Esterification of Salicylic Acid via Acetic Anhydride for the Pro-­‐
duction of Acetylsalicylic Anhydride (Aspirin) Dana M. Feuerhammer
Department of Chemistry, American University, Washington, D.C. 20016
Date of Publication: February 25, 2014
ABSTRACT: This experiment utilized esterification
and Le Chatelier’s principle to create acetylsalicylic
anhydride from salicylic acid, acetic anhydride, and
the catalyst phosphoric acid. 2.551g crude aspirin
was obtained, with 4.908g recrystallized product and
a 97.7% yield and 2.3% error. The TLC resulted in rf
values of .83 for salicylic acid, .83 and .67 for crude
product, and .67 for recrystallized product. These
results formed the conclusion that pure aspirin was
made.
INTRODUCTION
Acetylsalicylic acid, or aspirin, has been
utilized as a pain reliever for centuries, first seen
in ancient Rome and Greece. Salicin, an extract
acquired from the bark of willow and poplar
trees, was the first to be used as a pain reliever
(analgesic). It was later found in the 19th century
that salicin is a glycoside formed from a molecule of salicylic acid and a sugar molecule and
could therefore be utilized as a pain reliever. Unfortunately, salicylic acid attacks mucus molecules causing gastric pain, ulcers, and vomiting,
but was improved with the addition of an acetyl
group. Today, each tablet include 325mg of acetylsalicylic acid (1).
Aspirin is a selective COX1 inhibitor that
acts by acetylating a residue in the active site,
irreversibly inactivating COX1, which in turn
inhibits the production of Prostaglandins. Prostaglandins are fatty acid derivatives with inflammation, pain, and immune response effects, catalyzed by the enzyme cyclooxygenase (COX)
from aracodonic acid. COX1 catalyzes thromboxane, a powerful platelet activator and blood
vessel constrictor. With aspirin inhibiting COX1,
this effect is reduced (2).
Through this mechanism, aspirin can act
as an anti-inflammatory, an analgesic, heart attack/stroke preventer, and an antipyretic. With a
lack of platelet activation, aspirin acts as a blood
thinner and therefore decreases the risk of clotting and its associated medical emergencies. Because prostaglandins are needed for pain response, aspirin’s inhibition of COX creates pain
relief. Prostaglandins are also responsible for signaling the hypothalamus to increase body temperature, and therefore aspirin acts as a fever reducer (3).
Negative effects of aspirin include Reye’s
syndrome, blood thinning, and gastric disturbance. Reye’s syndrome is a brain disorder that
strikes children and persons under 18 who take
aspirin after having the flu or chickenpox. In
newborn babies and their mothers, the lack of
clotting can cause uncontrolled bleeding. (1). For
people with arthritis, the amount of aspirin needed daily for pain relief and to control inflammation creates gastric disturbance, but can be buffered out (3).
To test for the purity of aspirin synthesized in lab, thin layer chromatography (TLC) is
used. This is a capillary action technique where a
polar silica-coated plate is dotted with the sample
substances a half inch from the bottom of the paper and placed in a glass container with a saturating paper and solvent and covered. The samples
will then rise through capillary action with the
mobile front (polar, strong solvent), with the
more polar substances interacting with the silica
more strongly and moving less far than a less polar substance (4).
In this experiment, aspirin is synthesized
using salicylic acid and acetic anhydride and then
analyzed through TLC using a silica plate and an
ethyl acetate-methylene chloride solvent.
MATERIALS AND M ETHODS
2.0g of salicylic acid, 5.0 mL of acetic
anhydride, and 5 drops of 85% phosphoric acid
solution were added and swirled together under a
fume hood in an Erlenmeyer flask. The flask was
then placed in a 70C hot-water bath on a hot plate
for about 15 minutes. The mixture was stirred
occasionally and 2mL of distilled water was added after 10 minutes. When the vapors ceased indicating the completion of the reaction, the mixture was removed from the hot both and 20ml of
distilled water was added and cooled to room
temperature.
