SYNTHESIS OF ASPIRIN THROUGH ESTERIFICATION OF SALICYLIC ACID

Berba, E. S, Calderon, K. D., Cayabyab, K. M., Cosare, S. M., Delos Santos, A. I.

Univeristy Of Santo Tomas
Faculty Of Pharmacy

Abstract
Aspirin (also known as acetylsalicylic acid) is in a group of drugs called salicylates. It is
an effective analgesic that can reduce the mild pain of headache, toothache, muscle pain, and join
pain. Aspirin behaves as an antipyretic drug and it is an anti-inflammatory agent capable of
reducing swelling and redness associated with inflammation. It is also an effective agent in
preventing strokes and heart attacks due to its ability to act as an anticoagulant by preventing
platelet aggregation.
[1]
In this experiment, the group is assigned to produce aspirin from the 2
grams of the compound salicylic acid and acetic anhydride through the process of esterification.
After producing aspirin, they are expected to put the aspirin into a series of tests (Ferric Chloride
test, Starch test and Melting point determination test) to see the possible impurities present in
their product. The group was able to produce 1.3273g of synthesized aspirin. The percentage
yield of aspirin is 50.87%. As for the series of tests that was introduced on the synthesized
aspirin, the group found out that it has salicylic acid but has no starch present. The synthesized
aspirin has a higher melting point compared to the pure aspirin. These results showed that the
prepared aspirin is impure. This impurity maybe due to the incomplete esterification of the
salicylic acid, decomposition of the produced aspirin to salicylic acid and the uncrystallized
aspirin during the experiment.

Background of Study

Aspirin is a non-steroidal anti-
inflammatory drug (NSAID). NSAIDs are
medications with analgesic, antipyretic, and
in higher doses anti-inflammatory effects.
Aspirin has also become increasingly
popular as an antiplatelet - used to prevent
blood clot formation - in long-term low
doses to prevent heart attacks and strokes in
high risk patients. Nowadays, aspirin is
often given to patients immediately after a
heart attack to prevent recurrence or cardiac
tissue death.
[2]

Aspirin is a derivative of salicylic
acid, making it a member of the salicylate
family of compounds. Salicylates are natural
compounds found in plants such as the
willow tree, and are among the oldest known
and widely used therapeutics commonly
used to relieve pain, fever, and
inflammation.
Aspirin is chemically designated as
acetylsalicylic acid and has a chemical
structure that is comprised of three chemical
groupsan aromatic ring, an ester group,
and a carboxylic acid group. Aspirin is
prepared by chemical synthesis from
salicylic acid by acetylation with acetic
anhydride. In 1897, Felix Hoffman of Bayer
patented a commercial process to achieve
the synthesis of aspirin from salicylic acid.
Aspirin became a generic drug in the 1930s
when the Bayer patent expired.
[3]


Figure 1: Acetylation of Salicylic Acid
with Acetic Anhydride
The objective of this experiment is to
1) synthesize aspirin using salicylic acid and
acetic anhydride, and 2) to test the purity of
the synthesized aspirin using multiple tests.
After the researchers synthesized
aspirin, they put the synthesized aspirin into
a series of test, namely, the FeCl
3
test for the
presence of salicylic acid, Starch test, and
melting point determination test. In the
Ferric chloride test, the researchers mixed
FeCl
3
, a compound with a yellow color, to
the synthesized aspirin. This test is used to
detect the presence of salicylic acid, where
the carboxylic acid reacts with aqueous
ferric (Fe(H
2
O)
6
+3
) ion. The COOH group
and the OH group of the salicylic acid
together can form a complex with (Fe(H
2
O)
6
+3
), which exhibits an intense violet color. In
aspirin, however, the OH group of salicylic
acid was replaced with an -O-COCH3
group, which prevents the second bond
being formed with the aqueous ferric
(Fe(H
2
O)
6
+3
) ion. This produces a slight
yellow color.
[4]
With these results, this test
can be useful to detect whether the
researchers successfully synthesized aspirin
or if the salicylic acid did not react
successfully.

The second test is the Starch test.
This test is used to detect the presence of
starch in a compound with the use of iodine.
When starch reacts with iodine in water, it
forms an iodo-starch complex that exhibits
an intense blue color. The complex
structures energy level spacing, which is
just right for absorbing visible light, is what
gives the complex its color.
[5]

The third test is the melting point
determination test. The melting point is the
temperature where a solid material starts to
change it state into a liquid form. Pure
crystalline solids have clear, sharply defined
melting point, thus they melt precisely at a
certain temperature. Most pure organic
compounds melt neatly within a range of
1.5C or melt with decomposition over a
narrow range of temperature ( 2C) at
heating rates below 0.5C/min.
[6]


