Acetylsalicylic Acid (Aspirin) Synthesis

Telow AJV
Sumicad, CJ, Tavanlar, EMMT, Chem 40.1, Institute of Chemistry, University of
the Philippines Los Baos

I.

Introduction

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.
Aspirin, also known as acetylsalicylic acid is as salicylate drug often used
as analgesic to relieve minor aches and pains, as an antipyretic to reduce fever,
and as an anti-inflammatory medication. The history of aspirin and its medical
use can be traced way back in the second millennium BCE. Medicines from
willow and other salicylate-rich plants appear in the Egyptian pharmacology
papyri. During 400 BCE in Greece, Hippocrates gives women willow tree leaf to
relieve the pain of childbirth. He also used salicylic tea to reduce fevers. Willow
bark extract then became known for its effectiveness in reducing fever, pain and
inflammation in the mid- eighteenth century. By nineteenth century, pharmacists
were experimenting with and prescribing a variety of chemicals related to
salicylic acid, an active component of willow extract.
In 1853, chemist Charles Frdric Gerhardt treated acetyl chloride with
sodium salicylate to produce acetylsalicylic acid for the first time; in the second
half of the nineteenth century, other academic chemists established the
compound's chemical structure and devised more efficient methods of synthesis.
In 1897, scientists at the drug and dye firm Bayer began investigating
acetylsalicylic acid as a less-irritating replacement for standard common
salicylate medicines. Aspirin was first isolated by Felix Hoffmann, a chemist in
the German company Bayer. By 1899, Bayer had dubbed this drug Aspirin and
was selling it around the world. The word Aspirin was Bayer's brand name,
rather than the generic name of the drug; however, Bayer's rights to the
trademark were lost or sold in many countries. Aspirin's popularity grew over
the first half of the twentieth century, spurred by its effectiveness In the wake of
Spanish flu pandemic of 1918, and aspirin's profitability led to fierce
competition and the proliferation of aspirin brands and products. Some of the
1918 flu deaths were probably due to Aspirin poisoning.
Aspirin's popularity declined after the development of acetaminophen/
paracetamol in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane
and others discovered the basic mechanism of aspirin's effects, while clinical
trials and other studies from the 1960s to the 1980s established aspirin's
efficacy as an anti-clotting agent that reduces the risk of clotting diseases.
Aspirin sales revived considerably in the last decades of the twentieth century,

and remain strong in the twenty-first with widespread use as a preventive

treatment for heart attacks and strokes.
In the preparation aspirin, salicylic acid is reacted with an excess of
acetic anhydride. A small amount of a strong acid is used as a catalyst which
speeds up the reaction. In this experiment, phosphoric acid will be used as the
catalyst. The excess acetic acid will be quenched with the addition of water. The
aspirin product is not very soluble in water so the aspirin product will
precipitate when water is added. The synthesis reaction of aspirin is shown
below:

II.

Objectives

This laboratory exercise aims to:

by
and

1. to synthesize acetylsalicylic acid from salicylic acid

nucleophilic acyl substitution;
2. to describe and explain the differences in the
properties of acetylsalicylic acid and salicylic acid by
simple chemical tests.

III. Methodology

A. Schematic Diagram
1 gram salicylic acid in 125-mL Erlenmeyer flask
+ 3-mL acetic anhydride
+ 1 drop 85% phosphoric acid
-swirl
- heat in steam bath for 15 mins
+ 2-mL dH2O
+ 20-mL ice cold H2O
-cool to RT
-place in an ice bath
-perform suction filtration

residue

filtrate
-- wash several times
-- transfer crystals to pre-weight watch glass

air dry

weight dry aspirin

calculate % yield

crude aspirin

set aside small quantity for MP determination

transfer the rest to 125-mL Eflask

95% ethanol dropwise

swirl until almost all dissolves

cold dH2O dropwise until almost all crystals appear

cool flask in a cool bath
suction filtration
calculate % recovery

(continuation)

residue

filtrate

wash crystals with small portions of cold H2O

transfer crystals to pre-weight watch glass

air dry

weight dry aspirin

calculate % recovery

transfer aspirin to vial

label

determine the MP of crude and

recrystallized aspirin

Compare

Characterization of Aspirin:

Reaction with KMnO4 :

5 drops dilute, slightly acidic KMnO4 in test tube
+ pinch of the sample

- warm the tube in water bath for 5

mins.
- examine mixture

Reaction with FeCl3 :

pinch of the sample in test tube
+ 3 drops 2.5% aqueous FeCl 3
+ 1-mL dH2O
- examine mixture

Differentiation of the synthesized acetylsalycylic acid from commercially

available aspirin:

pinch of the sample test tube

+ 5 drops H2O and iodine
- examine

B. Set-ups

Figure 11.1. Suction filtration set-up

C.

