The Synthesis and Analysis of Aspirin
Mariam El-Magbri
Department of Chemistry, American University, Washington, D.C. 20016
Date of Publication: February 26, 2014
ABSTRACT: Acetylsalicylic acid commonly
known as aspirin is the most widely used drug in
the world today. Its analgesic, antipyretic, and
anti-inflammatory properties make it a powerful
and effective drug to relive symptoms of pain,
fever, and inflammation. The purpose of this ex-
periment was to synthesize aspirin by reacting
salicylic acid and acetic anhydride in the pres-
ence of phosphoric acid to form acetylsalicylic
acid. After synthesis, the sample of acetylsalicyl-
ic acid was purified by recrystallization and TLC
analysis was utilized to check the purity of the
sample. The actual yield of aspirin synthesized
was 0.546 grams and the theoretical yield was
2.628 grams, thus the percent yield was 20.77%
resulting in a percent error of 79.22%. The Rf
values of crude product, salicylic acid, and re-
crystallized product were 0.590 and 0.897, 0.818,
and 0.606 and 0.879 respectively. Due to these Rf
values, it was brought to the conclusion that the
crude and recrystallized aspirin were composed
of both salicylic acid and acetylsalicylic acid.
INTRODUCTION
Aspirin, chemically known as acetylsalicylic ac-
id, is the most commonly used anti-inflammatory
drug. It is effective in relieving symptoms of pain
(analgesic) due to headaches, injury, or arthritis,
treating fever (antipyretic) and inflammation, and
preventing blood clots (1). It was extracted by the
Native Americans from willow and poplar tree
bark about 2500 years ago. Native Americans
used willow bark in teas to reduce fever. In 1763,
Reverend Edward isolated and identified one of
the compounds used to synthesize aspirin, which
came to be known as salicylic acid. Large quanti-
ties of salicylic acid became available; however,
it caused severe stomach irritation. In 1893,
German chemist Felix Hoffman synthesized an
ester derivative of salicylic acid, acetylsalicylic
acid (“aspirin”). The acetyl group cloaks the
acidity when ingested. The drug then passes
through the small intestine where it gets convert-
ed back to salicylic acid, and enters the blood-
stream. Although, weaker than salicylic acid, as-
pirin had medicinal properties without the bitter
taste and harsh stomach irritation. The company
Bayer patented aspirin in 1899, which has made
aspirin one of the most widely used and commer-
cially available drugs today (2).
Aspirin is a nonsteroidal anti-inflammatory drug
(NSAID) which works to reduce levels of prosta-
glandins, chemicals released due to inflamma-
tion, pain, and fever. Prostaglandins are located
on receptors of different cells types, thus having
multiple effects. Cyclooxygenase is the enzyme
that makes prostaglandins. NSAIDs inhibit the
enzyme reducing the levels of prostaglandins, in
turn reducing inflammation, fever, and pain. As-
pirin is not only anti-inflammatory, but also anal-
gesic and antipyretic. Prostaglandins carry out
fever and pain by activating the hypothalamus,
the portion of the brain that controls autonomic
and endocrinal functions. Inhibiting prostaglan-
dins suppresses fever and pain by stopping nerve
signals that are sent to the brain. Suppression of
prostaglandins also desensitizes the function of
platelets and the ability of blood clots, thus aspi-
rin’s antithrombotic effects have been approved
to prevent heart attacks and strokes (2).
Despite the medicinal and wonderful properties
of aspirin, negative effects have been associated
with this drug. Symptoms associated with aspirin
include nausea, vomiting, rashes, swelling, and
hives. Aspirin can still cause stomach irritation In this experiment, aspirin will be synthesized by
resulting in the risk of internal bleeding and ul- reacting acetic anhydride with salicylic acid in
cers. Aspirin has also been known to interfere the presence of phosphoric acid. The reaction
with platelet functioning and may cause Reyes equation is displayed below. After synthesis, the
syndrome in children (1). sample will be purified by recrystallization meth-
ods. The purity of the sample will then be ana-
Thin Layer Chromatography (TLC) is a tech- lyzed using TLC. The results section will present
nique used in organic chemistry to separate a all the numerical data necessary for this experi-
mixture of organic compounds. TLC is also used ment (synthesis of aspirin masses, theoretical
to identify and determine the purity of a com- yield, percent yield and error, and TLC analysis).
pound. Through capillary action, compounds can After synthesis and analysis, it will be deter-
separate due to their different affinities for the mined if the crude and recrystallized samples
mobile and stationary phases. The stationary were composed solely of either salicylic acid,
phase in TLC is the adsorbent, which is coated on acetylsalicylic acid, or a combination of both (3).
a sheet of metal, plastic or glass. It is usually sili-
ca or alumina; however, in this experiment silica Figure 1: Reaction of Aspirin (Snelling, 2013)
was used. The mobile phase is the solvent which
slowly rises due to capillary action and polarity.
In this experiment the mobile phase was the 18:2
solution of ethyl acetate: methylene chloride,
which is slightly polar. Different compounds
travel at different rates and distance in respect to
the solvent front. Polar stationary phases absorb
polar compounds, thus silica being a polar sta-
tionary phase will absorb polar compounds. Non- MATERIALS AND METHODS
polar compounds will remain free and move with Goggles
respect to the solvent front. The polarity of a
compound is determined by its functional groups Gloves
