Exercise 11

Synthesis of Aspirin
(Acetylsalicylic Acid from Salicylic Acid)

Sharmaine S. Bungabong
Group 2
5L

I. INTRODUCTION

Organic synthesis is an important aspect in the industry of organic chemistry.

This aspect of organic chemistry has contributed much to the knowledge there is
regarding the reactions undergone by the specific families of compounds.
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, is the common name for the compound acetylsalicylic acid, widely
used to reduce fever and as a pain killer. Nowadays, salicylic acid is administered in
the form of aspirin which is less irritating to the stomach than salicylic acid. It is an
acetyl derivative of salicylic acid. It is a white, crystalline, weakly acidic substance
which melts at 135C.
To prepare 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. (McMurry, 2008) The aspirin
product is not very soluble in water so the aspirin product will precipitate when
water is added.
Nucleophilic acyl substitution simply means the replacement of one nucleophile
attached to a carbonyl group with another. For the synthesis of aspirin from salicylic
acid, the acyl component being nucleophilically substituted is acetic anhydride. The
nucleophile attached to the acyl group that is being replaced is acetic acid, or
acetate ion (CH3COO-) before protonation. The newly formed nucleophile attacted
to the acyl group is salicylic acid, the substrate that is being acylated. (Schmid,

1991). The synthesis reaction of aspirin is shown below:

Figure 11.1 Balanced chemical equation for the synthesis of aspirin

Since acetic acid is very soluble in water, it is easily separated from the aspirin
product. The aspirin isolated in this step is the crude product. A purified product
can be obtained through recrystallization of the crude product in hot ethanol. In this
experiment, the crude product will be the desired product. The percent yield of the
crude product will be determined for this reaction. The purity of the product will also
be analyzed ( Casey, 2006).
Lastly, melting point is a property possessed by a certain compound. The
melting point range of pure aspirin is 138-140 degree Celsius and the melting point
range of the salicylic acid starting material is 158-161 degree Celsius. If impurities
are present in your crude sample, the melting point range for your product will be
theoretically lower than the range of pure aspirin.

II. OBJECTIVE
The objectives of this exercise are as follows:
1. to explain the concept of organic synthesis;
2. to synthesize acetylsalicylic acid from salicylic acid nucleophilic acyl
substitution; and

3. to describe and explain differences in the properties of acetylsalicylic acid

and salicylic
Acid by simple chemical test.

III. MATERIALS AND METHODS

A. Schematic Diagram of the Procedure
1. Preparation of Acetylsalicylic Acid (Aspirin)
1g Salicylic acid; 125 mL Erlenmeyer flask
-add 3 mL acetic anhydride & 5 drops 85%
phosphoric acid
-swirl to mix, heat in water bath (15 min.)
-slowly add 2 mL dH 2O
-add 20 mL ice-cold dH2O (after vigorous reaction
ended) cool to RT, place in ice bath for complete
crystallization
-collect product by suction filtration

Residue (crystals)
-wash crystals with cold dH 2O
-transfer to a pre-weighed watch glass; air dry

Filtrate (discard)

-weigh dry aspirin & calculate percentage yield

2. Recrystallization of Aspirin
Crude aspirin in 125 mL Erlenmeyer flask
-add dH 2O dropwise until crude aspirin dissolves
-warm in hot water bath; recrystallize by cooling
to RT and then in a cool bath
-collect crystals by suction filtration-was crystals with
cold H2O
Residue (crystals)

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
-propose method of differentiation product from starting
material
-differentiate synthesized acetylsalicylic acid from
commercial aspirin
-dissolve in 2 mL H 2O and 1 mL iodine solution; observe
reaction

4. Proposed Method of Differentiation

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
add 2 drops of sample
heat gently
examine mixture after 5 minutes
I2/KI Test
Dissolve a pinch of sample in 2 mL H2O and 1
--- Observe

B. Set-ups

Figure 11.2. Suction filtration setup

Figure 11.3 Hot water bath setup

Figure 11.4. Melting Point Determination Set-up

C. Use of necessary chemicals

Name & Structure

Function

Physical

Hazards

Precautions

Properties
Solid granules
Odor:
Odorless
Reagent

MW: 138.12
g/mol

Keep away
Pulmonary
Irritants

from heat.
Keep away
from sources

Salicylic acid

Color: white

of ignition.

