Synthesis of Acetylsalicylic Acid (Aspirin)

Mary Coleen A. David, Eunice Mae D. del Valle, Sean Romeo B. Desagon, Maria Cauline M. Fang, Jenicca Pamela
Y. Go, Jan Chrtien M. Guillo
Group 3, 2F-Pharmacy, Organic Chemistry Laboratory, Faculty of Pharmacy, University of Santo Tomas

ABSTRACT
Acetlysalicylic acid, also known as Aspirin, is one of the most widely used medications
to reduce fever and is also used as a pain killer. It is an acetyl derivative of salicylic acid. The
objectives of this experiment are to calculate the percentage yield of aspirin and explore the
chemical process in the synthesis of aspirin. Aspirin is synthesized via an esterification reaction
between Salicylic Acid and Acetic Anhydride in the presence of concentrated sulfuric acid acting
as a catalyst. Test for impurities such as the Ferric Chloride test, Starch test, and preparation of
methyl salicylate were performed. It was concluded that impurities were present in the crude
sample of Acetylsalicylic Acid.

INTRODUCTION
Aspirin, a common name for
compound acetylsalicylic acid, is a
prototypical analgesic used in the treatment
of mild to moderate pain. It is an acetyl
derivative of salicylic acid. It is a white,
crystalline, weakly acidic substance which
melts at 136C (277F) and has a boiling
point of 140C (284F). The name, salicylic
acid, came from the word Salix which is the
willow family of plants. It was derived from
willow bark extracts. In folk medicine,
willow bark teas were used as headache
remedies and other tonics. To reduce
irritation to the stomach, salicylic acid is
now administered in the form of aspirin
rather than salicylic acid.
Aspirin acts as an inhibitor of
cyclooxygenase (COX) which result in the
inhibition of biosynthesis of prostaglandins.
It acts as a chelating agent where an acetyl

group is covalently attached to a serine

residue in the active site of the COX
enzyme.
Salicylic acid is reacted with an
excess of acetic anhydride to prepare the
aspirin. A small amount of a strong acid is
used as a catalyst which speeds up the
reaction. The synthesis reaction of aspirin is
shown below. A vinegar-like smell can be
observed in formulations containing high
concentrations of aspirin. This is due to the
decomposition through hydrolysis in moist
conditions which can yield salicylic and
acetic acid.

Crystallization is chemical solid

liquid separation technique. It is a process of
crystal formation in a solution. It is based on
the principle of solubility. Solutes can be
more soluble in hot liquid solvents
compared to cold liquid solvents. Pure solid
crystals after crystallization process can be
separated from the dissolved impurities by
filtration.
The ferric chloride test is used to
determine the presence of salicylic acid in
commercial aspirin. A purple color can be
observed when ferric chloride reacts with
phenols.
The starch test is used to determine
the presence of starch. A purple-black color
can be observed when there is an iodine
solution reacts with starch. For Aspirin,
starch test is used to identify whether the
drug contains pure aspirin or has used starch
as an additive.

MATERIALS AND METHOD

MATERIALS
The materials used in this
experiment are: analytical balance, hard
glass test tubes (2010cm), glass rod, beaker (1L, 250mL,
150mL), iron ring/tripod, plastic bottle,
Bunsen burner/hot plate, clamp, Pasteur
pipette, microspatula, and watch glass.
Salicylic acid, acetic anhydride,
concentrated sulfuric acid were the reagents
utilized. Commercial aspirin, benzoic acid,
benzyl alcohol, 2% ferric chloride, iodine

solution, and methyl alcohol are also the

reagents used for this experiment.
METHOD
After preparing the materials needed
for the experiment, to synthesize aspirin, a
250-ml beaker filled with three-fourths of
tap water was subjected to boil. The beaker
is supported by the iron ring and iron stand.
A 250-ml plastic wash bottle filled with
distilled water was packed ice which was
placed in a larger
beaker.
While
boiling, exactly
2.00 g
salicylic acid was
tared
in a watch glass
through the use
of
analytical
balance and it
was
transferred in a
clean,
dry 20-cm test tube. 5.00 ml of acetic
anhydride was dispensed to the test tube and
5 drops of concentrated sulfuric acid
( H 2 SO4 ) was added. Using a stirring rod,
the mixture was stirred until the salicylic
acid dissolved completely.

The burner was turned off when the

water in the beaker began to boil vigorously.
The test tube was placed in a hot water bath
to allow the mixture to react within a
temperature range of 70C to 80C in 20-30
minutes. The content of the test tube was
stirred well for 1 minute.
The test tube was then removed from
the water bath and its contents were slowly
and cautiously poured in a 150-ml beaker
filled with 5 ml distilled water. Once the
mixture has subsided, the mixture was
stirred for a minute while room temperature
water was added slowly, a few drops at a
time, a maximum of 40 drops was reached
or a cloudy solution was formed. After
which, the solution was removed from the
setup. Then the inner walls of the beaker
was scratched gently using the stirring rod to
induce crystal formation. Once the crystals
of aspirin has appeared, the test tube was
rinsed with a small volume of ice-cold
water. A 20-ml of ice cold water was added
into the 150-ml beaker then the beaker was
packed in ice for at least 10 minutes to
accumulate the crystals. The aspirin crystals
were filtered using a pre-weighed filter
paper and was dried overnight. Then, dried
aspirin crystals were weighed.
Confirmatory tests were performed
next. The crystals were first subjected to
ferric chloride test for salicylic acid. 6 test
tubes were prepared, each containing 1mL
of water. Small amount of salicylic acid,
powdered commercial aspirin, synthesized
aspirin, benzoic acid, and 1mL of benzoyl
alcohol were each placed in their
corresponding test tubes using the
microspatula. The sixth test tube filled with

1 ml water was the controlled variable. All

six tubes were shaked and dissolved in 1 ml
of water. Then, using a Pasteur pipette, a
drop of 2% aqueous solution of ferric
chloride was added. The resulting color was
observed and noted.
The second confirmatory test was the
starch test. Three 10cm test tubes, each
containing 2mL of water were prepared.
Small amount of prepared aspirin and
commercially available aspirin were each
added to their corresponding test tubes. The
third test tube filled with water was the
controlled variable. A drop of iodine
solution was added in each test tube. The
resulting color was observed and noted.