and masses. Salicylic acid is more polar than as-
pirin. Acetylsalicylic acid has ester and acetyl Lab coat
functional groups and has a larger mass than sali- Salicylic Acid
cylic acid. Salicylic acid has a hydroxyl function-
al group. Hydroxyl groups are more polar than 50 mL Erlenmeyer Flask
acetyl groups, thus salicylic acid will absorb to
Acetic Anhydride
the silica more willingly than the acetylsalicylic
acid due to hydrogen bonding. Furthermore, the 85% Phosphoric Acid
acetylsalicylic acid will be in a free state and
travel further because the ester and acetyl func- 250 mL hot water bath
tional groups no longer have hydrogen bonds that
bond to the polar silica plate. If a sample is com- Stirring rod
posed of a mixture of compounds, they will sepa- Distilled Water
rate into a series of sports along the TLC plate. If
a sample is pure, only one spot will be displayed. 250 mL ice bath
The crude aspirin might have two different spots
because it is not entirely pure. UV light is used to Vacuum filter apparatus
visualize the compounds on the plate. TLC re-
1 110-mm Filter paper
sults are expressed in Rf values. Rf is the distance
traveled by the sample over the distance traveled 2 pieces of round filter paper
by the solvent front (3).
2 Watch glasses
125 mL Erlenmeyer Flask
10 mL Ethanol
400 mL beaker
Silica gel coated TLC plate
Spotting pipettes
18 mL Ethyl acetate
2 mL methylene chloride
Ruler
UV light
Part 1: Synthesize Aspirin
Goggles, lab coats, and gloves were obtained for
protection and used throughout the entire exper-
iment. The reaction described below was con-
ducted under a fume hood. 2.0 grams of salicylic
acid was placed into a 50mL Erlenmeyer flask
along with 5.0 mL of acetic anhydride and 5
drops of 85% phosphoric acid solution. The mix-
ture was handled with care and then swirled to
rinse off any pieces of solid. A 70-80°C hot water
bath was prepared using a 250 mL beaker. The
mixture previously prepared was kept in its flask
and submerged in the water bath. Stirring occa-
sionally, the mixture was heated for 15 minutes,
until it started to release vapors. 2 mL of distilled
water was added 10 minutes into the heating pro-
cess. Once the reaction reached completion and
no vapors appeared, it was removed from the hot
plate and 20 mL of distilled water was added.
The mixture was then cooled to room tempera-
ture and then transferred into an ice bath for five
minutes. Crystals of aspirin started to form as the
mixture cooled. Once the mixture cooled, a vacu-
um filtration was set up. Filter paper was massed
and recorded to the nearest 0.001 g before the
solid was filtered. The mixture was then filtered
with vacuum suction. After most of the liquid
was drawn through the funnel, suction was turned
off, and the crystals were washed with 5mL of
cold, distilled water. After about 15 seconds, suc-
tion was turned back on and the crystals were
washed with cold, distilled water two more times
in the same procedure. After filtration, the dried
recrystallized product along with the filter paper
was massed to 0.001g and recorded in the data
table. The mass of the dry aspirin sample was
calculated and recorded in the data table (3).
Part 2: Purification of Aspirin
1 g of crude crystals was set aside for TLC analy-
sis in Part 3. The mass of the remaining crude
was measured. The remaining crude was added to
a 125 mL Erlenmeyer flask. Approximately 10
mL of hot solvent (ethanol/water) was added to
the crude aspirin, which was then placed into a
warm water bath until all crystals dissolved.
Once the crystals dissolved, the mixture was tak-
en out, covered with a watch glass and cooled
slowly. When the solution reached room tem-
perature, it was placed into an ice bath to com-
plete the crystallization process. After about ten
minutes in the ice bath, vacuum filtration was
used again to filter the crystals. The crystals were
rinsed with two 3mL portions of ice cold deion-
ized water and one 2 mL portion of ice cold etha-
nol. After rinsing, the crystals were placed onto a
tared watch glass (3).
Part 3: TLC Analysis
A developing chamber was prepared using a 400
mL beaker and watch glass. A piece of 110-mm
filter paper with the bottom trimmed straight
across was placed into the chamber in order to
saturate the chamber with solvent vapors. 18 mL
of ethyl acetate and 2 mL of methylene chloride
were measured out and placed in to the 400 mL
beaker and covered with the watch glass. Before
introducing the TLC plate, the solvent traveled
all the way to the top of the filter paper. In three
separate small beakers, about 3mg each of sali-
cylic acid, crude product, and recrystallized
product was dissolved by placing 5-6 drops of
TLC solvent in each beaker. The TLC plate was
prepared by marking ½ inch from the bottom and
marking 3 hashes evenly spaced for each of the
spotted compounds. The TLC plate was spotted
(no more than 1/8 in diameter) with the salicylic
acid, crude product, and recrystallized product at
each hash mark making sure a different spotting
pipette was used for each compound. Once the
TLC plate was prepared, it was placed into the
developing chamber and the watch glass was re-
placed on top. When the solvent front stopped
moving (approximately ½ inch from the top), the Product 2.9 cm 0.879
plate was removed and the solvent front was im-
mediately marked. It then was dried and exam- Calculations:
ined under a UV light. Spots that were seen were
Equation 1: Mass of acetic anhydride used
circled and measured using the Rf calculation.
The TLC solvent was discarded in the appropri- =Volume (mL)xDensity(g/mL)
ate container and all materials were washed and
placed back in their appropriate location (3). Mass of acetic anhydride

