SYNTHESIS OF ACETANILIDE

Silverio, A.
1
, Soriano, R.
1
, Tan, J.
1
, Tequillo, H.
1
, Tolentino, M.
1

University of Santo Tomas, Faculty of Pharmacy
1

ABSTRACT
The experiment is performed to understand the chemical synthesis of acetanilide, a derivative of aniline.
Acetanilide, produced from the nucleophilic acyl substitution of aniline and acetic anhydride, is synthesized and
purified by recrystallization. Color Test and Azo-Dyestuff Test are performed in order to determine the purity of the
synthesized acetanilide. A series of color reactions were observed upon the addition of chemical reagents in both
tests. The first part of the Color Test showed the transition of colors from dirty white precipitate to purple crystal in
solution. The second part of the Color Test started from dirty white precipitate until it formed a green solution.
Finally, the Azo-Dyestuff Test started as a brown solution and formed a yellow precipitate in the end. To further
check the purity, the melting point determination is done. After getting the average of the two trials, a temperature of
115 C is obtained, close to the melting point of pure acetanilide which is 114 C.
INTRODUCTION
Acetanilide is also known as N-
phenylacetamide, acetanil or acetanilid, and was
formerly known by the trade name Antifebrin.
[1]


Figure 1. Chemical structure of Acetanilide.
Acetanilide was the first aniline derivative
found to possess analgesic and antipyretic properties,
and was quickly introduced into medical practice by
A. Cahn and P. Hepp in 1886.
[2]
But its unacceptable
toxic effects, the most alarming being cyanosis due to
methemoglobinemia, prompted the search for less
toxic aniline derivatives. In 1948, it was established
that acetanilide is mostly metabolized to paracetamol
in the human body and that it was the paracetamol
that was responsible for the analgesic and antipyretic
properties.
[3]
The observed methemoglobinemia after
acetanilide administration was ascribed to the small
proportion of acetanilide that is hydrolyzed to aniline
in the body. Acetanilide is no longer used as a drug in
its own right, although the success of its metabolite,
paracetamol, is well known.
Acetanilide is used as an inhibitor of
hydrogen peroxide decomposition and is used to
stabilize cellulose ester varnishes. It has also found
uses in the intermediation in the rubber accelerator
synthesis, dyes and dye intermediate synthesis, and
camphor synthesis. Acetanilide is used for the
production of 4-acetamidobenzenesulfonyl chloride,
a key intermediate for the manufacture of the sulfa
drugs.
[4]
It is also a precursor in the synthesis of
penicillin and other pharmaceuticals.
[5]

Acetanilide can be produced by reacting
acetic anhydride with aniline through nucleophilic
acyl substitution. Aniline, as an amine, serves as the
nucleophile which gains a carbonyl group and loses a
proton. Acetic anhydride serves as the electrophile
and is the source of an acyl group to form an amide
which is acetanilide and a by-product, acetic acid.
[6]

Figure 2. Nucleophilic acyl substitution of aniline
and acetic anhydride to produce acetanilide and
acetic acid.
Recrystallization is a widely-used technique
to purify a solid mixture. The desired product is
isolated from its impurities by differences in
solubility. Insoluble impurities and colored impurities
can be removed from hot solvent through the use of
filtration. Soluble impurities remain in the cold
solvent after recrystallization. The desired product
should be as soluble as possible in hot solvent and as
insoluble as possible in cold solvent.
[7]

EXPERIMENTAL
A. Compounds Tested
Aniline (=1.02g/mL) is a toxic organic compound
with the formula C
6
H
5
NH
2
. Consisting of a phenyl
group attached to an amino group, aniline is the most
prototypical aromatic amine. Its main use is in the
manufacture of precursors to polyurethane and other
industrial chemicals. Like most volatile amines, it
possesses the odor of rotten fish. It ignites readily,
burning with a smoky flame characteristic of
aromatic compounds.
[8]


Figure 3. Chemical Structure of Aniline.

Acetic Anhydride, (=1.082g/mL) also known as
ethanoic anhydride, is the chemical compound with
the formula (CH
3
CO)
2
O. Commonly abbreviated as
Ac
2
O, it is the simplest isolatable acid anhydride and
is a widely used reagent in organic synthesis. It is a
colorless liquid that smells strongly of acetic acid,
formed by its reaction with the moisture in the air.
[9]


Figure 4. Chemical structure of Acetic Anhydride.

