Synthesis of Aspirin
Isabella Roig
Department of Chemistry, American University, Washington, D.C. 20016
Date of Publication: February 26, 2014
ABSTRACT: The purpose of this experiment was syn-
thesize acetylsalicylic acid from the reaction of salicylic
acid and acetic anhydride. Following the synthesis of
acetylsalicylic acid, commonly known as aspirin, the
crude product was recrystallized and a TLC analysis was
conducted to analysis the purity of the recrystallized and
crude products. The actual yield of 0.546g of acteylsali-
cylic acid from 2.015g of salicylic acid, which was
found to be the limiting reagent of the reaction. This
experiment produced a 20.79% yield and, correlatively,
a 79.21% error. The Rf values from the TLC analysis of
salicylic acid, the crude product, and the recrystallized
product were 0.818, 0.590 and 0.897, and 0.606 and
0.879 respectively. Because there were two spots shown
in the TLC analysis for both the crude product and the
recrystallized product, it was concluded that the crude
and recrystallized product were comprised of both sali-
cylic acid and acetylsalicylic acid.
INTRODUCTION
Acetylsaliclic acid is commonly known as aspi-
rin, the anti-inflammatory pain reliever. Aspirin
as it is now known was first produced one hun-
dred and ten years ago. It is naturally found in
plants such as the willow tree and myrtle as sali-
cylic acid. Ancient Greeks, Romans, and Egyp-
tians used willow bark and myrtle to reduce pain
and inflammation. Salicylic acid is very acidic
and painful to digest. In 1853, Charles Fredric
Gerhardt was the first add acetyl to the salicylic
acid. In 1897, Felix Hoffman took the acetylsali-
cylic acid, purified it, and made it more stable
and easier to digest. In 1899, Berlin trademarked
aspirin. When the first World War took place, the
Allies no longer has access to aspirin. After win-
ning the war, the Allies required the Germans to
release the patent for aspirin. Today, aspirin is
available in more than eighty countries. (1)
Aspirin has two main uses in the body. The first
is being an anti-prostaglandin. Aspirin reduces
levels of prostaglandins, which are chemicals re-
leased in the body because of pain, fever, and in-
flammatory. By decreasing the amount of prosta-
glandins in the body, aspirin reduces fever, pain,
and inflammation. Aspirin also works as a blood-
thinning agent. These two main uses of aspirin
are due to effect of aspirin on the enzyme cy-
clooxygenase, COX. Aspirin inhibits the enzyme
COX, which stops the formation of prostaglan-
dins and therefore stops inflammation. In addi-
tion to hindering the formation prostaglandins,
the inhibition of COX also reduces the ability of
platelets to aggregate. For this reason, increased
bleeding is a common side effect of aspirin and it
is not recommended for pregnant women.(2)
Although the decrease in prostaglandins is very
helpful to stop inflammation, prostaglandins are
also very helpful in the body and necessary. Pros-
taglandins line the stomach and protect the body
from stomach acid. Aspirin depletes the body’s
store of prostaglandins, diminishing the protec-
tive lining on the stomach. This can leads to
stomach ulcers. Prolonged and constant use of
aspirin is very dangerous in this way. (2)
Thin Layer Chromatography, TLC, is a technique
used to separate organic compounds. By separat-
ing compounds, TLC can be used to determine
the purity of a substance. There are two phases:
mobile and stationary phase. The mobile phase
flows through the stationary phase. Through ca-
pillary action, compounds travel with the mobile
phase and separate due to their different polarity
strengths. In this experiment, silica gel plate was
used as a polar stationary phase. The mobile
phase was a 9:1 mixture of ethyl acetate: meth-
ylene chloride, making it predominately polar.
Polar stationary phases better absorb polar com-
pounds. Nonpolar compounds will not travel as
far along the silica plate as polar compounds. The
polarity of a compound is determined by its func-
tional groups. Hydroxyl groups are more polars
than esters. Because acetylsalicylic acid has an
ester groups and salicylic acid has a hydroxyl
group, acetylsalicylic acid will travel farther
along the polar silica gel plate. A UV light is
used to see the distances the spots of the com-
pounds traveled on the plate. TLC results are ex-
pressed in Rf values. Rf is the distance the solute
traveled divided by the distance the solvent
front.(3)
In this experiment, acetyl anhydride and salicylic
acid are reacted together while in the presence of
phosphoric acid to synthesize acetylsalicylic acid.