BP: 211C
MP: 159C

Liquid

Keep
container dry.

Odor: Strong
Reagent
Acetic anhydride

Keep away

MW: 102.09

Corrosive and

from heat.

g/mol

toxic

Keep away
from sources

Color: Light

of ignition.

BP: 139.9C
MP: -73.1C
= 1.082
g/mL
Liquid
Odor:
Odorless
Catalyst

Do not
Extremely

MW: 98.00

corrosive and

g/mol

toxic

gas/fumes/
vapor/spray.
Never add
water to this

Color: clear

Phosphoric acid

breathe

product.

BP: 158C
MP: 21C
Liquid

Keep
container dry.

Odor: Sharp
Iodine solution

Differentiating

MW: NA

Do not ingest.
Skin irritant

Do not

agent

Color: Red-

and toxic

brown

breathe
gas/fumes/
vapor/spray.

BP: 100C
MP: 0C

Liquid
Odor:
Odorless
Solvent
Water

MW: 18.02
g/mol

Completely

NA

safe

Color:
Colorless
BP: 100C
MP: NA
FeCl3

Differentiating
agent

Liquid
Odorless

Mild oxidizing

Iron(III)

agent

chloride is
toxic, highly

MW: 162.2

corrosive and

g/mol

acidic. The
anhydrous

Color: Yellow

material is a

Density:

powerful

2.898 g/ml

dehydrating
agent.

KMnO4

Differentiating
agent

Liquid

Strong

May cause

oxidizer.

kidney

Reproductively

damage. May

MW: 158.034

active. Contact

be harmful if

g/mol

with other

swallowed.

Odorless

Color: purple
Density:

material may

Causes severe

cause a fire.

eye and skin

irritation with

2.043 g/mL

possible
burns.

IV. DATA AND RESULTS

Table 11.1 Sample descriptions of reagents
Sample

Description

Salicylic acid
Phosphoric acid
Iodine solution
Crude Aspirin
Acetic Anhydride
FeCl3
KMnO4
2% Iodine

Table 11.2 Synthesis of Aspirin (Acetylsalicylic acid)

Mass of salicylic acid used (g)
Volume of acetic anhydride used (mL)
Mass of acetic anhydride used (g)
Mass of synthesized aspirin (g)

Table 11.3 Observation on the preparation of aspirin.

CONDITIONS
Before heating: Salicylic acid + acetic
anhydride + phosphoric acid

OBSERVATIONS

After heating:
Upon addition of 1 portion of 2ml
distilled water
Upon addition of 40ml ice and cold water
after suction filtration
Final appearance of dried crystals

Table 11.4 Recrystallization of Pure Aspirin

Mass of crude aspirin (g)
Mass of filter paper (g)
Mass of filter paper+ aspirin (g)
Mass of aspirin (g)
Percentage recovery (%)
Melting point of crude aspirin (C)
Melting point of synthesized aspirin (C)

Table 11.5 Observation for the recrystallization process:

CONDITIONS
Before heating: 95% ethanol + crystals
After heating:
Upon addition of 1 portion of 2ml
distilled water
Upon addition of 40ml ice and cold water
after suction filtration
Final appearance of dried crystals

OBSERVATIONS

Table 11.6 Weight and MP of synthesized aspirin.

Weight of watch glass + filter paper
Weight of watch glass + filter paper +
crude aspirin
Weight of crude aspirin
MP of commercial aspirin
%yield of crude aspirin

Table 11.7 Comparison of the MP of crude and recrystallized sample

CRUDE SAMPLE
Temp. when melting starts
(C)
Temp. when melting
completes (C)
MP range (C)

MP of pure sample (lit. value):

PURIFIED

A.3. CHARACTERIZATION OF ASPIRIN

Table 11.8 Result of differentiation test of synthesized aspirin from starting material
Substance

Observations
Solubility

+/-

in H2O

FeCl3 Test

+/-

KMnO4

+/-

Tollens Test

+/-

Test

Acetic
anhydride
Salicylic
acid
Synthesize
d Aspirin

Table 11.9 Differentiation of synthesized aspirin from commercially available aspirin