Chemical Data Sheet

Table 11.1 Chemical data sheet for the synthesis of aspirin

Name and
structure of
the reagents
salicylic acid

Functions in
the exercise
Starting
material

Physical
properties

Hazards

a white
Skin and eyes
powder-like
irritants
substance with
an MP of

Precautions

In case of
contact,
immediately
flush skin with

acetic
anhydride

phosphoric
acid

159C and a
density of
1.44g/cm3

plenty of water

Converts
a colorless
Corrosive and
salicylic acids liquid with a
flammable
hydroxyl group density of 1.08
into an acetyl
g/cm3
group

Keep away
from heat.
Wear gloves,
eye protection
and face
protection

Serves as the
catalyst

a colorless
viscous liquid
with a density
of 1.88 g/cm3
and a boiling
point of 158C

95% ethanol

Used for the

recrystallizatio
n

KMnO4

Differentiating a purple liquid

agent

FeCl3

For the
Brown liquid
characterizatio with a molar
n of the
mass of
synthesized 162.20g/mol, a
aspirin and
boiling point
commercial
of 306 C and
aspirin
a density of
2.9g/mL

IV.

Data

Extremely
corrosive

Avoid direct
contact. Wear
chemical
protective
clothing

a colorless
Skin and eyes
Keep away
liquid with a irritants. Long
from heat.
melting point term use can
Wear gloves,
of 114C and a
result to
eye protection
density of
serious liver
and face
3
789.00kg/m
damage
protection
Highly
In case of
explosive
contact,
when reacted
immediately
with
flush skin with
concentrated plenty of water
sulfuric acid
for at least 15
minutes
Corrosive,
toxic and
acidic

Flush skin with

water in case
of direct
contact

Table 11.2. Description of reagents

SAMPLE

DESCRIPTION

salicylic acid

white, powder-like substance

acetic anhydride

clear liquid with strong odor

phosphoric acid

clear, colorless liquid with strong odor

95% ethanol

clear, colorless liquid with strong odor

KMnO4

purple liquid

FeCl3

brown liquid

Iodine solution

clear liquid

Table 11.3. Preparation of Aspirin

SAMPLE

DESCRIPTION

Salicylic acid + acetic anhydride + salicylic acid was dissolved

85% phosphoric acid
Mixture at room temperature

crystals were formed

Mixture after ice bath

more crystals were formed

Suction Filtration:
residue

fine, white crystals

filtrate

clear liquid with small amounts of crystals

Crude aspirin

fine white crystals

Table 11.4. Recrystallization of Aspirin

DESCRIPTION
Crude aspirin + ethanol

dissolution of most crystals occurred

Mixture during cooling

crystals were formed

Mixture after cooling

more crystals were formed

Suction Filtration:
residue
filtrate

fine, white crystals

clear liquid

Table 11.5. Recovery data of recrystallized aspirin

OBSERVATIONS

Weight of watch glass + filter paper

(g)

1.355

Weight of watch glass + filter paper +

product (g)

2.135

Weight of product (g)

0.780

Theoretical yield

1.300

% yield

60%

% recovery

59%

Table 11. 6. Melting point determination

SAMPLE

MELTING POINT RANGE (C)

Crude aspirin

106-112

Recrystallized aspirin

114-118

Table 11.7. Differentiation of starting material from the product

TEST

SYNTHESIZED ASPIRIN

SALICYLIC ACID

KMnO4

disappearance of violet
color and formation of
brown precipitate

the solution remained purple

FeCl3

the solution remained

brown and not all of the
sample dissolved

the solution became darker shade

of brown and not all of the
sample dissolved

Table 11.8. Differentiation of synthesized acetylsalicylic acid from commerciallyavailable aspirin by iodine test
SAMPLE

OBSERVATIONS

Synthesized
acetylsalicylic acid

all of the sample dissolved and the solution is turbid

Commercially- available all of the sample dissolved and the solution became
aspirin
faint purple

V.