RESULTS =(5.00mL)(1.08g/mL)=5.40g
Table 1: Synthesis of Aspirin Equation 2: Mass of aspirin synthesized
Mass of Salicylic Acid 2.015 g =(mass aspirin & filter paper)-(mass filter paper)
Used (g)
=(0.678g)-(0.132g)=0.546g
Volume of Acetic An- 5.00 mL
hydride used (mL) Equation 3: Limiting Reagent

Mass of Acetic 5.40 g 1  mol  salicylic  acid

2.015g  Salicylic  Acid x
Anhydride used 138.12g
(1.08g/mL)
=0.01459 mol
Mass of Aspirin and 0.678 g
!  !"#  !"#$%"  !"#$%&'%(
filter paper (g) 5.40  g  Acetic  Anhydride x !"#.!"  !

Mass of filter paper (g) 0.132 g =0.05289 mol

*Salicylic Acid is the limiting reagent*
Mass of aspirin synthe- 0.546 g
sized (g) Equation 4: Theoretical Yield
Theoretical yield of 2.628 g 1  mol    acetyl  salicylic  acid
aspirin moles  of  Salicylic  Acid x
1  mol  salicylic  acid
Percent Yield 20.77% 180.16  g
𝑥
1  mol  acetyl  salicylic  acid
Percent Error 79.22%
1  mol    acetyl  salicylic  acid
Table 2: TLC Analysis =  0.01459  mol  Salicylic  Acid x
1  mol  salicylic  acid

Compound Distance Distance Rf !"#.!"  !

𝑥 !  !"#  !"#$%&  !"#$%&#$%  !"#$
=2.628 g acetyl salicyl-
of Compound
Traveled ic acid
Solvent (cm)
(cm) Equation 5: Percent Yield

Crude 3.9 cm 2.3 cm & 0.590 actual  yield

Percent  Yield:   x  100
3.5 cm & theoretical  yield
Product 0.897 !.!"#$
Percent  Yield:   !.!"#$
x  100 = 20.77%
Salicylic Acid 3.3 cm 2.7 cm 0.818