SUBSTANCE
Synthesized aspirin
Commercially available aspirin

Reaction with Iodine Solution

V. SAMPLE CALCULATIONS
Theoretical yield of Aspirin:
(Given 1g salicylic acid; 3 mL acetic anhydride)
(CH3CO)2O + C6H4(OH)COOH -> C9H8O4 + CH3COOH
Mole ratio= 1:1:1 (salicylic acid: acetic anhydride: aspirin)
MMsalicylic acid = 138.12 g/mol
MMacetic anhydride = 102.09 g/mol ; = 1.082 g/mL
MMaspirin = 180.15 g/mol
Moles salicylic acid = grams salicylic acid/MM salicylic acid = 1g salicylic acid/138.12g/mol
= 0.00724 or 7.24 x 10-3 moles salicylic acid
Massacetic anhydride = vol. acetic anhydridex acetic anhydride = 3 mL x 1.082g/mol
= 3.246 g

acetic anhydride

Molesacetic anhydride = gramsacetic anhydride/MMacetic anhydride = 3.426g/102.09g/mol =

= 0.03356 or 3.34 x 10-2 molesacetic anhydride
0.00724 moles salicylic acid x ( 1mole aspirin/1mole salicylic acid) x
(180.15g/molaspirin)
= 1.30 g aspirin (limiting reactant)
0.03356 molesacetic anhydride x ( 1mole aspirin/1mole acetic anhydride) x
(180.15g/molaspirin)
= 6.04 g aspirin (excess reactant)
Since aspirin (from salicylic acid) < aspirin (from acetic anhydride), salicylic
acid is the limiting reactant, and acetic anhydride is the excess reactant.
Theoretical yield=MMaspirin x molessalicylic acid=180.15g/mol x .00724 mol = 1.30
g aspirin

VI. RESULTS AND DISCUSSION

Aspirin can be made by using a process called esterification. Esterification occurs
when a carboxylic acid and an alcohol combine in a reaction to produce an ester.
This reaction can be used to synthesize aspirin from salicylic acid. In the lab, the
carboxylic acid alcohol mixture is heated in the presence of H 2PO4, phosphoric acid,
which acts as a catalyst. During the reaction process, a molecule of water splits off
and the remaining carboxylic acid and alcohol fragments become attached
producing an ester.

Fig. 11.5 General Reaction of Esterification

Fig. 11.6 Esterification of Aspirin Usng Acetic Acid

The first part of the experiment was the preparation of Acetylsalicylic Acid (Aspirin).
A white, milky mixture was obtained when salicylic acid, acetic anhydride and
phosphoric acid (a catalyst) were mixed. The mechanism of the reaction is:

Fig. 11.7 The synthesis of Aspirin

For further explanation, an acetic anhydride instead of acetic acid was used
because acetic anhydride has a faster reaction time. The catalyst concentrated
H2PO4 is added to speed up the reaction. The flask containing this solution is then
heated in a boiling water bath for about 15 minutes. This process is
called esterifcation.

Fig. 11.8 Esterification of Aspirin In Our Lab Using Acetic Anhydride

The flask is then removed and allowed to cool. Ice cold distilled water is slowly
added to the flask to decompose any unreacted acetic annhydride.

Fig. 11.9 Decomposition of Unreacted Acetic Anhydride

This shows that the oxygen in salicylic acid attacks one of the carbons in acetic
anhydride. Also, the mechanism shows how acetic acid was separated from the
acetylsalicylic acid.
In the first part of the experiment, heating of the mixture was done and a clear
yellow liquid was obtained (Table 2). Heating was employed so that salicylic acid
would melt and react with acetic anhydride. On the other hand, water was added
after heating (not at the start of the experiment). This is to prevent the reaction of
acetic anhydride with water at the start of the experiment, if this had happened, no
aspirin could have formed. In this manner, acetic anhydride was decomposed after
the formation of aspirin.
After the adding 40mL ice-cold water, cooling to room temperature and placing in
an ice bath, the liquid became whitish / cloudy with white precipitates. This addition
of cold water is very important in purification and isolation of the crystals from the
liquid since aspirin is insoluble in cold water. Ice cold distilled water is added to the
flask again. The flask is then chilled in an ice-water bath for about 10 minutes until
crystallization of the aspirin is complete. The aspirin crystals are collected on a
Buchner funnel and washed with additional ice cold distilled water. ice cold distilled
water is used instead of room temperature distilled water because aspirin is
insoluble in cold water and would not be dissolving any of the aspirin product. The
acetic acid and H2PO4 are water soluble, in any temperature water, and can be
removed by washing the aspirin with the chilled water. Salicylic acid is only slightly
soluble in water and any unreacted salicylic acid cannot be removed completely in
the washing process. Once the aspirin crystals are purified they are allowed to dry.
They are then weighed and tested for purity.