Sample Calculations

1.0g SA ( 1 mol SA/ 138.16 g) ( 1 mol ASA/1 mol SA) ( 180.21g/ 1 mol ASA) =
1.30g

3.00 mL AA ( 1.08g AA/ 1mL)( 1 mol AA/ 102.11g)(1 mol ASA/ 1 mol AA)
(180. 21g/ 1 mol ASA) = 5.72g

% yield = Actual yield/ Theoretical yield X 100%

= 0.78g/ 1.30g X 100% = 60%

% recovery = Recovery yield / Actual yield X 100%

= 0.457g/ 0.78g X 100% = 59%

VI.

Results and Discussion

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 (see Fig. 11.2). Figure 11.3
below shows the balanced chemical reaction of the synthesis of acetylsalicylic
acid.

Figure 11.2. Structure of Acetic Anhydride

Figure 11.3. The balanced chemical reaction of the formation of

aspirin.
Because the reaction is slow in pure acetic anhydride, the catalyst,
commonly strong acids like phosphoric acid was used for the reaction.
According to Le Chateliers principle, the presence of excess acetic anhydride
forces the equilibrium towards the desired product, which in this case is the
aspirin. In addition to this, the catalysts were also used to ensure that side
reactions, which may cause the percentage yield to increase, will be avoided.
The reaction behind the synthesis is nucleophilic acyl substitution.
According to McMurry (2000), nucleophilic acyl substitution happens when the
initially formed intermediate expels one of the substitutes originally bonded to
the carbonyl carbon leading to the formation of a new carbonyl compound. In
this experiment, the specific nucleophilic acyl substitution is esterification. It
occurs when a carboxylic acid in salicylic acid and an alcohol combine in a
reaction to produce an ester.

Figure 11.4. Mechanisms on the formation of aspirin

Phosphoric acid protonates the carbonyl oxygen atom (C=O) of the
anhydride to make it more prone to nucleophilic attacks. It gives the anhydride
a positive charge thus, making it more susceptible to nucleophilic attacks. The
nucleophilic hydroxyl group of salicylic acid attacks the electron deficient acetic

anhydride resulting to a tetrahedral intermediate. The hydroxyl group (-OH)

attached to the electrophilic carbon removed the hydrogen as proton thus
donating the electron to form a double bond (C=O).The loss of the proton
regenerates the phosphoric acid and thus, producing acetylsalicylic acid.
To enhance the synthesis reaction, addition of heat and water after
heating were done. The synthesis of reaction is favored by heating the mixture
because it speeds up the dissolution process of salicylic acid and increases its
solubility as well. Because this specific reaction is an endothermic process,
addition of heat would favor a forward reaction resulting to the formation of
products. Aside from that, nucleophile was completely facilitated by the
addition of water after heating. Water was used in order to provide medium for
further nucleophilic substitution.
The theoretical yield obtained is 1.30 grams after knowing that salicylic
acid is the limiting reagent. The actual yield obtained is 0.78 grams thus, the %
yield is 60% . This results are relatively low because of possible sources of error
such as loss of product in the filter paper because of prolonged air dying,
decomposition to acetic acid in solution so there wasn't a complete conversion
of reagents and insufficient heating.
Upon obtaining the crude aspirin, recrystallization was done. This is
performed to remove the traces of impurities. After cooling to room
temperature and immersing on an ice cold water bath, suction filtration method
was done to separate the filtrate from the residue which contains the
recrystallized products. Suction filtration is the most practical technique to use
when fast filtration of mixture is desired. It employs vacuum which can aid in
the passage of filtrate through the filter paper (Basic Organic Chemistry:
Laboratory Manual, 2012). In addition, since aspirin is an ester, it should not be
recrystallized from hot water because it will allow the crude sample to be
hydrolyzed and yield undesirable products. The % recovery obtained is 59%.
After performing the synthesis of aspirin from salicylic acid, the
verification of the identity and purity of the product through melting point
determination was also performed.
In differentiating salicylic acid from the synthesized product, FeCl 3 test
and KMnO4 test were conducted. For the FeCl 3 test, the positive will give a
change from yellow-brown solution to a violet colored complex. For this test, the
result is positive because of the presence of phenol in it. The oxygen atoms of
the acid group COOH, and of the -OH group on the salicylic acid together can
form a complex with Fe(H2O)6 +3. The test result on aspirin is negative because
iron complex cannot be formed due to the absence of a hydroxyl group attached
to benzene.
For the KMnO4 test, a positive result was obtained from the synthesized
aspirin as seen by the disappearance of violet color and formation of the brown
precipitate. Theoretically, salicylic acid would give a positive result because of
the presence of hydroxyl group (-OH). Recalling the reactions in alcohols,
KMnO4 was used to detect the presence of primary and secondary alcohols.