Vacuum filtration was then used to dry
the solution, occasionally rinsing the crystals
with distilled water. The dried crystals were then
massed and a small sample was set aside for later
TLC analysis. 1g of remaining crude aspirin was
used in re-crystallization, adding to 20mL of hot
ethanol/water solvent over a warm water bath
until the crystals dissolved, without boiling. The
solution was then removed, covered, and allowed
to slowly cool to room temperature when it was
then placed in an ice bath. The pure crystals were
then dried with a vacuum filter and rinsed with
3mL of ice-cold deionized water and 2mL of icecold ethanol.
A TLC apparatus was then set up with a
beaker and watch glass as a developing chamber,
a silica gel coated plate as the stationary phase,
and 10mL of 9:1 ethyl acetate methylene chloride
mixture as the mobile phase. The silica paper was
dotted with three substances: salicylic acid, crude
product, and recrystallized product all dissolved
in ~5 drops of solvent. The plate was placed in
the developing chamber with a saturated paper,
covered with a watch glass, and run until the mobile front reach ~1/2 inch from the top of the silica paper. The paper was then removed and analyzed under a black light.
RESULTS
Mass of salicylic acid 2.001
used (g)
Volume of acetic anhy- 5
dride used (mL)
Mass of acetic anhydride 5.4
(g)
Mass of aspirin & filter 2.876
paper (g)
Mass of filter paper (g)
.325
Mass of aspirin synthe- 2.551
sized (g)
Mass of recrystallized 4.908
aspirin (g)
Table 1: Raw Data
Theoretical yield= moles of limiting reagent
Eq. 1
Moles salicylic acid = 2.001g /138.12g mol =
0.0145 !limiting reagent
Moles acetic anhydride= 5.4g /102.09gmol=
0.0529
Theoretical Yield= 0.0145 mols x 180.157 gmol
= 2.612g
% Yield= (actual yield/theoretical yield) x100
Eq. 2
(2.551g/2.61g) x100= 97.7%
% Error= ([theoretical-experimental)/theoretical]
x100
Eq. 3
% Error= [(2.612g-2.551g)/2.612] x100 = 2.3%
Theoretical Yield
2.162g
% Yield
97.7 %
% Error
2.3%
Table 2: Calculated Data
Table 1 shows the raw data collected from this
experiment. Equation 1 used this information to
find the theoretical yield of aspirin, which is
2.162g. Equation 2 used Table 1 to find the percent yield, which is 97.7%. Equation 3 used Table 1 to find percent error, which is 2.3%. Table 2
displays the calculated data.
librium derives from Le Chatelier’s principle,
which states that a system at equilibrium will adjust in order to minimize any stress placed on the
system. In the case of aspirin, Le Chatlier’s principle can be utilized to favor the products by adding water to the reactant side to debilitate the reactant acetic anhydride. In contrast, water can be
added to the product side to favor the reactants
(6).
The formation of acetylsalicylic acid is an
esterification. The acetyl group comes from acetic anhydride and the –OH group is attached to
the ring of salicylic acid (which also possesses a
carboxyl group) (5). This esterification replaces
the –OH group with the acetyl group, making the
product aspirin less acidic and therefore less
problematic for the consumers’ gastric system.
Figure 1: TLC
RF= solute distance/solvent front distance
Eq. 4
SA= 1.25/1.5= .83
Crude= 1.25/1.5= .83
=1/1.5= .67
Recrystallized= 1/1.5=.67
Figure 1 shows the TLC of salicylic acid (rf .83),
crude product (rf .83 and .67), and recrystallized
product (rf .67). The rf values were obtained using Equation 4.
DISCUSSION
Esterification is the acid catalyzed reaction of a carboxyl group and the –OH group of an
alcohol or phenol to form a carboxylate ester.