Methyl salicylate was prepared in a

similar manner as aspirin but at a lower
temperature. Exactly 1.00 g of salicylic acid
was placed in a 20-cm test tube. 5 ml of
methyl alcohol and 3 drops of concentrated
sulfuric acid ( H 2 SO 4 ) was then added to
the test tube. The contents of the mixture
were stirred until a dissolution of salicylic
acid in alcohol was formed. The test tube
was then placed in a 70C water bath for 15
minutes. The mint aroma produced inferred
the presence of methyl salicylate.

RESULTS AND DISCUSSION

A.

Reaction of Acetic Anhydride and

Salicylic Acid

Weight of watch glass + salicylic acid

Weight of empty watch glass
Weight of salicylic acid
Volume of acetic anhydride
Volume of concentrated sulfuric acid
Weight of filter paper + product
Weight of dry filter paper
Weight of product

49.7 g
47.7 g
2.00 g
5.00 mL
5 drops
6.00 g
3.00 g
3.00 g

Synthesis of Acetylsalicylic Acid:

To calculate for the actual yield of

synthesized aspirin, the theoretical yield of
acetylsalicylic acid will be based on the
limiting reagent. The limiting reagent in the
reaction is salicylic acid. The purpose is to
identify if the actual experiment has

obtained a complete reaction of salicylic

acid and acetic anhydride. From the
calculation, 115% was synthesized aspirin
which presents that the demonstrated
experiment has slight impurities obtained.
These impurities refer to the presence of
salicylic acid.

Calculations:
Chemical Equation:
C7 H 6 O3+C 4 H 6 O3 C 9 H 9 O4 +CH 3 COOH
Limiting reagent:
Salicylic Acid:
2.00 g C 7 H 6 O3

180.16 g C 9 H 9 O4
1 mol

=2.61 g C9 H 9 O4
138.12 g C7 H 6 O3
1 mol

Acetic Anhydride:
5.00 ml C 4 H 6 O3

180.16 g C 9 H 9 O4
1.082 g
1 mol

=9.55 g C 9 H 9 O4
1ml
102.09 g C4 H 6 O3
1 mol

Theoretical yield:
2.00 g C 7 H 6 O 3

180.16 g C 9 H 9 O4
1 mol

=2.6082 g C9 H 9 O 4
138.12 g C7 H 6 O3
1 mol

Percentage yield:
3.00 g synthesized aspirin
100=115
2.6082 g C 9 H 9 O4

B. Ferric Chloride Test

Ferric chloride is used for determination of purity of a substance. It is used to determine
the presence or absence of phenols in a given sample. Illustration of the reaction of ferric
chloride is shown below.

Test Tube
Salicylic acid
Commercial aspirin
Synthesized aspirin
Benzoic acid
Benzyl alcohol
Control

Observations
Purple solution
Pink solution
Purple solution
Clear solution with white
crystalline ppt
Bubbly solution
Colorless

The reaction of salicylic acid with

aqueous ferric

( Fe ( H 2 O )6+3 )

ion

produced an intense purple color. The

oxygen atoms of the carboxylic acid group
(COOH ) and hydroxyl group (OH )
on salicylic acid can form a complex group
with ferric

( Fe ( H 2 O )6+3 )

Inference
(+) Salicylic acid present
() No presence of salicylic acid
(+) Salicylic acid present
() No presence of salicylic acid
() No presence of salicylic acid
() No presence of salicylic acid
positive result. This means that commercial
aspirin reacted to iodine and that it contains
starch. No reaction occurred in the
synthesized aspirin and the controlled
variable. The result inferred that there is no
starch present in both synthesized aspirin
and water.
D. Preparation of Methyl Salicylate

ion. The purple

color indicates the presence of salicylic acid.

In aspirin, the hydroxyl group (OH ) was
replaced by ester (OCOC H 3)

during

esterification and nucleophilic substitution

which prevents the complex or second bond
formation. This will emanate a yellow
solution.

Methyl alcohol was used to dissolve

salicylic acid. It was subjected to water bath
for it to produce an odor. The presence of
methyl salicylic acid was confirmed in the
mixture when it produced a mint-like odor.
Methyl salicylate and acetylsalicylic acid are
derivatives of salicylic acid. Illustration for
the reaction of methyl salicylate is shown
below.

C. Starch Test
The iodine test or starch test is used
to test for the presence of starch.
Test Tube
Commercial aspirin
Synthesized aspirin
Control

Observation
(+) Purple colored solution
() No reaction
() No reaction

Commercial aspirin formed a blueblack colored solution which indicates a

References:

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http://mason.gmu.edu/~jschorni/che
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Prentice Hall. Pg. 40-48, 257-264,
530
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Engel, R. (1999). Introduction to
Organic Laboratory Techniques A
Microscal Approach (3rd ed.).

Saunders College Publishing. Pg. 6070, 100-109

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