Recrystallized 3.3 cm 2.0 cm & 0.606

&
Equation 6: Percent Error shift towards the desired product, aspirin. Le
Chatelier’s principle also favors the reactants be-
|!"#$!%  !"#$%!!"#$%#!&'()  !"#$%|
Percent Error: !"#$%#!&'()  !"#$%
x  100 cause aspirin can be converted back to salicylic
acid and acetic anhydride and once the changes
|  !.!"#  !  !!.!"#  !  | are adjusted, a new equilibrium will be estab-
Percent Error: x  100= 79.22%
!.!"#  ! lished (3).
Equation 7: Rf Salicylic acid contains two acidic functional
!"#$%&'(  !"#$%&  !"#$%&%'  (!") groups; a phenol group and a carboxylic acid.
Rf= !"#$%&'(  !"  !"#$%&'  !"#$%  (!") The phenol group on the salicylic acid causes
stomach irritation. An ester is formed from the
!.!  !"
Rf (Crude product, spot 1)= =0.590 cm phenol group and carboxylic acid on the acetic
!.!  !"
acid. It is desirable to do away with one of these
!.!  !" groups because the acids on the molecules are
Rf (Crude product, spot 2)= !.!  !"
=0.897 cm
what cause irritation. By replacing one of the acid
!.!  !" groups, the acid strength is reduced making it
Rf (Salicylic Acid)= !.!  !"
=0.818 cm easier to digest (4).
Rf (Recrystallized product, spot 1)= Figure 2: Synthesis of Aspirin Mechanism
!.!  !"
!.!  !"
=0.606 cm

Rf (Recrystallized product, spot 2)=

!.!  !"
!.!  !"
=0.879 cm

Table 1 displays all the raw and calculated data

for the synthesis of aspirin. Salicylic acid was the
limiting reagent and acetic anhydride was in ex-
cess. The actual yield of aspirin synthesized was
0.546 grams and the theoretical yield was 2.628
grams, thus the percent yield was 20.77% result-
ing in a percent error of 79.22%. Table 2 dis-
plays all data for TLC analysis. 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 process of forming a carbox-
ylate ester by reacting a carboxyl group with a
hydroxyl group or phenol group. The formation
of acetylsalicylic acid is an esterification reaction
as well as an equilibrium process. Le Chatelier’s
principle is also known as the equilibrium law
and allows one to determine the effects on equi-
librium due to pressure, temperature, and concen-
tration. As the reactants are used, the concentra-
tion of the reactions decreases and the concentra-
tion of the products increases. Le Chatelier’s
principle is used to favor products, because ex-
cess acetic anhydride forces the equilibrium to