The mechanism of reaction is displayed in Figure
1 below. Following the synthesis of aspirin, it
will be recrystallization as a method of purifica-
tion. To further test the purification of the recrys-
tallization, a TLC analysis will be conducted to
examine the crude product, the recrystallized
product, and salicylic acid.
Figure 1: Reaction of Aspirin
MATERIALS AND METHODS
Lab coat
Goggles
Gloves
50 mL Erlenmeyer Flask
125 mL Erlenmeyer Flask
400 mL Beaker
250 mL Hot Water Bath
250 mL Ice Water Bath
Acetic Anhydride
Salicylic Acid
85% Phosphoric Acid
Distilled Water
10 mL Ethanol
18 mL Ethyl Acetate
2 mL Methylene Chloride
2 Watch Glasses
Stirring Rod
Vacuum Filter Appartatus
1 110-mm Filter Paper
2 pieces of round Filter Paper
Silica Gel Coated TLC Plate
Spotting Pipettes
UV Light
Part 1: Synthesize Aspirin
2.0g of salicylic acid is measured into a 50mL
Erlenmeyer flask. 5.0mL of acetic anhydride and
5 drops of 85% phosphoric acid solution were
added to the flask. The flask is swirled to rinse
any bits of solid that may be on the inner walls of
the flask. The 50mL flask is partially submerged
in a 70-80°C hot water bath. The mixture is heat-
ed for 15 minutes, or until the mixture stopped
releasing vapors. The mixture is also occasionally
stirred while heating. After 10 minutes in the wa-
ter bath, 2mL of distilled water is added to the
mixture. After 15 minutes of heating in the hot
water bath, the mixture is removed from the bath
and 20mL of water is added to the flask. The
mixture is then cool to near room temperature
and transferred to an ice bath for five minutes.
Crystals of apririn formed while the mixture
cooled. Filter paper was weighed and the mass
was recorded to the nerest 0.001g. Vacuum filter-
ation was set up and the mixture was suctioned
with the vacuum. When the most of the liquid
had been drawn through the funnel, the suction
was turned off and the crystals were washed with
5mL of cold, distilled water. After 15 seconds,
the suction was turned back on and the crystals
were rinsed twice more with 5mL of cold, dis-
tilled water. The filter paper and product were
transferred to a tared watch glass. The mass of
the product on the filter paper was recorded to the
nearest 0.001g.
Part 2: Purification of Aspirin
0.5g of the crude crystals were set aside for TLC RESULTS
analysis. The remaining crude aspirin was added Table 1: Synthesis of Aspirin
to a 125mL Erlenmeyer flask. 10mL of hot sol-
vent (ethanol/water) was added to the crude aspi- Mass of salicylic acid (g) 2.015
rin in a warm water bath until all the crystals Volume of acetic anhydride (mL) 5
were dissolved. The mixture was not boiled. The Mass of acetic anhydride used (g) 5.4
flask was covered with a watch glass, removed
Mass of filter paper (g) 0.132
from the warm water bath, and left to cool slow-
ly. When the solution reached room temperature, Mass of aspirin and filter paper (g) 1.35
it was placed in an ice bath to complete cyrstali- Mass of aspirin synthesized (g) 0.546
zation. The crystals were vacuum filtered after 10 This table shows the data that was collected in
minutes in the ice bath. The crystals were rinsed this lab. The mass of the aspirin and the filter pa-
with two 3mL portions of ice cold deionized wa- per is not equal to the mass of synthesized aspirin
ter and one 2mL portion of ice cold ethanol. The plus the mass of the filter paper. This indicates
crystals were place on a tared watch glass and the that some aspirin was lost, and not a full yield
mass was recorded. was collected during the experiment. This is sup-
ported by the large percent error calculated be-
Part 3: TLC Analysis low.
