Synthesis of Aspirin (Acetylsalicylic acid)

Authors: ABESAMIS, M., ACOSTA, M., AGUSTIN, F., *AQUITANIA, M.,

BAGSICAN, M.

Abstract
Acetylsalicylic acidC9H9O4, known as Aspirin, is one of the popular and
versatile medicines that cure diseases. It is considered a powerful drug for
relieving pain (analgesic), reducing fever (antipyretic), and reducing swelling
(anti-inflammatory). The synthesis of acetylsalicylic acid is derived from
salicylic acid which can be extracted in willow trees and allowing it to react
with acetic anhydride and a catalyst through the principle of crystallization.

I. Introduction

Salicylic vinegar-like odor when it reacts

acid C7H6O3is a with water to form acetic acid. The
fine white boiling point of acetic anhydride is
crystal and 140°C and the melting point is
odorless. It is -73°C. It is soluble in ether,
extracted in chloroform and benzene. It is
willow and soluble in water when acetic
poplar bark that anhydride decomposes. The
has been used density of acetic anhydride is 1.082
as an analgesic Figure 2 Structural g/ml in liquid state and its
for centuries. formula of Salicylic molecular weight is 102.09 g/mol.
Th Acid Acetic anhydride is most widely
e used for the conversion of cellulose
to cellulose acetate, which is a
component of photographic film
and other coated materials. It is
also known as acetyl ether.

boiling point of salicylic acid is Figure 1 Structural formula of

211°C and the melting point is Acetic anhydride C
159°C. The density of salicylic acid ryst al
is 1.44 g/mol. Salicylic acid is very lization is one of the most used
reactive in moisture, light, heat, purifying methods in organic
and incompatibilities such as iron experiments. It is a process of
salts, lead acetate, iodine and crystal formation in a solution.
nitrous ether. It is used in medicine Organic compounds that are solid
such as making aspirin and in room temperature are usually
pharmaceutical applications, purified by crystallization. The
including methyl salicylate. substance to be purified is
dependent to its solubility in
Acetic anhydride C4H6O3 is change of temperature whether in
a colorless liquid with a pungent a hot or cold solvent. It is the main
factor that affects crystallization.
The substance to be crystallized
should show the ideal solubility
behavior in solvent. A substance
can be purified when both the
desired substance and the impurity
have similar solubility at its boiling
point temperature, and when the
impurity represents only a small
fraction of total solid. The desired
substance will crystallize on
cooling, but the impurities will not.
The objectives obtained in
this experiment are the following:
(1) to be able to explore the
chemical process in the synthesis
of aspirin; (2) and to calculate for
the percentage yield of the
synthesized aspirin.
II. Methodology
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 and it was transferred
in a clean, dry 20-cm test tube.
Exactly 5.00 ml acetic anhydride
was dispensed to the test tube and
5 drops of concentrated sulfuric
acid H2SO4 was added. The
mixture is stirred using a stirring
rod until the salicylic acid was
dissolved. 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 the react
within a temperature range of 70°C
to 80°C in 20-30 minutes. The
content of the test tube was stirred
well in 1 minute. Then, the test
tube was removed from the water
bath and its contents were poured
slowly and cautiously in 150-ml
beaker filled with 5 ml distilled
water. When the mixture subsided,
the mixture was stirred in 1 minute
while a drop of room temperature
water was added at a time, until it
reached a maximum of 40 drops or
the solution became cloudy. When
the solution became clear, a few
drops of water were added
dropwise until crystals of aspirin
reappeared. When there are no
crystals found, the inner walls of
the beaker was scratched gently
using the stirring rod to induce
crystal formation. Once the crystals
of aspirin appeared, the test tube
was rinsed with a small volume of
ice-cold water from the wash
bottle. 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 allow the
aspirin to be crystallized. The
aspirin crystals were filtered using
a pre-weighed filter paper and it
was dried overnight. Then, dried
aspirin crystals were weighed.
To test the purity of the
synthesized aspirin, it was
subjected to ferric chloride test for
salicylic acid. 1 ml water was
placed in 6 10-cm test tubes. A
small amount of each sample was
added in every test tube using a
microspatula. Salicylic acid was
placed in the first test tube,
powdered commercial aspirin in the
second test tube, synthesized
aspirin in the third test tube,
benzoic acid in the fourth test tube
and 1 ml of benzoic acid in the fifth
test tube. The sixth test tube filled
with 1 ml water was the control
used. The sample used was
dissolved in 1 ml water then a drop
of 2% aqueous solution of ferric
chloride was added using a Pasteur
pipette. The observed color
produced was noted.
Another test of purity used
was starch test. A 2 ml of water
was placed in 3 10-cm test tube. A
small amount of each sample was
added in every test tube. The
powdered commercial aspirin was
placed in the first test tube and
salicylic acid in the second test
tube. The third test tube with 2 ml
water was the control used. A drop
of iodine solution was added in
each test tube. The observed color
produced was 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. A 5 ml
of methyl alcohol and 3 drops of
concentrated sulfuric acid H2SO4
was added to the test tube. The
mixture is stirred until the salicylic
acid is dissolved in alcohol. Then,
the test tube was subjected in
70°C water bath for 15 minutes.
The mint aroma produced inferred
the presence of methyl salicylate.
III. Discussion
Figure 3 Structural formula
of Aspirin (Acetylsalicylic
acid)
The
synthesized acetylsalicylic acid is
prepared by allowing salicylic acid
to react in acetic anhydride with a
strong acid as a catalyst such as
concentrated sulfuric acid and
phosphoric acid. The principles in
crystallization are applied to obtain
the desired product, aspirin. The
difference in solubility of the
synthesized acetylsalicylic acid to
its mother liquor at a lower
temperature will crystallize to
obtain the desired substance. In
Table 1, the used materials and
substances are presented with
their corresponding weight or
volume. The weight and volume
were accurately measured using
the apparatus.
 Table 1. Reaction of Acetic Anhydride and Salicylic Acid
Weight of watch glass + salicylic acid…….55.9455 g
Weight of empty watch glass………………....53.9374 g
Weight of salicylic acid…………...………….......2.0081 g
Volume of acetic anhydride……………………....….5.00 ml
Volume of concentrated sulfuric acid…...…….…....5 drops
Weight of filter paper + product ...…………..2.8310 g
Weight of dry filter paper....…………..…...……0.2000 g
Weight of product ...…………..…………………....2.6310 g