Methods
Materials
The materials used in the experiment
are hard glass test tube, 10-ml graduated
cylinder, dropping pipette, beaker,
thermometer, stirring rod, filter paper,
evaporating dish and funnel.
Procedure
The researchers weighed 2 grams of
salicylic acid and transferred it into a hard
glass test tube. 5 ml of acetic anhydride and
5 drops of concentrated sulphuric acid were
carefully added. The solution was stirred
continuously until the salicylic acid was
completely dissolved. In a water bath, with a
temperature of 70-80
O
C, the hard glass test
tube was placed while occasionally stirring
it. After 20-30 minutes, the test tube was
removed from the water bath and drops
room temperate water was added until the
solution becomes cloudy. The inner wall of
the test tube was scratched and rinse with
ice-cold water. The solution was placed into
a beaker and 20 ml of ice cold water was
added and then stirred. The solution was
filtered using a pre-weighed filter paper and
was allowed to dry. The filtrate was placed
on an evaporating dish and was left inside
the oven for 24 hours. The aspirin was
weighed using an analytic balance and
transfer it into a wide mouth amber bottle.
For the Ferric Chloride test of
Salicylic acid, 1 ml of water was placed in 6
test tubes and add salicylic acid,
commercially available aspirin, prepared
aspirin, benzoic acid, benzyl alcohol and
control. Shake the solution and add 1 drop
of 2% aqueous Ferric Chloride. The color
was observed after.
For Starch test, place 2 ml of water
in 3 test tubes and add prepared aspirin,
commercially available aspirin and control.
Then add 1 drop of Iodine. Observe the
color.
For the melting point determination
test, an oil bath was prepared. The prepared
aspirin and pure aspirin were placed in a
capillary tube separately. The ends of the
capillary tube were sealed. The capillary
tubes were then attached to a thermometer
and were immerse into the oil bath and the
temperature was observed where the
prepared aspirin and pure aspirin started to
melt and completely dissolved.
Results and Discussion

Synthesis

Figure 2.The Mechanism of Aspirin
Synthesis
[7]

Aspirin is made from the reaction or
esterification of salicylic acid with acetic
anhydride where in it is catalyzed by an
acid. The mechanism is as follows: The acid
protonates the acetic anhydride, then the
proton from the acid attacks the carboxyl
oxygen which in turn pulls the two electrons
in one of the pi bonds. It delocalizes the
electrons and spreads them out between the
two oxygen atoms. Then, the delocalized
electrons, in the presence of the hydroxyl
group, rearrange in such a manner as to
create temporary bonds between the two
reactants. The proton from the hydroxyl
group attacks the positively charged carbon
(C attached to new OH group) of the
anhydride. The oxygen of the
-
OH group of
the salicylic acid then becomes positively
charged. After that, the positive charge shifts
to the oxygen atom between the two carbon
atoms of the anhydride as the hydrogen
atom of the

OH groups makes a bond with

the said oxygen of the anhydride. The
electrons of the

OH group of the anhydride

delocalizes since there is a positively
charged oxygen atom that must be
neutralized. As the electrons delocalizes, the
bond between the carbon and oxygen (in the
center of the anhydride) breaks, producing a
protonated aspirin and an acetic acid.
Finally, the deprotonated acid, being
negatively charged, acts as a nucleophile
and abstract the hydrogen of the protonated
aspirin. This results to the synthesis of
acetylsalicylic acid and acetic acid. Conc.
sulfuric acid, a strong acid was added to
catalyze the reaction or to act as a facilitator
to the nucleophilic acetylation of the
salicylic acid. The H
+
from conc. Sulfuric
acid protonates the carbonyl oxygen of
acetic anhydride to make the carbonyl
groups more susceptible to nucleophilic
attack
.
[8]

Heating and addition of water were done to
enhance the synthesis reaction. Through
heating the dissolution process of salicylic
acid speeds up and also increases the
solubility, because this reaction is an
endothermic process that favors the addition
of heat resulting on the formation of
products. The temperature is controlled not
to exceed 80
o
C for the aspirin might get
hydrolyzed and turn back being salicylic
acid and acetic anhydride. Through the
addition of water, it gives way for further
nucleophilic substitution. Scratching was
done so that it would act as the site of crystal
formation. After the crystal formation as
observed, cold water was added in order to
separate aspirin from other products. Aspirin
is insoluble in cold water, and the chilled
aspirin can be separated easily by using the
filter method.

The aspirin that was synthesize from
salicylic acid through weigh 1.3273g. The
process used to synthesize aspirin is called
esterification, it happens when acetic
anhydride and salicylic acid combine to
produce an ester with a presence of an acid
catalyst which is the sulphuric acid and heat.
The formation of ester occur when
molecules of water split and the remaining
acetic anhydride and salicylic acid
fragments become attached.

