Synthesis of acetylsalicylic acid (Aspirin) via the acidic acetylation of salicylic acid

Meltrick R. Torres, Anthea Jae O. Ungsod, Jacquelyn Faye S. Usero,

Bryan Paul B. Uy, Roi Marion H. Uy, Group no. 8, 2G- Faculty of Pharmacy
Organic Chemistry Laboratory, University of Santo Tomas
ABSTRACT
Organic synthesis is the process where a desired organic compound is constructed or prepared from commercially
available materials. The objective of organic synthesis is to design the simplest synthetic routes to a molecule.
Acetylsalicylic acid, also known as aspirin, is one of the most widely used medications to reduce fever and is also used
as a painkiller. It is an acetyl derivative of salicylic acid. It is a white, crystalline, weakly acidic substance which melts
at 135C. Your two primary objectives in this experiment will be to synthesize and analyze aspirin.

INTRODUCTION
Aspirin is synthesized through the reaction of
salicylic acid with acetyl anhydride, which causes
a chemical reaction that turns salicylic acid's
hydroxyl group into an acetyl group, (ROH R
OCOCH3). For the reaction to take place, an
inorganic acid such as phosphoric acid is used as
a catalyst.

EXPERIMENTAL
A. Compound test or samples used
The reagents or sample used were salicylic
acid, acetic anhydride, KMnO4, FeCl3, and
Iodine solution.

B. Procedure
Before we started with the following steps we
prepared a 250-ml beaker and it was put on a
hot
plate.
Bring
to
boil.

Aspirin is most widely sold over-the-counter

drug. It has the ability to reduce fever (an
antipyretic), to reduce pain (an analgesic), and to
reduce swelling, soreness, and redness (an antiinflammatory agent). One of the first recorded
accounts for the discovery of aspirin appeared in
England, in 1763, crediting the bark of willow
trees with a beneficial effect in alleviating distress
due to fevers, aches, and pains. Later, the
compound salicylic acid (named for the Latin
word for willow, salix) was isolated from willow
bark. It proved to be the active ingredient. By
1860, organic chemists were able to synthesize
salicylic acid from basic starting materials, this
furthered the therapeutic use of the substance,
but there were problems. Salicylic acid proved to
be irritating to the membranes of the throat,
mouth, and stomach. These problems are directly
associated with the high acidity of the compound,
but a simple remedy was discovered, namely,
replacement of the acidic phenolic hydrogen atom
with an acetyl group. Synthesize acetylsalicylic
acid from salicylic acid by nucleophilic acyl
substitution; and differentiate acetylsalicylic acid
from salicylic acid by simple chemical tests.
These test are: Reaction of Acetic Anhydride and
Salicylic Acid, Starch Test, and Ferric Chloride
Test.

1.Reaction of Acetic anhydride (A.A.) and

Salicylic Acid (S.A.)
For the reaction of acetic anhydride and
salicylic acid it was weighed exactly 2.00 g of
salicylic acid in a tarred watch glass and transfer
it into a clean, dry 20-cm test tube. Exactly 5.00
ml of acetic anhydride was added into the test
tubes; 5 drops of concentrated H2SO24 were
added. Using a long stirring rod stir until salicylic
acid completely dissolves. Remove the prepared
water bath on the hot plate when it already boils.
Be sure to place the beaker on a surface with
wire gauze. The tests tubes inside the beaker and
stirs the contents of the test tube for 1 minute
and allow it to remain on the water bath with a
70-80 degrees Celsius for 20 minutes. After
remove the test tube and SLOWLY CAUTIOUSLY
transfer its contents into a 150-ml beaker
containing 5ml of distilled water and a reaction
will take place here. Wait for the reaction to
subside and then stir the mixture for 1 minute.
Slowly add distilled water (up to 40 drops) to
induce crystal formation, scratch the inner
surface of the beaker if no crystals form. The test
tubes were rinsed previously with ice-cold water
from wash bottle and the rinsed solution was
added to the 150-ml beaker. A 20 ml of ice-cold
water was measured and it was added into the
beaker. The beaker was stirred and packed in an
ice for 10 minutes and crystallization of ASA was
formed. Using a pre-weighed filter paper crystals
were filtered and it was allowed to dry overnight.

The dried ASA weight was measured

percentage yield was computed.

and

2. Ferric chloride Test for Salicylic Acid

6 test tubes were prepared containing 1 ml each
of distilled water. Corresponding samples were
placed on the 6 test tubes. On test tube 1: a
crystal of salicylic acid was the sample, on test
tube 2: a powdered commercial acetyl salicylic
acid was the sample, on test tube 3: the
synthesize acetyl salicylic acid was the sample, on
test tube 4: benzoic acid was the sample, on test
tube 5: a 1ml of Benzyl alcohol was the sample,
and on test tube 6 it has no sample to know the
difference of each sample. All the sample solid
were shake and dissolved, then a drop of 2%
aqueous solution of ferric chloride was added
using a pipette. Colors produced were observed.
3. Starch Test
3 test tubes were prepared containing each 2 ml
of distilled water. The corresponding samples
were placed on the 3 test tubes. On test tube 1:
containing a pinch amount of the synthesized
ASA, on test tube 2: containing a pinch amount
of powdered commercial ASA, and on test tube 3:
there is no sample contained to have a control on
the difference of other samples. A drop of Iodine
solution was put on each test tube and a blue or
black color indicated the presence if starch the
color were observed.