A 400-mL beaker and a watch glass were used as Table 2: TLC Analysis
the developing chamber. A piece of 110-mm fil-
ter paper was placed at the bottom of the chamber Distance
to saturated the chamber with solvent vapors. Solvent Distance Spot Rf
Compound
20mL of a 9:1 ethyl acetate and methylene chlo- Traveled Traveled (cm) Value
ride mixture was added to the 400mL beaker. In (cm)
three separate beakers, 3mg of salicylic acid, 3mg 0.589
Crude Prod-
of the crude product, and 3mg of the recrystal- 3.9 2.3 & 3.5 &
uct
lized product were dissolved in 5-6 drops of the 0.897
TLC solvent. A horizontal line was lightly Salicylic Acid 3.3 2.7 0.818
marked using a pencil on the silica gel coated
TLC plate approximately ½ inch from the bot- 0.606
Recrystalized
tom. Three even spaced hashes were marked to 3.3 2.0 & 2.9 &
Product
be the origin points for the spotted compounds. A 0.878
different spotting pipette was used to spot the The crude and recurstalized products both had
TLC plate with the salicylic acid, the crude prod- two spots on the TLC Plate. This indicates that
uct, and the recrystallized product on the three neither were pure and there was more than one
hashes. The pipette lightly touched the TLC plate substance in each
at the hash mark to transfer some of the liquid to
Calculations:
the plate. The spots were no larger than about 1/8
of an inch. The plate was placed in the develop- Equation 1: Determining the Limiting Reagent:
ing chamber and the watch glass was place on top Molecular Weight of Salicylic Acid:138.12 g/mol
of the beaker. The plate was allowed to develop (2.015g Salicylic Acid) x (1 mol/ 138.12g)
until the solvent from was approximately ½ inch =0.01458 mol
from the top. The plate was removed and the sol-
vent front was immediately marked. The plate Molecular Weight of Acetic Anhydride:
was left to dry before it was examined under the 102.09g/mol
UV light. The spots were circled as they were (5.4g Acetic Anhydride) x (1 mol/ 102.09g)
seen and their centers were marked. The distance =0.05289 mol
the solvent traveled and the distance each spot
traveled were recorded. Salicylic Acid is the limiting reagent.

Equation 2: Theoretical Yield:
(0.01458 mol Salicylic Acid) x (1 mol Acetylsal-
icylic Acid/ 1 mol Salicylic Acid) x (180.16g/ 1
mol Acetylsalicylic Acid)= 2.6267g Acetylsali-
cylic Acid
Equation 3: Percent Yield:
Perecent Yield =(Actual Yield/ Theoretical
Yield) x 100
(0.546g/ 2.6267g) x 100 = 20.79%
Equation 4: Percent Error:
Percent Error: ((Actual Yield- Theoretical Yield)/
Theoretical Yield) x 100
(( 0.546-2.6267)/ 2.6267) x 100= 79.21%
Equation 5: Rf Value:
Rf Value = (Distance Solute Traveled/ Distance
Solvent Traveled)
Rf (Crude Product, Spot 1)= (2.3cm/ 3.9cm)=
0.590
Rf (Crude Product, Spot 2)= (3.5cm/ 3.9cm)=
0.897
Rf (Salicylic Acid)= (2.7cm/ 3.3cm)= 0.818
Rf (Recrystallized Product, Spot 1)= (2.0cm/
3.3cm)= 0.606
Rf (Recrystallized Product, Spot 2)= (2.9cm/
3.3cm)= 0.879
Table 1 displays the raw data from this experi-
ment. This experiment began with 2.015g of sali-
cylic acid and produced a yield of 0.546g of ace-
tylsalicylic acid. Using Equation 1, it was deter-
mined that salicylic acid was the limiting reagent.
Equation 3 determined that the theoretical yield
of 2.6267g of acetylsalicylic acid. Equation 4
calculated the percent yield was 20.79%. The
percent error was 79.21%. Table 2 presents the
data of the TLC analysis part of the experiment.
The Rf values of crude product, salicylic acid,
and recrystallized product were 0.590 and 0.897,
0.818, and 0.606 and 0.879 respectively.