Above is the reaction occurring between salicylic
acid, phosphoric acid, and acetic anhydride.
Phosphoric acid attacks the carbon oxygen bond
(C=O) of the acetic anhydride giving it a positive
charge, thus acetic anhydride is more prone to
nucleophilic attacks. The nucleophile in the reac-
tion is salicylic acid. It was formed when the ox-
ygen on the phenol group of salicylic acid at-
tacked the partial positive charge of a carbon
from acetic anhydride, transferring electrons to
oxygen. Salicylic acid then attacks the acetic an-
hydride because of its positive charge. The oxy-
gen from the phenol group now has a positive
charge and the carbonyl groups withhold a nega-
tive charge. A tetrahedral intermediate is then
formed. The electrophilic carbon is attached to
the –OH group. The –OH group protonates the
hydrogen and donates an electron to form a dou-
ble bond between carbon and oxygen (C=O). The
phosphoric acid is then reformed again as it gains
the loss of the proton. Acetylsalicylic acid is thus
formed (4).
In pure acetic anhydride, the synthesis of aspirin
is slow, so a catalyst (phosphoric acid) was used
to hasten the reaction. Phosphoric acid is present
in the beginning and end of the reaction. Since it
is water soluble it is easily removed by washing
the crystals with cold distilled water. The phos-
phoric acid also ensured that side reactions that
could take place and increase the percent yield
were avoided (4).
The salicylic acid and acetic anhydride mixture
was heated at 70-80 degrees Celsius to increase
solubility and collision of particles, thus speeding
up the dissolving process of salicylic acid. The
synthesis of aspirin is in endothermic reaction,
and by adding heat it will push the reaction for-
ward to favor formation of the products. After
heating the mixture for 10-15 minutes, water was
added to recrystallize the product. Acetic acid is
very soluble in water, thus it can be easily sepa-
rated from aspirin since it is not very soluble in
water. Aside from the addition of water to recrys-
tallize the product, the addition of water pro-
motes nucleophilic substitution (4).
In the experiment the crude aspirin is dissolved in
a mixture of hot water and ethanol. Aspirin has a
solubility of 10mg/mL in water and a solubility
of 50mg/mL in ethanol. Ethanol has a polarity of
5.2 and water has a polarity of 9, making ethanol
a less polar solvent, thus substances like aspirin
with low polarity dissolves in like less polar sol-
vents. Additionally, aspirin should not be recrys-
tallized solely from hot water because it yields
impurities and allows the crude to get hydro-
lyzed. Furthermore, aspirin should be recrystal-
lized in hot ethanol to dissolve impurities and
obtain a purified product. The crude aspirin was
not clean from recrystallization because it was
exposed to the environment (5).
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. It can be
concluded that the crude and recrystallized prod-
uct were composed of both acetylsalicylic acid
and salicylic acid. Since the crude and recrystal-
lized product were not pure, two spots appeared
one correlating with salicylic acid and the other
correlating with acetylsalicylic acid. Polar sta-
tionary phases absorb polar compounds, thus sili-
ca being a polar stationary phase will absorb po-
lar compounds. Nonpolar compounds will remain
free and move with respect to the solvent front,
which is slightly polar. Acetylsalicylic acid has
ester and acetyl functional groups and has a larg-
er mass than salicylic acid. Salicylic acid has a
hydroxyl functional group. Hydroxyl groups are
more polar than acetyl groups, thus salicylic acid
will absorb to the silica more willingly as dis-
played by an Rf value of 0.818 due to hydrogen
bonding. The acetylsalicylic acid traveled further
as displayed by Rf values of 0.897 in the crude
product and 0.879 in the recrystallized product
because the ester and acetyl functional groups no
longer have hydrogen bonds that bond to the po-
lar silica plate.
The actual yield of aspirin synthesized was 0.546
grams and the theoretical yield was 2.628 grams,
thus the percent yield was 20.77% resulting in a
percent error of 79.22%. It is difficult to obtain a
percent yield of 100% because products can react
to produce the reactants. The percent yield is
relatively low because of possible sources of er-
ror. One possible source of error could result
from loss of product due to exposure to atmos-
pheric air causing prolonged air drying. Another
possible source of error could be due to insuffi-
cient heating, which would also yield a loss of
product. A lower yield could also result from an
incomplete conversion of reactants to products
due to decomposition of acetic acid in the solu-
tion (5).
CONCLUSION
All in all the actual yield of aspirin was 0.546 g.
Given that 2.015 g of aspirin was used, the theo-
retical yield was 2.628. The percent yield and
percent error were 20.77% and 79.22% respec-
tively. Because the percent yield was low, a lot of
the product was lost. 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. Furthermore, we can con-
clude that acetylsalicylic acid traveled further
because it is less polar than salicylic acid. The
crude product and recrystallized product were
composed of both salicylic acid and aspirin, as
displayed by two spots on the TLC plate. Salicyl-
ic absorbed to the silica more willingly than the
acetylsalicylic acid as displayed by an Rf value of
0.818, thus the acetylsalicylic acid traveled fur-
ther as displayed by Rf values of 0.897 in the
crude product and 0.879 in the recrystallized
product. To prevent error in the future, the water
bath could be sufficiently heated. Also less expo-
sure to atmospheric air could be prevented by
conducting the entire experiment under a fume
hood.
REFERENCES
(1) Ogbru, Omudhome. MedicineNet. Acetylsali-
cylic Acid.
http://www.medicinenet.com/acetylsalicylic_acid
/article.htm (accessed Feb 23, 2014).
(2) Snelling. Volstate.edu. Synthesis of Aspirin.
http://www2.volstate.edu/chem/1110/Synthesis_o
f_Aspirin.htm (accessed Feb 23, 2014).
(3) Williamson, K.; Masters, K. Macroscale and
Microscale Organic Experiments, 6th ed.; Cen-
gage Learning: Belmont, 2011.
(4) Esobel. UPLB College Student. Synthesis of
Aspirin.
http://theuplbcollegestudent.blogspot.com/2011/0
5/full-report-synthesis-of-aspirin.html (accessed
Feb 23, 2014)
(5) Lewis. Aspirin: A Curriculum Resource for
Post-16 Chemistry Courses. 2nd ed.; Royal Socie-
ty of Chemistry: London, 2003.
ACKNOWLEDGMENTS
We thankfully acknowledge support from The
American University in Washington D.C, Medi-
cine.Net. and Volstate. We are also grateful to
Omudhome Ogbru, C.R. Snelling, Kenneth L.
Willamson, Esobel, David Lewis and to the stu-
dents at American University for their participa-
tion in the experiment.
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.