4. Preparation of Methyl salicylate

Exactly 1.00g S.A. was weighed and placed into a
2-0-cm test tube, a 5 ml methyl alcohol was
added and 3 drops of H2SO4 was also added. The
contents were stirred and the S.A. in the alcohol
was dissolved. Then the test tube was placed in a
70 degrees Celsius water bath for 15 minutes.

Figure 1. Reaction of Acetic anhydride

(A.A.) and Salicylic Acid (S.A.)
This shows that oxygen in salicylic acid attacks
one of the carbons in acetic anhydride. Also, the
mechanism shows how acetic acid was separated
from acetylsalicylic acid.
Table 1.1 Sample descriptions of reagents
SAMPLE
Salicylic acid

Acetic anhydride
KMnO4
FeCl3
Iodine Solution

Table 1.2 Preparations of Aspirin

SAMPLE
DESCRIPTION
Salicylic acid + acetic
anhydride + 85%
phosphoric acid
Mixture at room
temperature
Mixture after ice bath
Suction Filtration:
Residue
Filtrate

RESULTS AND DISCUSSION

The first part of the experiment was the
preparation of Acetylsalicylic Acid (Aspirin). A
white, milky mixture was obtained when
salicylic
acid,
acetic
anhydride
and
phosphoric acid (a catalyst) were mixed. The
mechanism of the reaction is:

DESCRIPTION
White, powder-like
substance
Clear liquid with strong
odor
Purple liquid
Brown liquid
Clear liquid

Crude aspirin

Salicylic was dissolved

Crystals were formed
More crystals were
formed
Fine, white crystals
Clear liquid with small
amounts of crystals
Fine white crystals

Table 1.3 Recrystallization of Aspirin

DESCRIPTION
Mixture during cooling
Mixture after cooling
Suction filtration:
Residue
Filtrate

Crystals were formed

More crystals were
formed
Fine, white crystals
Clear liquid

Table 1.4 Recovery Data of recrystallized

aspirin
OBSERVATIONS
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
Theoretical Yield
Actual Yield
% Yield

98.8 g
96.8g

5.0 ml

% Yield= Actual yield/Theoretical Yield

(2.0g of the weighted product/2.61g) x100
=76.6%

5ml
3.7g
1.7g
2.0 g
2.61g
2.0g
76.6%

SAMPLE

MELTING POINT RANGE

Crude aspirin
Recrystallized aspirin

106-112
114-118

(C)

Table 1.6 Differentiation of starting material

from the product
TEST
SYNTHESIZE
SALICYLIC
D ASPIRIN
ACID

FeCl3

Disappearance of
violet color
formation of
brown precipitate
The solution
remind brown
and not all of the
sample dissolved

SAMPLE
Synthesized
acetylsalicylic acid
Commercially-available
aspirin

Acetic Acid:
5.00 mL C4H603 (1.08g AA/ 1mL)( 1 mol AA/
102.11g)(1 mol ASA/ 1 mol AA)
= 5.4g
Theoretical Yield:
0.01488 mol(180.16g/1molC9H8O4)
=2.61g

2.0g

Table 1.5. Melting point determination

KMnO4

=2.61g

In this exercise, the goal was to produce

acetylsalicylic acid through the organic synthesis
from the reaction of salicylic acid to acetic
anhydride, the starting materials. Instead of
using acetic acid, acetic anhydride was used as
solvent since the anhydride reacting with water
to form acetic acid tends to drive the reaction to
the right. It results from the elimination of a
molecule of water from two molecules of acetic
acid.

Figure 2. Structure of Acetic Anhydride

The solution
remained purple
The solution
became darker
shade of brown
and not all of
the sample
dissolved

OBSERVATIONS
All of the sample
dissolved and the
solution is turbid
All of the sample
dissolved and the
solution became faint
purple

Reference:
[1] Bathan, G.I., Bayquen, A.V., Crisostomo,
A.B.C., Cruz, C.T., de Guia, R.M., Farrow, F.L.,
Pea, G.T., Sarile, A.S. & Torres, P.C. (2014).
Laboratoy Manual in Organic Chemistry Revised
Edition. Manila: C&E Publishing, Inc. pp. 13-14
[2]
http://www.academia.edu/8631192/Synthesis_of
_Aspirin
[3]

CALCULATIONS:
Salicylic acid:
2.0g C7H6O3 ( 1 mol SA/ 138.16 g) ( 1 mol
ASA/1 mol SA) ( 180.21g/ 1 mol ASA)

http://www.academia.edu/8631192/Synth
esis_of_Aspirin
[4]
http://theuplbcollegestudent.blogspot.com/2011/
05/full-report-synthesis-of-aspirin.html