DISCUSSION
Esterification is the reaction of an alcohol or
phenol and a carboxyl group in the presence of an
acidic catalyst to form a carboxylate ester. The
particular esterification process in this experi-
ment of forming acetylsalicylic acid from salicyl-
ic acid and acetyl anhydride is also an equilibri-
um process. (4) Le Chatelier’s principle, which is
also known as the equilibrium law, can be used to
predict the effect of a change in conditions on an
equilibrium process. Temperature, concentration,
volume, and pressure are all changes in condi-
tion that would cause the equilibrium of the reac-
tion to shift. As the reaction proceeds, the reac-
tants are depleting while the concentration of the
products is increasing. It is also stated in the
principle that if more of the product were added
to the reaction, this would cause the equilibrium
to be shift and the creation of more of the reac-
tants. Le Chatelier’s principle can be used to fa-
vor the creation of the product of the reaction,
aspirin, due to the equilibrium shift caused by the
excess acetic anhydride. The principle can also
be used to favor the reactants if the necessary
conditions were adjusted to convert aspirin to sal-
icylic acid and acetic anhydride. (5)
Salicylic acid contains two acidic functional
groups: a phenol group and a carboxylic acid.
The phenol group of the molecule is very acidic
and causing harsh stomach irritation, which
therefore makes it difficult to digest. To ease
stomach digestion of aspirin, the strength of the
acid is reduced by the formation of an ester from
the phenol and carboxylic acid.(6)
Figure 2: Mechanism of Reaction for the Synthe-
sis of Aspirin

Figure 2 details the reaction occurring between
salicylic acid, phosphoric acid, and acetic anhy-
dride. When the phosphoric acid, acting as a cata-
lyst, attacks the carbon oxygen bond (C=O) of
the acetic anhydride, it gives it a positive charge.
This results in the acetic anhydride being more
prone to nucleophilic attacks. Salicylic acid is the
nucleophile of this reaction. The partial positive
carbon on the acetic anhydride transferred elec-
trons to the oxygen on the phenol group of sali-
cylic acid after it was attacked. This results in the
formation of a tetrahedral intermediate. The –OH
group, which has an attached electrophilic car-
bon, forms a double bond between the carbon and
oxygen (C=O) by pronating the hydrogen and
donating an electron. This loss of a proton re-
forms phosphoric acid and produces acetylsali-
cylic acid.
Because the synthesis of aspirin is a slow reac-
tion, a catalyst is needed. Phosphoric acid acts as
a catalyst to speed up the reaction between Sali-
cylic acid and acetic anhydride. Phosphoric acid
is present in the beginning and end of the reac-
tion. Due to its water solubility, it is easily re-
moved by washing the crystals with cold distilled
water. The phosphoric acid was used to aid the
transfers of hydrogens and electrons. At the end
of the reaction, it was recreated in its original
state.
The reaction was heat at 70-80 degrees Celsius to
speed up the reaction of the synthesis. The heat-
ing caused the salicylic acid to dissolve more
quickly as well as increase in solubility. This is a
endothermic synthetisis reaction. Therefore the
increase in temperature causes the reaction ot
move forwrad, favoring the formation of prod-
ucts.. (6)After heating the mixture for 10-15
minutes, water was added to the crude product to
purify the crystals. The addition of water sepa-
rates the crystals from the very water soluble ace-
tic acid. recrystallize the product. The water was
added after heating the mixture because the aspi-
rin would not have formed if the acetic anhydride
had already reacted with water. Water also aided
in nucleophilic substitution at this point in the
recrystallization. The following figure details the
reaction of water and acetic anhydride.
Figure 3: The Reaction Mechanism of Water and
Byproducts
The crude aspirin is dissolved in a mixture of hot
water and ethanol. Water has a polarity of 9. Eth-
anol has a polarity of 5.2. (7) Of the two solvents,
ethanol is the less polar one. Aspirin has a solu-
bility of 10mg/mL in water and a solubility of
50mg/mL in ethanol. Like dissolves like, there-
fore less polar solvents dissolve less polar so-
lutes. Therefore water and ethanol are great sol-
vents to help purify aspirin. The crude aspirin
may not have been clean from the earlier recrys-
tallization due to its contact and exposed with the
environment.
Pure aspirin was not made in this experiment.
The Rf values of crude product, salicylic acid,
and recrystallized product were 0.590 and 0.897,
0.818, and 0.606 and 0.879 respectively. Because
the crude and recrystallized product showed two
spots on the TLC plate, it can be concluded that
the crude and recrystallized product were com-
posed of both acetylsalicylic acid and salicylic
acid. The spots of the crude and recrystallized
product TLC analysis correlate to be either sali-
cylic acid or acetylsalicylic acid.