Since the phenol group is absent in the synthesized aspirin, a negative result
should be obtained.
Another test was conducted to differentiate the synthesized aspirin from
the commercially-available aspirin. For the iodine test, the positive result is the
solution turning blue or violet because of the presence of starch. In this
particular experiment, it is the commercially-available aspirin that has a color
change which is the solution exhibited a faint violet color. Theoretically, this
holds true because pharmaceutical companies add starch to tablet medicines to
give them its characteristic shapes.
Lastly, the melting point determination was conducted. One way of
identifying a substance is through its melting point. The range of the melting
point can give one an idea on the purity of the sample. The theoretical melting
point range of aspirin is 128-137C. In this experiment, the obtained melting
point range of of the crude aspirin is 106- 112C and for the recrystallized
aspirin, it is 114-118C. The result of melting point determination means that
the samples have impurities in it. Narrow difference in the melting point range
of the sample and the theoretical melting point range means that the substance
is pure because of the uniform forces present in the molecules. When the range
is wide, it means that the sample contains impurities. In this exercise, melting
point determination is done. And the results show that it has a wide difference
from the theoretical melting point range of aspirin. Thus it can be inferred from
the results that the sample is not pure.
VII.

Summary and Conclusion

Synthesis of organic compounds involves guidelines and steps that should

be followed. The first one is the establishment of the starting materials which is
in this are the salicylic acid and acetic anhydride together with the phosphoric
acid that served as the catalyst for the reaction. The synthesis of aspirin
involved the acid-catalyzed nucleophilic acyl substitution. The specific
nucleophilic acyl substitution for this experiment is esterification. It happens
when a carboxylic acid from the salicylic acid and an alcohol combine in a
reaction therefore producing an ester.
In this experiment, phosphoric acid was used as a catalyst to hasten the
reaction between the salicylic acid and acetic anhydride. Heat and addition of
water was also done for efficient production of the desired product. The percent
yield obtained for this experiment is 60%. Low %yield can be caused by
insufficient heating and that the product was lost in the filter paper because of
prolonged air drying.
The next step that was done was the recrystallization of the crude sample
to obtain a more purified organic compound. Recrystallization was done by
suction filtration. The last step for this experiment is the verification and
differentiation of the samples. Through the KMnO 4 test, it was verified that the
synthesized product was indeed to be acetylsalicylic acid or most commonly
known as aspirin. Another test that was conducted is the iodine test wherein the
commercially-available aspirin gave the positive result due to the presence of

starch in it. Unfortunately, FeCl3, did not give the theoretical results.

VIII.

References

Aspirin timeline. (2013). Retrieved on October 5, 2013 from

http://www.telegraph.co.uk/health/healthnews/8185164/Aspirin-timeline.html
History of Aspirin. (2013). Retrieved on October 5, 2013 from
http://en.wikipedia.org/wiki/History_of_aspirin
Institute of Chemistry. (2012). Basic Organic Chemistry Laboratory
Manual. University of the Philippines Los Baos College Laguna. 72-75.
Material safety data sheet. (2013). Retrieved on October 6, 2013 from
http://www.inchem.com.ph/productpages/fecl3_msds.pdf
McMurry, John. (2000). Organic Chemistry. 7th Edition USA.
MSDS for potassium permanganate. (2013). Retrieved on October 6, 2013
from http://www.sciencelab.com/msdsId=9927406

Phosphoric acid. (2013) retrieved on October 6, 2013 from

http://www.ccohs.ca/oshanswers/chemicals/chem_profiles/phosphoric.html
Rodriguez, E.B. (1997). Basic Principles of Organic Chemistry. UP Open
University: Diliman Quezon City . 295 336.

IX.

Remarks and Recommendation

The synthesis of organic compounds is indeed very helpful in chemistry

and through this process, one can have a glimpse on how chemical processes
works in real life.
The researcher recommends the use of other tests in order to obtain more
accurate results in the differentiation of the synthesized aspirin from the
commercially-available aspirin.