Purification is needed to eliminate any salicylic acid and acetic anhydride that did
not react, as well as the acetic acid product and phosphoric acid. Isolation was done
through suction filtration, white, sugar-like crystals were obtained.
The crude/impure product was then weighed and it weighed 1.28 g . This is quite far
from the theoretical yield because it still contains impurities. This data was used to
calculate the percent recovery on the latter part of the exercise.
The second part of the experiment was recrystallization. This is the second part
of the purification process. Here, 95% ethanol was added dropwise to the crystals
until dissolved and after this, distilled water was added dropwise until cloudy/until
recrystallization. Ethanol was used to dissolve aspirin along with the impurities such
as salicylic acid and others. Cold water, on the other hand, is used to recrystallize
only aspirin, thus, leaving all the impurities behind. Since aspirin is an ester, it
should not be recrytallized from hot water since esters hydrolyses in hot water. After
cooling in an ice bath (which further facilitates recrystallization and purification), the
mixture was then suction filtered.
On the other hand, the calculated percent recovery was 98.1369%. The weight of
the recovered sample was 2.85g. The calculation for percent yield was shown in
Table 11.6. The percent yield was _____%, meaning there was a slight error. Perhaps,
the sample was not weighed properly or it was weighed when still wet.
As for the melting point data, the range of the crude sample was ______C and the
range of the purified sample was ______C. Comparing the results to the literature
value of 135C, both the purified and crude had a precise value BUT since the
purified sample has a narrower range, it is logically more comparable to the
literature value.
The computed % recovery of the recrystallized aspirin from the formula: % recovery
= (mass of crude aspirin/mass of recrystallized aspirin) x 100, is 41.19%.
The melting point of the crude and recrystallized aspirin was determined
using a MP determination test. Results showed that crude aspirin had a wider MP
range of 119-135C compared to 130-135C MP range of the recrystallized aspirin.

This means that there is still more impurities in the crude than in the recrystallized
aspirin.
In differentiating salicylic acid to acetylsalicylic acid, ferric chloride was used
because compounds containing phenol group will generate a colored complex such
as blue red green or purple. In the laboratory, a purple complex was observed in
salicylic acid because it has a phenol group.
In Table 11.7 and 11.8, the differentiation of synthesized acetylsalicylic acid from
commercially available aspirin was accounted for. The test used in this part was
Iodine test, which is a test for the presence of starch (since iodine can form a black
complex with starch).After dissolving synthesized aspirin in 2mL water and 1mL
iodine solution, a mixture of red-orange liquid and white precipitates was obtained
while when commercially available aspirin was dissolved in 2mL water and 1mL
iodine solution, a black precipitate in a dark brown to black solution was formed.
This shows that commercially available aspirin contains starch.
In the characterization of Aspirin, an iron III chloride test was done to determine the
purity of our aspirin. Iron III chloride combines with the phenol group to form a
purple complex. If salicylic acid is present (impurity) the product will turn purple
when FeCl3 is added, because salicylic acid is a phenol.
Purple color was observed when FeCl 3 added which is a sign of an impure product,
therefore, salicylic acid may have been present. Salicylic acid is NOT water soluble
and cannot be removed by using cold distilled water. If the solution is heated long
enough the reaction will not be complete.
No color change and appearance of yellow color, or a faint purple tinge signifies a
pure product, it means no unreacted salicylic acid is present.

