EXERCISE 11

SYNTHESIS OF ASPIRIN

PRINCESS ANGELINE O. LACATANGO

GROUP 5

7L
 I. INTRODUCTION

Organic chemistry is the science that deals with the synthesis of organic compounds from
readily available resources. Organic synthesis aims to create the simplest synthetic routes to
create a new product.

Aspirin, or acetylsalicylic acid, is a type of an anti-inflammatory drug that is often used as an

analgesic to relieve minor aches, pains and fever. With its antiplatelet effect, aspirin can be
used to help prevent heart attacks, strokes, and blood clot formation. Low doses of it can then
be given after a heart attack to reduce the risk of the occurrence of another one.

The medical use of aspirin can be traced way back in 400 BC. Willow tree leaves are given
to women by Hippocrates to relieve the pain of childbirth, and he also uses salicylic tea to
reduce fevers. Though the active ingredient of the said drugsalicylic acidwas first discovered
by Edward Stone in 1897, aspirin was first synthesized by Felix Hoffman, a chemist in Bayer in
1897. It then became one of the mostly used medication by people, with about 40,000 tons of
it being consumed each year.

In this experiment, aspirin will be synthesized from salicylic acid through various chemical
procedures. The synthesis reaction of aspirin is as follows:

Figure 11.1 Synthesis of Acetylsalicylic Acid.

II. OBJECTIVES

In this laboratory exercise, the students are expected:

1. To explain the concept of organic synthesis;
2. To synthesize acetylsalicylic acid from salicylic acid by nucleophilic acyl substitution; and
3. To describe and explain differences in the properties of acetylsalicylic acid and salicylic
acid by simple chemical tests.

III. MATERIALS AND METHODS

A. SCHEMATIC DIAGRAM OF THE PROCEDURE
1. PREPARATION OF ACETYLSALICYLIC ACID (ASPIRIN)

1.0 g SALICYLIC ACID

- Put in 125 ml Erlenmeyer Flask

- Add 3 ml acetic anhydride and 5 drops 85%
phosphoric acid
- Swirl and then heat for 15 minutes
- Add 2 ml distilled water
- Add 20 ml ice cold water
- Cool to room temperature and place in an ice
bath
- Filter through suction filtration

RESIDUE FILTRATE (discard)

- wash with cold water

- transfer in pre-weighed watch glass

- Air dry

- Weigh
 2. RECRYSTALLIZATION OF ASPIRIN

CRUDE ASPIRIN IN 125 ml ERLENMEYER FLASK

- add dH2O dropwise until crude aspirin dissolves

- warm in hot water bath; recrystallize by cooling
to RT and then in a cod water bath
-collect crystals by suction filtration-was crystals with cold H2O

RESIDUE FILTRATE (discard)

-transfer to a pre-weighed watch glass; air dry
-weigh aspirin & calculate percentage recovery
-transfer to a clean and dry vial and label properly
-determine melting points of crude and recrystallized aspirin; account for difference

3. CHARACTERIZATION OF ASPIRIN
PINCH OF ASPIRIN

-dissolve in 2 mL H2O and 1 mL iodine solution

FeCl3 Test

1 mL dH2O in each test tube

put spatula tip of salicylic acid, acetyl chloride and aspirin in each tube
add 3 drops FeCl3
Observe

KMnO4 Test
1 mL diluted, slightly acidic KMnO4
add 2 drops of sample
examine mixture after 5 minutes
 H2O Test

