
http://en.wikipedia.org/wiki/Salicylic_acid
[4]
http://en.wikipedia.org/wiki/Acetic_anhydride
[5]
http://en.wikipedia.org/wiki/Benzoic_acid
[6]
http://en.wikipedia.org/wiki/Benzyl_alcohol