Figure 4 Synthesis of Acetylsalicylic acid

Salicylic acid has two for a catalyst is required to hasten

important functional groups
present, the carboxylic group and
the phenol group. In the reaction
of salicylic acid and acetic
anhydride, the hydroxyl group -OH
on the benzene of the salicylic acid
reacted with acetic anhydride to
form an ester functional group;
thus, the formation of
acetylsalicylic acid is referred to as
an esterification reaction.
Esterification is a reaction wherein
refluxing of the carboxylic group
and the primary or secondary
hydroxyl group occurs to prepare
an ester. This reaction requires the
presence of an acid catalyst. It can
be expressed by the H+ in the
equation. Acetic anhydride reacts
slowly with salicylic acid. A need
the reaction. In this experiment,
concentrated sulfuric acid is used
as the acid catalyst. The formation
of ester is also referred as a
nucleophilic substitution SNreaction
wherein the catalyst attracts the
H+ of hydroxyl group. The salicylic
acid becomes more negative that it
will attract the acyl group -OCOCH3
of the acetic anhydride. Since
acetic anhydride is polar, it has a
partially positive group and a
partially negative group. The
partially positive acyl group
attaches to the salicylic acid to
synthesize acetylsalicylic acid. The
by-product of this reaction is acetic
acid.
 Figure 5 Hydrolysis of Aspirin (Acetylsalicylic acid)
When the reaction is
completed, unreacted salicylic acid
and acetic anhydride will be
present with the acetylsalicylic
acid, acetic acid and the catalysts.
Crystallization method is used to
purify the acetylsalicylic acid from
other substances in the mixture. At
room temperature, the
acetylsalicylic acid is insoluble in
water. During heating when the
salicylic acid is subjected to warm
water bath, it dissolves. This will
let the reaction of the mixture to
occur at a temperature range of
70°C to 80°C in 20-30 minutes.
Acetic anhydride is used as the
solvent in this experiment because
it has relatively low boiling during
heating. In the principle of le
Chatelier, the presence of excess
acetic anhydride forces the
equilibrium towards the desired
product. Through heating the
solution, there will be acceleration
of the reaction to approach
equilibrium. Water is not used as a
solvent for this experiment
because water may hydrolyze the
obtain aspirin to decompose into
salicylic acid and acetic acid. After
transferring the mixture in the
beaker, addition of ice-cold water
was done dropwise to form cloud of
small crystals. This will hasten
crystallization process of
acetylsalicylic acid. Upon cooling, it
was packed with ice, acetylsalicylic
acid became insoluble as its
solubility decreased and eventually
formed the crystals. The crystals
were obtained in acetic anhydride,
the mother liquor. Ice-cold distilled
water was used in filtering to rinse
the mixture to obtain the desired
substance, aspirin. The aspirin was
dried overnight and weighed
accurately.
To calculate for the actual
yield of synthesized aspirin,
limiting reagent should be
identified first. In the calculations,
the limiting reagent in the reaction
is salicylic acid. The theoretical
yield of acetylsalicylic acid will be
based on the limiting reagent. This
is to identify if the actual
experiment obtain a complete
reaction of salicylic acid and acetic
anhydride. From the calculation,
100.45% was synthesized aspirin
which presents that the
demonstrated experiment has
slight impurities obtain. These
impurities refer to the presence of
salicylic acid. Ferric chloride test
clarifies the purity of the obtain
substance.
 Calculations:
Chemical Equation:
C7H6O3+C4H6O3⟶C9H9O4+CH3COOH