B. Procedure
1. Reaction of Aniline and Acetic Anhydride
20 drops of aniline and 10mL of distilled water were
placed in a hard glass test tube. 20 drops of acetic
anhydride were added to the aniline solution and
stirred for 5 minutes or until the solid, a white
precipitate formed. 10mL of water was added and the
test tube was heated in a water bath. It was stirred
occasionally until the entire solid dissolved. The test
tube was set aside for 5 minutes to cool and chilled in
an ice bath for 10 minutes. Using pre-weighed filter
paper, the solution was filtered and the residue was
collected. The residue was pressed to remove excess
water using another filter paper. The sample was
allowed to dry completely. The acetanilide was
weighed and the % yield computed. The sample was
stored in an amber bottle until next experiment
period.
2. Color Test
0.5g of acetanilide was placed in a test tube and
treated with 1mL of concentrated HCl. The solution
was diluted with 12mL of water and was gently
heated to boiling. The solution was cooled and
divided into 2 equal parts: a) to one portion, 1mL of
free aqueous calcium hypochlorite was added; b) to
another portion, 1mL of 2% KMnO
4
solution was
added.
3. Azo-Dyestuff Test
0.5g of acetanilide was boiled with 1mL of
concentrated HCl in a water bath. The test tube was
cooled and placed in an ice bath for 10 minutes. The
solution was diluted with 5mL of distilled water. 4
drops of 10% KNO
2
was added and made alkaline
with NaOH. A pinch amount of beta naphthol was
added. The color reaction was observed.
4. Melting Point Determination
The test substance was pulverized by means of a
clean spatula. The reducing of size was done in a
watch glass. The open end of a capillary tube was
pushed into the powdered test substance. The
powder was moved to the closed end of the capillary
tube by tapping it on the table until the powdered test
substance occupied 1-2 mm of the capillary tube end.
The opposite end of the filled capillary tube was
sealed. The capillary tube was attached to a
thermometer using rubber bands by aligning the bulb
of the thermometer to the closed end of the capillary
tube. An oil bath was made by half filling a 100ml
beaker with warm cooking coil. The oil bath was
heated. The thermometer/ capillary tube assembly
was placed in an oil bath. The surface level of the
aspirin must be beneath the surface level of the oil
bath. The beaker was placed on a hot plate and the oil
was frequently stirred to distribute heat uniformly.
The temperature at which the aspirin melts was
noted. The procedure was repeated twice and the
results were averaged. The experimental result was
compared with the accepted value.

Figure 5. An illustration of the setup used in Melting
Point Determination.

RESULTS AND DISCUSSION
Synthesized acetanilide is an odorless solid chemical
of leaf or flake-like appearance. It is obtained by
mixing premeasured amounts of aniline and acetic
anhydride.

The first part of Color Test resulted in a transition of
colors from dirty white precipitate to purple crystals
in this order:
Dirty white precipitate- clear, colorless solution-
brown ring- clear, colorless solution- clear, light pink
solution- dark blue turbid solution- purple crystals in
solution

The second part of Color Test gave a transition from
dirty white precipitate to green solution in this order:
Dirty white precipitate- clear, colorless solution-
brown ring- clear, colorless solution- clear, light pink
solution- yellow solution- green solution

The Azo-Dyestuff Test likewise gave a transition
from brown solution to yellow precipitate in this
order:
Brown solution- purple solution- white precipitate-
orange precipitate- yellow precipitate

Melting point determination determines the purity of
the synthesized compound by comparing the
experimental melting point to the theoretical melting
point.

Trials Temperature (
o
C)
1 112
o
C
2 118
o
C
Average 115
o
C
Table 1. Results of Melting Point Determination.

On average, the synthesized compound has a melting
point close to the theoretical melting point, which is
114
o
C.

The raw and derived data collected during the
experiment is as follows:
Sample Name: Acetanilide
A. Mass of Aniline
(

) (

)
B. Mole of Aniline
(

)
C. Mass of Acetic Anhydride
(


) (

)

D. Mole of Acetic Anhydride
(

)

The limiting reagent is Acetic Anhydride while the
excess reagent is Aniline.
E. Theoretical Moles of Acetanilide
(

) (

) (


)

F. Theoretical Mass of Acetanilide
(

)
G. Mass of Filter Paper: 1.5699g
H. Mass of the Filter Paper and Acetanilide:
2.7294g
I. Calculation of Percentage Recovery

The percentage yield is 80.93%.

CONCLUSION
Acetanilide is an odorless powder with a leaf or
flake-like appearance. It is synthesized via
nucleophilic acyl substitution by reacting aniline and
acetic anhydride. It produces purple crystals and a
green solution when subjected to Color test and gives
a yellow precipitate in Azo-Dyestuff Test. It has a
melting point of 114
o
C.

REFERENCES
[1]
http://chemicalland21.com/lifescience/phar/ACET
ANILIDE.htm
[2]
Cahn, A .; Hepp, P. (1886), "The antifebrin, a new
antipyretic," Centralbl. Klin Med. 7:. 561-64.
[3]
Brodie, B. B.; Axelrod, J. (1948),"The fate of
acetanilide in man", J. Pharmacol. Exp. Ther.94 (1):
2938.
[5]
Ashfords Dictionary of Industrial Chemicals (3
rd

ed.). 2011. p.33.
[6]
Acetanilide, SIDS Initial Assessment Report,
Geneva: United Nations Environment Programme,
September 2003.
[7]
http://wwwchem.uwimona.edu.jm/lab_manuals/c1
0expt23.html
[8]
en.wikipedia.org/wiki/Aniline
[9]
en.wikipedia.org/wiki/Acetic_anhydride