SYNTHESIS OF SALICYLIC ACID DERIVATIVES

Eloisa Mae N. Halili, Jevan D. Historillo, Celine Joy J. Juan, Zhyldaine Lye S. Matibag, Jarell R.
Obispo, Sabrina Audrey E. Ortega
Group 6 1L Medical Technology Inorganic and Organic Chemistry Laboratory

ABSTRACT

Acetylsalicylic acid, commonly known as Aspirin is the most widely used drug in the world today. Commonly
used for its analgesic, antipyretic, and anti-inflammatory properties to relieve symptoms of pain, fever, and
inflammation. The objective of this experiment was to synthesize Acetylsalicylic acid and Methyl salicylate
and characterize the products using Ferric Chloride Test. Acetylsalicylic acid was synthesized by reacting
salicylic acid and acetic anhydride in the presence of concentrated sulfuric acid that involves the acetylation
of the phenolic group of salicylic acid under acid-catalyzed conditions. Methyl Salicylate was synthesized by
reacting salicylic acid, methyl alcohol and concentrated sulfuric acid. The sample obtained, salicylic acid,
benzoic acid, phenol, acetylsalicylic acid product and methyl salicylate product, and commercial white
aspirin tablet, were introduced to Ferric Chloride Test. The Ferric Chloride Test is used to detect presence
of Phenols which is indicated by a purple or pink colored solution. Salicylic Acid, Acetylsalicylic acid product,
Methyl Salicylate product displayed a light pink color, phenol displayed a dark purple solution, and benzoic
acid and commercial white aspirin tablet displayed a clear solution. Although Acetylsalicylic acid is the same
with the commercial white aspirin tablet, the acetylsalicylic acid product still has trails of salicylic acid which
has a phenol structure hence the light colored solution unlike in the commercial white aspirin tablet it is
already pure acetylsalicylic acid.

INTRODUCTION Methyl salicylate is an organic ester naturally

It is well known that Acetylsalicylic acid and
Methyl Salicylate acid have its outgrowing uses
especially on pharmaceutical industry. These
acids require the presence of salicylic acid for
acetylation and esterification under acid-
catalyzed conditions. Salicylic acid is a simple
phenolic compound synthesized in a wide range
of prokaryotic and eukaryotic organisms,
including plants’ Leaf and bark of willow tree
which was widely used as a medication for pain.
Acetylsalicylic acid, commonly known as
aspirin, is the prototypical analgesic used in the
treatment of mild to moderate pain. Aspirin
remains a common over-the-counter analgesic
for humans, with application to small animal
veterinary patients as well. It was found that it
has analgesic, antipyretic, and anti-inflammatory
properties that is used in medication for
treatments such as arthritis, surgery, injury,
toothache, headache, menstrual cramps and sore
muscles.
produced by many species of plants, particularly
wintergreens. The compound was first extracted
and isolated from plant species Gaultheria
procumbens in 1843. It is synthetically produced,
used as a fragrance in foods and beverages, and
in liniments. It forms a colorless to yellow or
reddish liquid and exhibits a characteristic odor
and taste of wintergreen. For acute joint and
muscular pain, methyl salicylate is used as a
rubefacient and analgesic in deep heating
liniments. Also, It is used as a flavoring agent in
chewing gums and mints in small concentrations
and added as antiseptic in mouthwash solutions.
In this experiment, the synthesized products of
acetylsalicylic acid and methyl salicylate acid can
be characterized by its physical state,
appearance, odor and color by using Ferric
Chloride Test. The objectives of this experiment
are to determine the presence of phenols in a
given sample or compound through ferric chloride
test and compare the change in color by the
samples, including the commercial white aspirin
tablet after adding 2% FeCl3 (aq). Moreover, the
formation of a red, blue, green, or purple
coloration indicates the presence of phenols.
Methyl Salicylate - (oil of wintergreen or
wintergreen oil) is an organic ester naturally
produced by many species of plants, particularly
wintergreens. (DrugBank, n.d.)

EXPERIMENTAL
A. Test Compound/s used
Benzoic Acid - is a colorless crystalline solid and
the simplest aromatic carboxylic acid. (Human
Metabolome Database, n.d.)

Figure 1.4 Structure of Methyl Salicylate

Commercial Aspirin & Acetylsalicylic Acid - is an

orally administered non-steroidal anti-
inflammatory agent. (NClt, n.d.)

Figure 1.1 Structure of Benzoic Acid

Salicylic Acid - is a colorless, crystalline organic

carboxylic acid. (Human Metabolome Database,
n.d.)

Figure 1.5 Structure of Acetylsalicylic Acid

Acetic Anhydride - is an irritant and flammable.