This is an equilibrium reaction because as the
reactants are used up and the products increase,
the products react with one another to produce
the original reactants (5). Control over this equi-
In the first step, the oxygen of the carbonyl of the acetic anhydride is protonated by the
catalyst phosphoric acid. It is a strong acid (pKa
~2.1) so there are many protons available. This
protonation increases the electrophilicity of the
carbon of that carbonyl. The oxygen of the phenol in salicylic acid acts as a nucleophile and attacks the carbon of the carbonyl acting as the
electrophile within acetic anhydride, simultaneously breaking the pi bond to oxygen, and forming a tetrahedral intermediate. A proton transfer
then occurs releasing that hydrogen from the previously protonated oxygen. The other free oxygen on the original acetic anhydride atom is then
protonated, which causes a lone pair of electrons
to form a pi bond with the carbon holding the –
OH group. This transfer allows the acetic anhydride to leave. A final proton transfer to eliminate
the positive charge on the double bonded C-O
forms the final aspirin product.
Phosphoric acid is used as a catalyst in
this reaction. It is needed to protonate acetic anhydride in order to withdraw the positive charge
from the central carbon and make it a good electrophile for the salicylic acid to attack. The reaction is heated to 70-80C to increase the rate of
reaction between salicylic and acetic anhydride.
Without heating, the molecules would not excite
or react and little to no reaction would occur. After 10-15 minutes of heating, water was added to
not only re-crystalize the product, but also to destroy any remaining acetic anhydride and turn it
into acetic acid. The H20 adds across the anhydride bridge, cleaving it to release two acetic acid
molecules, which are much less reactive than
acetic anhydride (5).
The crude aspirin was dissolved in hot
water/ethanol mixture because salicylic acid and
aspirin are only slightly soluble at room temperature, but very soluble when heated. The crude
aspirin was not clean from re-crystallization earlier because the salicylic acid also recrystallized.
The addition of heat therefore separates these two
substances further. According to the TLC plate
obtained, aspirin was made. In the salicylic acid,
the rf value was recorded to be .83, representing
the least polar alcohol functional group. This rf
value is still shown in the crude product, but
there is also another peak with an rf value of .67
representing the equilibrium reaction keeping reactants around as well as the product of aspirin
with its new acetyl group. The final recrystallized
product only displays an rf value of .67, which
indicates that all OH groups were replaced by a
more polar, less-traveling acetyl group.
One reason why this experiment did not
have given a 100% yield is that the solution was
not left in the ice water bath, therefore not letting
the full amount of crystals to form. Another reason is that this is an equilibrium reaction, so
without the proper amount of water added to the
reactants to favor the products, the products
could have reacted and reduced the % yield (5).
CONCLUSION
This experiment gave a 97.7% yield with a 2.3%
error and a TLC plate displaying pure aspirin
with no trace of salicylic acid. This indicates that
the salicylic acid was successfully esterificated
by acetic anhydride catalyzed by phosphoric acid,
eliminating the acidic –OH group and leaving a
less harmful product for consumers. In future
replications of this experiment, it would be recommended that the final product be left to dry
overnight in order to get a more accurate final
weight of the product and avoid miscalculations
of percent yield.
REFERENCES
1. Williamson, K.; Masters, K. Macroscale and Microscale Organic Experiments 6e 2011 529-531
2. Farragher, K.; Stanford, J.; Murphy,
P.; Keenan, P. 2006 Aspirin Foundation
3. Wiley, J. Interactive Concepts in Biochemistry 2006 Section X
4. Rosen, J., Gothard, Q. Science
Online: Facts on File 2011 Chromatography
5. Snelling, C.R. Synthesis of Aspirin
2013 Volstate Education
6. Klein, David Organic Chemistry
2012 407-408
ACKNOW LEDGMENTS
Acknowledgement is due to Dr. Dehghan and
American University for providing the guidance
and supplies to make this experiment successful.
This assignment is my own work and I have cited all material used in its preparation. This assignment
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.
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