Dissolve a pinch of sample in H2O

- Observe

B. SET-UPS

Figure 11.2. Suction Filtration Set-up

C. LIST OF NECESSARY CHEMICALS

NAME OF THE FUNCTION IN PHYSICAL HAZARDS PRECAUTIONS

COMPOUND THE EXERCISE PROPERTIES
Salicylic Acid Starting White Powder Skin and Eye Avoid contact;
Material MW: 138.12 Irritant wear safety
g/mol gloves and
MP: 159C goggles
BP: 211C
Acetic Anhydride Solvent Clear, Corrosive and Wear safety
colorless toxic; can gloves, goggles
liquid cause and mask to
MW: 102.04 chemical prevent
g/mol burns inhalation of
MP: 73C fumes
BP: 139C
Phosphoric Acid Catalyst Clear, Corrosive and Avoid contact
colorless toxic and wear a
liquid mask to
MW: 98 prevent
g/mol inhalation of
BP: 158C fumes
95% Ethanol Used for Clear, Skin and eye Keep away
Recrystallization colorless irritant from heat.
liquid Wear safety
MP: 114C gloves, goggles
and mask.
Potassium Differentiating Purple Liquid Highly In case of
Agent reactive with contact,
concentrated immediately
sulphuric acid flush skin with
plenty of water
for 15 minutes.
Permanganate
Ferric Chloride Differentiating Clear, yellow Corrosive and Avoid contact.
Agent liquid toxic Wear safety
MM: 162.20 gloves, goggles
g/mol and mask.
Iodine Differentiating Clear colorless Eye, skin and Avoid contact
Agent liquid pulmonary and wear mask
MP: 0C irritant to prevent
BP: 100C inhalation of
fumes
Water Differentiating Clear colorless No necessary No necessary
Agent liquid hazard precaution
MP: 0C
BP: 100C
 IV. DATA
Table 11.1 Description of Reagents.
REAGENT
Salicylic Acid
Acetic Anhydride
Phosphoric Acid
95% ethanol
Potassium Permanganate
Ferric Chloride
Iodine Solution
Table 11.2. Preparation of Aspirin
Salicylic acid + Acetic Anhydride + 85%
Phosphoric Acid
Mixture at Room Temperature
Mixture after Ice Bath
Suction Filtration: Filtrate
Suction Filtration: Residue
Crude Aspirin
Table 11.3. Recrystallization of Aspirin.
Crude Aspirin + Ethanol
Mixture during cooling
Mixture after cooling
Suction Filtration: Filtrate
Suction Filtration: Residue
DESCRIPTION
White powder
Clear colorless liquid
Clear colorless liquid
Clear colorless liquid
Violet liquid
Clear yellow liquid
Clear colorless liquid
DESCRIPTION
White cloudy liquid
White cloudy mixture solidified
White cloudy mixture liquefied
Clear Liquid
Mixture of cream and needle-like crystals
Mixture of cream and needle-like crystals
DESCRIPTION
Clear liquid with few precipitates
Formation of white cloudy mixture
White cloudy mixture with needle-like crystals
Clear liquid
Clump of cream with needle-like crystals
Table 11.4. Recovery Data of Recrystallized Aspirin.

OBSERVATIONS
Weight of watch glass + Filter paper (g) 28.27 g
Weight of watch glass + Filter paper + 34.15 g
Product (g)
Weight of crude aspirin (g) 5.88 g
Weight of recrystallized aspirin (g) 3.19 g
Theoretical Yield 1.3 g
% yield 245%
% recovery 54.25%

Table 11.5. Melting Point Determination.

SAMPLE MELTING POINT RANGE (C)

Crude Aspirin 125-140 C
Recrystallized Aspirin 133 C

Table 11.6. Differentiation of Starting Materials from the Product.

TEST SYNTHESIZED SALICYLIC ACID ACETIC

ASPIRIN ANHYDRIDE
Potassium Liquid turned brown Liquid turned brown Violet liquid
permanganate test
Ferric Chloride Test Liquid turned violet Liquid turned violet Orange liquid
Water Insoluble, (-) (-) (+)

Table 11.7. Differentiation of Synthesized Acetylsalicylic Acid from Commercially-Available

Aspirin by Iodine Test.

SAMPLE OBSERVATION
Synthesized Acetylsalicylic Acid Red orange liquid with precipitate
Commercially-available Aspirin Violet colored liquid
 V. SAMPLE CALCULATIONS

Theoretical Yield:
1 1
1
138.12 1
180.16
= .

Percent Yield:
3.19
100 = %
1.30

Percent Recovery:
3.19
100 = . %
5.88

VI. RESULTS AND DISCUSSIONS

In order to synthesize acetylsalicylic acid, a mixture of acetic anhydride, phosphoric acid

and salicylic acid was created. This method employs esterification, wherein a carboxylic acid and
an alcohol combines in order to produce an ester. During the reaction process, a molecule of
water splits off and the remaining carboxylic acid and alcohol fragments become attached
producing an ester.
 Figure 11.3. General Reaction of Esterification.

Figure 11.4. Esterification using Salicylic Acid and Acetic Anhydride.

The phosphoric acid serves as the catalyst in the reaction since it donates an H+ to the
reaction complex in order to speed up the process.

The resulting mixture was then subjected to heat to effectively dissolve the salicylic acid
in order to produce a solution. The dissolution process produced a clear liquid solution. After
being heated for 15 minutes, distilled water was immediately added for the acetic anhydride to
decompose. This was not done before the heating process since the addition of water would
produce acetic acid, therefore the desired reaction of producing acetylsalicylic acid will not occur
since there is no available acetic anhydride in the mixture.

Ice-cold distilled water was added to lower the temperature and to initiate the
crystallization of the desired product. The addition of cold water is very important in the
purification process since aspirin is insoluble in cold water thus making the separation of aspirin
from impurities possible. The goal of purification is to eliminate any salicylic acid and acetic
anhydride that did not react, as well as the catalyst. The cold distilled water made the cloudy
mixture into solid. The flask is then submerged in a cold water bath to further complete the
crystallization, and further on makes the solidified mixture turn to liquid again, making filtration
possible.

Suction filtration was done because fast filtration of the mixture was preferred. It employs
the use of a vacuum which can aid in the passage of the filtrate. If a simple filtration set up was
used, solid particles present in the mixture would not let the liquid pass through. The collected
product (crude aspirin) have needle-like crystals, but it also has the presence of a cream-like
product. The resulting product has a mass of 3.13 g, which is very far from the theoretical yield
which is 1.3 g. This means that there are still a lot of impurities. The crude aspirin is also moist,
meaning the mass of the product might be composed of excess water that was not properly
removed from the product.

