SYNTHESIS OF METHYL SALICYLATE

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 this experiment
are hard glass test tube, 10-ml graduated
cylinder, dropping pipette, beaker, thermometer,
stirring rod, filter paper, evaporating dish and
funnel.
Procedure
The group weighed 2 grams of salicylic
acid and transferred it into a hard glass test tube.
They added 5 ml of acetic anhydride and
carefully added 5 drops of concentrated
sulphuric acid. They stirred it continuously until
the salicylic acid is completely dissolved. In a
water bath, with a temperature of 70-80
O
C,
place the hard glass test tube while occasionally
stirring it. After 20-30 minutes, remove the test
tube from the water bath and add drop wise
room temperate water until the solution becomes
cloudy. Scratch the inner wall of the test tube
and rinse with ice-cold water. Place the solution
into a beaker then add 20 ml of ice cold water
and stir. Filter the solution using a pre-weighed
filter paper and allow it to dry. Place the filtrate
on a evaporating dish and leave it inside the
oven for 24 hours. Weigh the aspirin and
transfer it into a wide mouth amber bottle.
For the Ferric Chloride test of Salicylic
acid, place 1 ml of water in 6 test tubes and add
salicylic acid, commercially available aspirin,
prepared aspirin, benzoic acid, benzyl alcohol
and control. Shake and add 1 drop of 2%
aqueous Ferric Chloride. Observe the color.
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,
Results and Discussion

Synthesis

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
4
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 X 1mol X 1mol X 180.15g = 9.52g
C
4
H
6
O
3
C
4
H
6
O
3
C
9
H
8
O
4
C
9
H
8
O
4
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


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 2. 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 3. 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.
[7]


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
[8]

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.
[9]


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.

References
[1]
Retrieved from
http://circ.ahajournals.org/content/125/10/e439.full at
August 9, 2014.

[2]
Retrieved from
http://www.medicalnewstoday.com/articles/161255.p
hp at August 9, 2014.
[3]
Interactive Concepts in Biochemistry. 2006. John
Wiley and Sons Publishers. Retrieved from:
http://www.wiley.com/legacy/college/boyer/0471661
791/cutting_edge/aspirin/aspirin.htm at August 9,
2014.
[4]
Schneider, R.F. (2013). Retrieved from
http://www.ic.sunysb.edu/Class/che134/susb/susb028
.pdf at August 9, 2014.

[5]
Retrieved from
http://antoine.frostburg.edu/chem/senese/101/redox/f
aq/starch-as-redox-indicator.shtml at August 6, 2014.

[6]
Stanford Research Systems. Retrieved from
www.thinkSRS.com/products/MPA.htm at August 6,
2014.

[7]
Chem 4563 Organic Qualitative Analysis
Phenols, Enols and Carboxylic Acids-Functional
Group Tests. Retrieved August 9, 2014, from
http://faculty.swosu.edu/william.kelly/pdf/qo8.p
df
[8]
Methodical Instruction for Students of the 1
Course Medical Faculty. Retrieved August 9,
2014, from
http://intranet.tdmu.edu.ua/data/kafedra/internal/
zag_him/metod_rozrobky/en/med/lik/ptn/biologi
cal%20and%20bioorganic%20chemistry/1%20c
ourse/02.%20Carboxylic%20acids.%20Lipids.H
eterofunctional%20compounds.htm
[9]
Iodine Test for Starch. Retrieved August 9,
2014, from
http://brilliantbiologystudent.weebly.com/iodine
-test-for-starch.html