Limiting reagent:
Acetic anhydride:
2.0081 g C7H6O3×1 mol138.12 g C7H6O3×102.09 g C4H6O31 mol×1 ml 1.082
g=1.37 ml C4H6O3

Salicylic acid:
5.00 ml C4H6O3×1.082 g1 ml×1 mol102.09 g C4H6O3×138.12 g C7H6O31
mol=7.3193 g C7H6O3

Theoretical yield:

2.0081 g C7H6O3×1 mol138.12 g C7H6O3×180.16 g C9H9O41 mol=2.6193 g C9H9O4

Percentage yield:
2.6310 g synthesized aspirin2.6193 g C9H9O4×100=100.45%

Table 2. Ferric Chloride Test

Test Tube Observations Inference
Salicylic acid Purple solution (+) Salicylic acid present
Commercial Pink solution (–) No presence of salicylic
aspirin acid
Synthesized Purple solution (+) Salicylic acid present
aspirin
Benzoic acid Light orange solution (–) No presence of salicylic
(cloudy) acid
Benzyl alcohol Yellow oily solution (–) No presence of salicylic
acid
Control Light yellow solution (–) No presence of salicylic
acid

Figure 6 Reaction of Ferric chloride test

(Yellow – Ferric ion; Purple – Reacted salicylic acid)
 Ferric as presented in present in the an acid catalyst
chloride is used Table 2. Thus, synthesized to form methyl
for there are aspirin and salicylate and a
determination impurities in control which is by-product of
of purity of a the obtain water. water. This
substance. The aspirin. reaction occurs
intense purple at a low
color produced Table 3. temperature. In
is caused by the Starch Test this
reaction of Test Tube Observation experiment,
salicylic acid Commercial (+) Blue-black methyl alcohol
with aqueous aspirin colored solution was used to
ferric FeH2O6+3 Synthesized (–) No reaction
Figure 7 dissolve
ion. The oxygen Preparation of salicylic acid. It
aspirin Methyl salicylate
atoms of the was subjected
Control (–) No reaction
carboxylic acid to water bath
Methyl
group for it to produce
Aspirin salicylate is
-COOHand an odor. The
tablets are obtained from
hydroxyl group presence of
acetylsalicylic winter green
-OH on salicylic methyl salicylic
acid pressed oil, an aromatic
acid can form a acid was
together with a liquid distilled
complex group confirmed in
small amount of from the leaves
with ferric the mixture
inert binding of the
FeH2O6+3 ion. when it
material, such wintergreen
It indicates the produced a
as starch, plant
presence of mint-like odor.
methylcellulose (Gaultheria
salicylic acid. In
and procumbens) or
aspirin, the Methyl
microcrystalline from the bark
hydroxyl group salicylate and
cellulose. of sweet birch
-OHwas acetylsalicylic
Commercial trees (Betula
replaced by acid are
aspirin reacted lenta). It has
ester -OCOCH3 derivatives of
to iodine. two main
during salicylic acid.
Formation of functional
esterification groups, the
blue-black
and nucleophilic ester group and
colored solution
substitution phenol group.
indicates a
which prevents Like,
positive result.
the complex acetylsalicylic
In the
formation. This acid, methyl
synthesized
will emanate a salicylate acid is
aspirin, there
yellow solution. prepared
was no reaction
However, the through the
occurred. The
synthesized process of
control did not
aspirin reacted esterification.
reacted in
in ferric chloride Methyl alcohol
iodine. This
which implies reacts with
infers that there
that salicylic salicylic acid in
is no starch
acid is present, the presence of
IV. Refere Miniscal Laborat (ACETY
nce e and ory L
Standar Techniq ETHER)
Lehman, J. d Taper ues – A . (n.d.).
(2002). Microsc Microsc Retriev
Multisc ale (2nd al ed
ale ed.). Approa October
Operati New ch (3rd 11,
onal York: ed.). 2009,
Organic W.H. Saunde from
Chemis Feeman rs http://c
try: A and College hemical
proble Compa Publishi land21.
m ny. Pg. ng. Pg. com/pe
Solving 19-35 60-70, troche
Approa 100- mical/A
ch to Pasto, D. J., 109 CETIC
the John, %20AN
Laborat C. R., & Williamson, HYDRID
ory Miller, K. E.ht
Course. M. S. (1994).
New (1998). Macros
Jersey: Experi cale SALICYLIC
Prentice ment and ACID.
Hall. and Microsc (n.d.).
Pg. 40- Techniq ale of October
48, ues in Organic 11,
257- Organic Experi 2009,
264, Chemis ments. from
530 try. Canda: http://j
New D.C. tbaker.
Mohrig, J., Jersey: Health com/ms
Hammo Prentice and ds/engli
nd, C., Hall. Compa shhtml/
Schatz, Pg. 43- ny. Pg. s0506.h
P., & 46 379- tm
Morril, 384
T. Pavia, D.,
(2003). Lampm ACETIC
Modern an, G., ANHYD
Project Kriz, RIDE
s and G., &
Experi Engel,
ments R.
in (1999).
Organic Introdu
Chemis ction to
try: Organic