After 15 minutes of water bath, the
walls of the tube were scratched and the
solution was rinsed with cold water. The
solution was then placed in an ice bath for
the crystallization of aspirin and again was
rinsed with cold water to remove acetic
anhydride and sulphuric acid since it is
soluble in water and aspirin is insoluble in
cold water. Therefore when the solution was
filtered the residue that was collected was
aspirin.
The percentage yield was calculated:

Salicylic acid

2C
7
H
6
O
3
= 1mol 1mol 180.15g


C
7
H
6
O
3
(X) C
9
H
8
O (X) C
9
H
8
O
4
138.07g 1mol 1mol
C
7
H
6
O
3
C
7
H
6
O
3
C
9
H
8
O
4


=2.609g C
9
H
8
O
4


Acetic Anhydride

5ml x 1.08g/ml = 5.4g C
4
H
6
O
3

5.4g 1mol 1mol 180.15g
C
4
H
6
O
3
(X)

C
9
H
8
O
4
(X) C
9
H
8
O
4
(X) C
9
H
8
O
4
102.089g 1mol 1mol
C
4
H
6
O
3
C
4
H
6
O
3
C
9
H
8
O
4

= 9.52g C
9
H
8
O
4


Percentage Yield = Actual Yield X 100
Theoretical yield
= 1.3723g X 100 = 50.87%
2.609g

The calculated percentage yield is
50.87%



Ferric Chloride Test

A B C D E F
Figure 3. Results of Ferric Chloride test
for the presence of Salicylic Acid

Table 1. Results of Ferric Chloride test
for the presence of Salicylic Acid
A. Benzyl
Alcohol
Immiscible, yellow
solution
(-)
B. Commercially
available
ASA
Light yellow solution
with precipitate
(-)

C. Control
(Pure Aspirin)

Clear solution with
precipitate
(-)
D. Salicylic Acid Violet solution with
precipitate
(+)
E. Benzoic acid Light yellow solution
with precipitate
(-)

F. Prepared
ASA

Violet solution with
precipitate
(+)



Figure 4. Reaction of FeCl
3
with phenol
Treatment of a 1% solution of FeCl3
in chloroform with a phenol yields a
triaryloxy complex. This reagent is useful
for detecting the presence of a hydroxyl
group attached directly to an aromatic
nucleus; alcohols do not undergo this
reaction. Most phenols yield intense red,
blue, purple or green colorations in the ferric
chloride test. Other functional groups
produce color changes with ferric chloride:
aliphatic acids give a yellow solution;
aromatic acids give a tan precipitate. All
phenols do not produce color with this
reagent. Highly hindered phenols (such as
2,6-di-tertbutyphenol) fail to give positive
tests.
Enols give a distinctive yellow color
when treated with FeCl3/CHCl3/pyridine.
[9]


Ferric Chloride test is used to check
the purity of the prepared aspirin. Because
the salicylic acid contains phenol, it is
suspected to form a violet solution for its
OH group will be reacting with the ferric
chloride solution.

Figure 4. Reaction of FeCl3 with Salicylic
acid
[10]


The salicylic acid together with the
prepared ASA yields a positive result with a
violet solution. This shows that the prepared
ASA contains impurities by the presence of
salicylic acid.

Benzyl alcohol, benzoic acid, pure
aspirin (control), and the commercially
available ASA yield a negative result. This
means that the compounds do not contain
phenols. And also the commercially
available ASA does not have any salicylic
acid content.







Starch Test

A. B. C.
Figure 5. Starch Test Result

Table 2. Results for Starch Test/ Iodine
Test
A. Prepared ASA Light yellow
precipitate
(-)
B. Control (pure
ASA)
Dark violet
solution
(+)
C. Commercially
available ASA
Violet
precipitate
(+)

The iodine test for starch is used to
determine the presence of starch in the
prepared aspirin, commercially available
ASA, and the control.
Starch is a polysaccharide consisting
of glucose units joined together by
glycosidic bonds. The chains formed during
the condensation reaction are either linear or
highly branched molecules.

Iodine on its own (small non-polar
molecule) is insoluble in water. Therefore
Potassium triiodide solution or Iodine
dissolved in potassium iodide solution is
used as a reagent in the test
The starch-iodide complex is formed
as charge - recall electrons are charged
particles - is transferred between the starch
and iodide ion. The transfer of charge
between the starch and the iodide ion
changes the spacing between the energy
levels/ orbitals. This changes results in the
starch-iodide complex absorbing light at a
different wavelength than any other species
aforementioned resulting in an intense
purple color.
[11]


The prepared ASA yields a negative
result, which means it doesnt contain
starch. While the commercially available
ASA and the control yields a positive result
which implies the presence of starch. The
control should have not resulted with a
positive result because it contains pure
aspirin. This may mean that starch was
added to the control (pure aspirin). The
commercially available ASA yields a
positive result because in the pharmaceutical
industry, starch is oftenly used as a binder
and surfactant.

Melting Point
The melting point of pure aspirin
ranges 135
o
C to 155
o
C while the prepared
aspirin ranges 150
o
C to 170
O
C. The
prepared aspirin has high melting point
compared to the pure aspirin since it
contained impurities. These impurities may
be due to incomplete esterification of
salicylic acid and uncrystallized aspirin
therefore the prepared aspirin is not pure.



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