Fig. 11.10 LEFT - pure (no phenol present), RIGHT - impure (phenol present)
Other tests that were performed were summarized in Table 11.7. Since salicylic
acid has a phenol group, it gave a positive result to FeCl3 Test and KMnO4 Test, both
of which react with phenol. Acetic anhydride gave a positive result to water
solubility test to form acetic acid. The recrystallized aspirin, an ester, did not give
any positive result to the tests since esters do not react with FeCl3 Test, KMnO4 Test
and Tollens Test. Small esters are actually fairly soluble in water but solubility falls
with chain length and hydrophobic parts. Since aspirin has a hydrophobic aromatic
ring, it did not dissolve in water. Having these results, the recrystallized sample was
then identified (or assumed) as acetylsalicylic acid.
The synthesized acetylsalicylic acid was differentiated from commercially
available aspirin using iodine solution. Commercially available aspirin have small
amount of inert binding material such as starch so it reacted with iodine and form a
blue-black colored solution. However, in the synthesized aspirin there was no
reaction observed which indicates that the generated product was pure.
The low yield and purity that we obtained in this experiment are not only
attributed to the experimental procedure and mechanism, but also to other
experimental flaws. The low yields could be due to several factors, such as
disturbance during crystallization, incomplete reaction and overheating. After all,
crystal formation is highly dependent on critical temperature and the level of
disturbance

the

saturated

solution

was

subjected

to.

Similar

to

previous

experiments, the usage of filter paper containing paper pulp reduced experimental
yields as some product was left behind in the Buchner funnel and on the filter paper

after suction filtration. Some were also stuck amongst the fibers of the filter paper
that was utilized.
VII. SUMMARY AND CONCLUSION
Aspirin was prepared from the reaction of salicylic acid and acetic anhydride.
Phosphoric acid was used as a catalyst. It was heated to have a higher rate of
reaction. The mixture was then cooled for the material to undergo crystallization.
Upon addition of cold water, acetic acid was formed and thus eliminated. The
crystals were separated through suction filtration. The other impurities, such as
salicylic acid, from the preparation of aspirin were removed in the process of
recrystallization.
The melting point range of the purified and crude samples were compared to the
literature value and it showed that the purified sample is logically near to the
literature value because of its narrow range.
The recrystallized product was differentiated from commercial aspirin through
iodine test and it showed that the commercial aspirin contains starch. Other tests
such as water solubility test, FeCl3 Test, KMnO4 Test and Tollens Test differentiated
the starting materials, salicylic acid and acetic anhydride, from aspirin.
Acetylsalicylic acid was differentiated from salicylic acid through ferric chloride
test. This test was used to observe the presence of phenol group in a compound.
Since salicylic acid has a phenol group, it reacted with ferric chloride, producing a
purple complex. The synthesized aspirin did not react because it has no phenol
group.
Synthesized aspirin was compared to commercially produced aspirin through
the iodine solution test. Commercially produced aspirin is not pure acetylsalicylic
acid, it contains binders such as starch will react to iodine solution and produce a
blue- black solution.

VIII. REFERENCE
Aspirin(Acetylsalicylic acid). Retrieved September 23, 2012 from
http://homepage/smc/edu/gallogly_ethan /files/Aspirin%20Synthesis.pdf
Brown, Lemay and Bursten. 2009. 11th Ed. Chemistry: The Central Science. Prentice
Hall, 534-537
Division of Organic Chemistry and Natural Products. (2004). Basic Organic
Chemistry Laboratory

Manual. 7th edition. UPLB : Institute of Chemistry, College

of Arts and Sciences.

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.
Schmid, G. H. Organic Chemistry. (1991). St. Louis, Missouri: Mosby-Year Book, Inc.
IX. REMARKS AND RECOMMENDATIONS
During the synthesis and recrystallization of acetylsalicylic acid, it is
preferable to maintain the temperature at a fixed 90C. This is because studies
carried out have determined that this is the critical temperature for acetylsalicylic
acid crystal formation. At this temperature, the formation of acetylsalicylic acid
crystals is at its optimum. Maintaining a certain temperature is almost impossible
when dealing with an oil bath on a hot plate. Thus, more advanced heating
technology could be utilized, such as heating mantles and heat controllers. Even the
common water bath can be used. Unlike the hot plate, the temperature of a water
bath is not prone to fluctuations, and a water bath provides us with the exact
temperature of the water it contains, unlike a hotplate.