Because of its reactivity toward water, alcohol
foam or carbon dioxide are preferred for fire
suppression. (Pubchem, n.d.)
Figure 1.2 Structure of Salicylic Acid

Phenol - is a toxic, colourless crystalline solid with

a sweet tarry odor that resembles a hospital
smell. (Human Metabolome Database, n.d.))

Figure 1.6 Structure of Acetic Anhydride

B. Procedure

1. Preparation of Acetylsalicylic Acid

Acetylsalicylic acid can be synthesized from
salicylic acid and acetic anhydride that involves
Figure 1.3 Structure of Phenol acid catalyzed conditions by the acetylation of
the phenolic group of salicylic acid.
 Figure 2.1.4 Addition of Acetic Anhydride to Salicylic
Figure 2.1.1 Acetic Anhydride Acid

Figure 2.1.5 Addition of 5 drops of concentrated

Figure 2.1.2. Salicylic Acid sulfuric acid to the mixture

2g of Salicylic acid, 4ml of acetic anhydride and Then the mixture was swirled and heated in a
5 drops concentrated sulfuric acid was mixed in a water bath at the temperature range of 70-80 C
container. until all the salicylic acid has dissolved.

Figure 2.1.3 Weighing of 2g of Salicylic Acid Figure 2.1.6 The mixture of Salicylic Acid, Acetic
Anhydride and Sulfuric Acid was heated at 70-80 C

After dissolving the salicylic acid, the mixture was

cooled by occasional shaking. Aspirin will begin to
crystallize.
 Figure 2.1.7 After heating, the mixture crystalized Figure 2.2.1 Weighing of Salicylic Acid
forming Aspirin

20ml ice cold distilled water was added to

complete the crystallization.

Figure 2.2.2 1g of Salicylic Acid in a Test Tube

Figure 2.1.8 20ml of Ice cold water was added to the

Acitate to complete crystalization process

The physical state, color and appearance of the

product were described. Then percent yield was
calculated.

2. Preparation of Methyl Salicylate

Methyl Salicylate can be produced under acid-
catalyzed conditions by etherifying salicylic acid
with methanol. It is now commercially
synthesized.
Figure 2.2.3 Methyl Alcohol was added to the Salicylic
1.00g salicylic acid was weighed out and was Acid that is suspended at the bottom of the test tube
place in a test tube.
Then 5ml of Methyl Alcohol and 3 drops
concentrated sulfuric acid was added.
Figure 2.2.4 3 Drops of Sulfuric Acid was added to the
mixture of Salicylic Acid and Methyl Alcohol
Salicylic acid in the alcohol was dissolved by
shaking the test tube. After dissolving the salicylic
acid, the test tube was placed in a 70 C water
bath for 15 minutes.
Figure 2.2.5 The mixture was placed in a water bath
at 70 C for 15 mins
The presence of methyl salicylate is indicates by
its mint odor. The physical state, color,
appearance and odor of the product were
described. Then percent yield was calculated.
Figure 2.2.6 The methyl salicylate final product
3. Ferric Chloride Test
Figure 2.3.1 1ml of distilled water in a test tube
1 mL distilled water was introduced in a tube.
Then the sample was added to it (pinch amount
if solid, 1ml if liquid). After adding the sample, the
tube was shaken to disperse the sample. Samples
used were the following: salicylic acid, benzoic
acid, phenol, acetylsalicylic acid product and
methyl salicylate product, and commercial white
aspirin tablet. A drop of 2% FeCl3 (aq) was
added. Then the color of the mixture was noted.
SET-UPS USED
Test

Computation for the limiting reactant

and excess reactant:

Limiting reagent
1𝑚𝑜𝑙 𝑜𝑓 C7H6O2 1𝑚𝑜𝑙 𝑜𝑓 C9H8O4
2g of C7H6O2 x x =
138𝑔 C7H6O2 1𝑚𝑜𝑙 𝑜𝑓 C7H6O2
0.014 mol of C7H6O2
Figure 3.1 Water bath setup used in Preparation of
Acetylsalicylic Acid
Excess reagent

1.08 𝑔 1𝑚𝑜𝑙 𝑜𝑓 C4H6O3

4ml of C4H6O3 x x x
𝑚𝐿 102 𝑔 C4H6O3
1𝑚𝑜𝑙 𝑜𝑓 C9H8O4
= 0.0423 mol of C4H6O3
1𝑚𝑜𝑙 𝑜𝑓 C4H6O3

Computation of theoretical yield:

0.014 mol of C7H6O2 x 180𝑔 C9H8O4

1 𝑚𝑜𝑙 𝑜𝑓 C7H6O2
= 2.59
grams of Aspirin

Computation of Percent Yield

𝐴𝑐𝑡𝑢𝑎𝑙 𝑌𝑖𝑒𝑙𝑑 2.61 𝑔
Figure 3.2 Water bath setup used in Preparation of x 100 = 100.04%
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑌𝑖𝑒𝑙𝑑 2.59 𝑔
Methyl Salicylate

RESULTS AND DISCUSSION Table 2. shows the data and results of

performed experiment for methyl
Table 1. shows the data and results of salicylate
performed experiment for Aspirin.
Weight of Salicylic 1 grams
Crystallizing solvent Cold water Acid

Weight of Salicylic 2 grams Volume of Methanol 4 mL

Acid
Theoretical Yield 1.12 grams
Volume of Acetic 4 mL
Anhydride Weight of Methyl 2.66 grams
Salicylate
Theoretical Yield 2.59 grams
Percent Yield 237.5%
Weight of Aspirin 2.61 grams
Ferric (III) Chloride Light Pink Solution
s 100.04% Test

Ferric (III) Chloride Light Pink Solution

Computation for the limiting reactant
and excess reactant:

Limiting reagent

1g of C7H6O3 x
1𝑚𝑜𝑙 𝑜𝑓 C7H6O3
x
1𝑚𝑜𝑙 𝑜𝑓 C8H8O3
= Fig. 5.2 Esterification of Aspirin using Acetic
138𝑔 C7H6O3 1𝑚𝑜𝑙 𝑜𝑓 C7H6O3 Anhydride
0.0072 mol of C8H8O3
The first part of the experiment was the
Excess reagent preparation of Acetylsalicylic Acid or commonly
known as Aspirin. A white, milky mixture was
5ml of CH3OH x
0.792 𝑔
x
1𝑚𝑜𝑙 𝑜𝑓 CH3OH
x obtained when salicylic acid, acetic anhydride and
𝑚𝐿 32.04 𝑔/𝑚𝑜𝑙 concentrated sulfuric acid were mixed.
1𝑚𝑜𝑙 𝑜𝑓 C8H8O3
= 0.12 mol of C8H8O3
1𝑚𝑜𝑙 𝑜𝑓 CH3OH

Computation of theoretical yield:

0.0072 mol of C9H8O4 x 154 𝑔 C8H8O3

1 𝑚𝑜𝑙 𝑜𝑓 C8H8O3
= 1.12
grams of methyl salicylate

Computation of Percent Yield

𝐴𝑐𝑡𝑢𝑎𝑙 𝑌𝑖𝑒𝑙𝑑 2.66𝑔
= x 100 = 237.5% Figure 5.3 Synthesis of Aspirin
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑌𝑖𝑒𝑙𝑑 1.12 𝑔

Acetic anhydride was used because of its faster

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
because the hydroxyl group in the salicylic acid is
replaced with an carboxylate ester. During the
reaction process, a molecule of water splits off
and the remaining carboxylic acid and alcohol
fragments become attached producing an ester.
reaction time. The catalyst concentrated sulfuric
acid was added to speed up the reaction. The
solution was then heated in a boiling water bath
until all the salicylic acid has dissolved. This
process is called esterification.
The solution is removed from the boiling water
bath and allowed to cool. Ice cold distilled water
is slowly added to decompose any unreacted
acetic anhydride.