Because the silica was a polar stationary phase, it
better absorbs polar compounds. Nonpolar com-
pounds are not as absorbed as polar compounds
and therefore more freely along the solvent front,
which is polar. Salicylic acid has a hydroxyl
functional group. Acetylsalicylic acid has an ester
functional group and has a larger mass than sali-
cylic acid. Esthers are not as polar as hydroxyl
groups are more polar than esters. Therefore, sal-
icylic acid was more to the silica than the ace-
tylsalicylic acid. This is reflected in the Rf value
of 0.818. The acetylsalicylic acid traveled further
along the TLC plate than the salicylic acid. From
this conclusion, it can be determine that the spot
with Rf values of 0.897 in the crude product and
0.879 in the recrystallized product were acetylsal-
icylic acid.
The experiment yielded 0.546g of synthesized
aspirin. The theoretical yield for this experiment
was 2.6267g. As seen in the results section by use
of Equations 3 and 4, the percent yield was
20.79% and the percent error was 79.21%. Be-
cause the synthesis of aspirin is an equilibrium
process, t is difficult to obtain 100% yield of be-
cause a large concentration of the products can
cause the reaction to reverse and create the reac-
tants. In addition to this reason, a few errors
could have contributed to the low percent yield of
this experiment. The percent yield is relatively
low because of possible sources of error. Pro-
longed exposure to the environment and atmos-
pheric air that may have caused air drying. Prod-
uct could have also been lost while using vacuum
filtration. Product may have slipped between the
filter top apparatus and the filter paper. Inade-
quate heating time or high enough temperature
may have not allowed for a complete dissolution,
resulting in a smaller product yield.
CONCLUSION
This experiment yielded 0.546g of acetylsalicylic
acid. The theoretical yield of this experiment was
2.6267g, given that 2.015g of the limiting rea-
gent, salicylic acid, was used. Respectively, the
percent yield and percent was 20.79% and
79.21%. As noted by the small percent yield,
much of the product was lost or not successfully
synthesized to aspirin. The Rf values of crude
product, salicylic acid, and recrystallized product
were 0.590 and 0.897, 0.818, and 0.606 and
0.879 respectively. The solvent used as a mobile
phase for the TLC analysis was a mixture of ethyl
acete and methylene chloride, making it predom-
inately polar. Because the salicylic acid is polar,
along with the mobile phase and stationary silica
gel phase, it had a lower Rf value than the acetyl-
salicylic acid as it was absorbed more to the
plate. Salicylic acid displayed an Rf value of
0.818, while the two higher spots of the crude
and recrystlization product that are presumed to
be acteysalicylic acid displayed respective Rf
values of 0.897 and 0.879. To prevent further er-
ror, the recrystallized product needs to be better
purified. To do so the experiment should be more
closely and entirely conducted under the fume
hood to prevent and decrease exposure to atmos-
pheric air. Also a more temperature controlled
hot water bath could also be helpful in better re-
crystallization, as well as a bit more distilled wa-
ter to aid in the dissolution of acetic anhydride
from the crystals.
REFERENCES
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Preventive Medicine, 2010.
http://www.aspree.org/AUS/aspree-
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cessed Feb 22, 2014)
2. How Aspirin Works; ASPREE: Mansh
University, Department of Epidemiology
and Preventive Medicine, 2010.
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content/aspirin/how-aspirin-works.aspx
(accessed Feb 22, 2014)
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and Microscale Organic Experiments, 6th
ed.; Cengage Learning: Belmont, 2011
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Feb 21, 2014)
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Reaction Rate. Chemguide, Oct. 2013,
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http://www.chemguide.co.uk/physical/bas
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Feb 21, 2014).
The author would like to acknowledge the Americam
University Chemistry Department as well as Dr.
Dehghan and TA, Karlena Brown and the students
who participated in the experiment. Acknowlegement
is also extended to those mentioned in the References
section of this paper.
This assignment is my own work and I have cited
all material used in its preparation. This assign-
ment has not previously been submitted at any
other time or any other course. I have not copied
in part or whole the work of other students or
person.
SIGNATURE____________________________
DATE__________________________________

ACKNOWLEDGMENTS
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