The crude aspirin then underwent recrystallization in order to remove the impurities still
present in the product. 95% ethanol was added to dissolve the aspirin along with the impurities.
The addition of cold distilled water aids in the formation of the aspirin crystals only, leaving the
impurities still dissolved in the liquid. Cold water was used instead of hot water since aspirin is an
ester. If exposed to hot water, an ester would hydrolyze. The placement of the flask in cold water
also facilitates the recrystallization process. Gradual decrease in temperature is essential since
this will enable the product to slowly recrystallize and will not cause impurities to be trapped in
the lattice of aspirin.

The acquired product is then again filtered through suction filtration. The mass of the
product is 2.50 g and the % recovery is 192%.

The melting point range of the crude aspirin is 125C-140C. It still has a lot of impurities
since it has a broad range. The determination of the melting point of a compound can be used
as an evidence for identification since compounds exhibit a definite melting point value. A broad
range signifies that the compound synthesized still exists with impurities.

In differentiating salicylic acid from the synthesized product, the ferric chloride and
potassium permanganate test was used. For the FeCl3 test, both samples yielded a violet liquid
solution, which means that there is a reaction since there was a change in color. Presence of a
violet colored complex means there is phenol in the product. Salicylic acid has a hydroxyl group
which means that the produced colored liquid is acceptable, but the acetylsalicylic acid should
have produced a liquid solution not different from the color of FeCl3 due to the absence of phenol.
This means that the produced acetylsalicylic acid was impure since there was still a presence of
OH bonded to it.

For the KMnO4 test, both the samples produced a brown liquid solution, once again
indicating an impure product. Theoretically, salicylic acid would have given a positive result due
to the presence of a hydroxyl group bonded to it. But due to the erroneous procedures in the
purification process, the acetylsalicylic acid that was synthesized was not pure.
 Acetic anhydride on the other hand produced a positive result when mixed with water
since once reacted with water, it would produce acetic acid which explains the method of the
addition of water after the heating process in the first part of the experiment.

For the differentiation of the synthesized aspirin in the laboratory from the commercially-
available aspirin, an iodine test was done. Upon the addition of iodine with the synthesized aspirin,
a red orange liquid with precipitates was observed. While on the other hand, the commercially-
available aspirin yielded a dark violet colored solution. This is due to the presence of starch in the
product since pharmaceutical companies use starch on tablet medicines in order to give them
their characteristic shapes.

VII. SUMMARY AND CONCLUSION

With the use of the starting materials salicylic acid, phosphoric acid and acetic anhydride,
acetylsalicylic acid was synthesized. After being subjected to heat, the mixture created was
exposed to a cold environment in order to aid the crystallization process. This enabled the
purification of aspirin by dissolving the impurities while aspirin was left in the mixture.

Since fast filtration of the mixture was desired, suction filtration was done in the
experiment. This enabled the separation of the liquid containing the impurities from the solid
part of the mixture containing the aspirin. The yielded product was weighed and was found out
to still contain too many impurities due to the large difference of the mass of the actual product
from the theoretical yield.

Recrystallization was done with the use of ethanol which dissolved the aspirin along with the
other present compounds in the mixture. The addition of cold water in turn enabled the
appearance of aspirin in the mixture, while the impurities were still left dissolved in the liquid.
After submerging the flask in a cold water bath, the mixture was then again filtered using
suction filtration, with the residue serving as the final recrystallized product.

Characterization of the salicylic acid from the synthesized acetylsalicylic acid was done to
determine the purity of the product. Theoretically, salicylic acid contains a hydroxyl group
bonded to it, thus would produce a violet colored complex when reacted with ferric chloride and
a brown colored liquid solution when reacted with potassium permanganate. If the synthesized
acetylsalicylic acid is pure, the mentioned tests would yield negative results, that is, there would
be no change of color.
 The iodine test was done to differentiate the synthesized acetylsalicylic acid from the
commercially-available aspirin. Since iodine reacts with starch, the commercially-available
aspirin produced a dark violet liquid while the other one had negative results.

VIII. REFERENCES

Brown, Lemay and Bursten. 2009. 11th Ed. Chemistry: The Central Science. Prentice Hall.

McMurry, R.S. 2008. 7TH Ed. Organic Chemistry. USA: Prentice Hall, 332-345.
Norman, R. C. and Coxon, J. (1993). Principles of Organic Syntheses. London, UK: Chapman
& Hall.

IX. REMARKS AND RECOMMENDATIONS

The organic synthesis of aspirin provided us the thought of the importance of organic
chemistry in real life through the production of such products that we mostly see and use in our
everyday lives. It gave the glimpse of how really helpful chemistry is and how essential it is for
us to know how these reactions work.

Errors done in the experiment can be prevented through carefully following the instructions
and closely watching differences in the process. Although researchers have observed that
during the recrystallization of acetylsalicylic acid, the temperature should maintained at a fixed
90C wherein the production of pure acetylsalicylic acid is at its optimum. With the use of an
effective heating apparatus, the removal of impurities to produce a pure product is more likely.