Fig. 9.4 Decomposition of Unreacted

Acetic anhydride

Fig. 4.1 General Reaction of Esterification

The acid catalyst attacks, also known as
protonation, the carbon-oxygen bond of the
acetic anhydride therefore giving it a positive
charge. The process makes the acetic anhydride
prone to nucleophilic attacks. Salicylic acid acts
as the nucleophile in the reaction. This is due to
the oxygen in the hydroxyl bond of salicylic acid
which is capable of giving electrons to the acetic
anhydride. The oxygen of the salicylic acid will
attack the partially positive charge of the oxygen
in the acetic anhydride. Through this, the oxygen
in the phenol group of salicylic acid gained a
positive charge and the carbonyl groups gained a
negative charge. After this reaction, a tetrahedral
intermediate is formed. The partially positive
carbon atom of the acetic anhydride is now
attached to the hydroxyl group of the salicylic
acid. This protonated the hydrogen to donate an
electron in order to form a double bond between
the carbon and oxygen atom thus producing
acetylsalicylic acid and a by product of acetic acid.
In the first part of the experiment, heating of
the mixture was done and as a result, a clear
yellow liquid was obtained. Heating was done so
that salicylic acid would melt and react with acetic
anhydride. On the other hand, water was added
after heating to prevent the reaction of acetic
anhydride with water at the start of the
experiment. Through this, acetic anhydride was
decomposed after the formation of aspirin.
An important technique in removing impurities
from solid organic compounds is recrystallization.
An impure aspirin is dissolved in a solvent at high
temperature. Then cooled at a low temperature
through an ice bath. After the addition of 20 mL
ice-cold water, cooling to room temperature and
placing in an ice bath, the liquid became whitish
or cloudy with white precipitates. The addition of
cold water is very important in purification and
isolation of the crystals from the liquid since
aspirin is insoluble in cold water. As the pure
aspirin crystallizes from the solution, the
dissolved by-product in the solution are excluded
in the crystallization. The crystallized aspirin were
collected 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. Recrystallization of aspirin is done
through the use of water as the crystallizing
solvent. Once crystallized, it went through
filtration to isolate the solid compound which is
the pure aspirin. Once the crystallized aspirin
were purified, they were left to dry. Then they
were weighed and tested for purity.
On the other hand, the calculated percent yield
of acetylsalicylic acid was 100.04%. The weight
of the recovered sample was 2.61g. The
calculation for percent yield was shown in Table
_____. This means that there was a slight error.
Perhaps, the sample was not weighed properly or
it was weighed when it was still wet.
Methyl salicylate, an organic compound naturally
produced by species specifically wintergreens. It
is solid purplish-white crystals with a menthol
scent.
When an acid reacts with an alcohol, it forms an
ester. This type of reaction may be known as
condensation reaction because the molecule of
H2O is removed from the reactants while the
remaining bits of the reactants condense
together to give the main product. This reaction
is also termed as an esterification, since the
product of the reaction is an ester, a compound
containing the COOR group.
The methyl salicylate is formed through
combination of transerification and a Fischer
esterification mechanism that involves
intermediate salicylic. The reaction begins with a
transerification to yield salicylic acid. This
intermediate goes through Fischer esterification
involving the addition of alcohol which reacts with
carboxylic acid group through an acid catalyst.
Since an intermediate is formed, the reaction
proceeds at a much slower rate and is
thermodynamically controlled, the heat provides
the energy needed for the reaction to form
methyl salicylate.
In the experiment, the calculated percent yield of
methyl salicylate was 237.5%. The weight of the
recovered sample was 2.66g. The calculation for
percent yield was shown in Table _____. Thus,
this implies an error in the experiment.
 Ferric (III) Chloride test is used to detect
phenols and to test the purity of Aspirin. When
Ferric (III) Chloride is introduced to a solution
containing phenol, it reacts to the hydroxyl group
of the salicylic acid and produces a purple or pink
colored solution. In the experiment, salicylic acid,
phenol, acetylsalicylic acid product, and methyl
acetylsalicylic product displayed a light purple
solution. However, for the commercial white
aspirin tablet, the hydroxyl group of the salicylic
acid went through esterification wherein it
replaces the hydroxyl group with a ester group
leaving the ferric ion nothing to react with
therefore resulting with no change of color of the
solution. Benzoic acid, also did not display any
change of color.
CONCLUSION
Human Metabolome Database. (n.d.). Benzoic
Acid. Retrieved on October 31, 2018 from
http://www.hmdb.ca/metabolites/HMDB000187
0
Human Metabolome Database. (n.d.). Phenol.
Retrieved on October 31, 2018
from http://www.hmdb.ca/metabolites/HMDB00
00228
Human Metabolome Database. (n.d.). Salicylic
Acid. Retrieved on October 31, 2018 from
https://pubchem.ncbi.nlm.nih.gov/compound/sal
icylic_acid#section=Top
NClt. (n.d.). Aspirin. . Retrieved on October 31,
2018
from https://ncit.nci.nih.gov/ncitbrowser/Conce
ptReport.jsp?dictionary=NCI_Thesaurus&ns=NC
I_Thesaurus&code=C287

In order to synthesize aspirin from its starting

material which is salicylic acid, proper procedure
is needed to have a pure desired product. The
mechanism used in this reaction is nucleophilic
acyl substitution, specifically esterification,
wherein carboxylic acids and alcohols reacted in
the presence of an acid catalyst, phosphoric acid,
to yield an ester product. In conclusion,salicylic
acid was successfully synthesized and the origin
of the synthesized compound is irrelevant to the
properties of the final product itself. salicylic acid
has the same chemical formula and structure
regardless of the starting product it is synthesized
from.

RECOMMENDATIONS

To reduce errors in percentage yield, the sample

must be free of moisture. Sufficient air drying
samples and glassware should be done to get the
exact actual yield of the synthesized product.

REFERENCES
DrugBank. (n.d.). Methyl Salicylate. Retrieved
on October 31, 2018 from
http://www.drugbank.ca/drugs/DB09543