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SYNTHESIS OF ACETANILIDE

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

University of Santo Tomas, Faculty of Pharmacy1

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 founduses 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 aproton. 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.

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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 C6H5NH2. 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 (CH3CO)2O. Commonly abbreviated as

Ac2O, 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 offree aqueous calcium hypochlorite was added; b) to

another portion, 1mL of 2% KMnO4 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% KNO2 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 capillarytube. 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

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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 insolution

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 (oC)

1 112oC

2 118oC

Average 115oC

Table 1.Results of Melting Point Determination.

On average, the synthesized compound has a meltingpoint close to the theoretical melting point, which is

114oC.

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%.

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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 114oC.

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 ofacetanilide in man",J. Pharmacol. Exp. Ther.94(1):

2938.

[5]Ashfords Dictionary of Industrial Chemicals (3rd

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

http://chemicalland21.com/lifescience/phar/ACEhttp://en.wikipedia.org/wiki/Julius_Axelrodhttp://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdfhttp://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdfhttp://wwwchem.uwimona.edu.jm/lab_manuals/chttp://wwwchem.uwimona.edu.jm/lab_manuals/chttp://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdfhttp://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdfhttp://en.wikipedia.org/wiki/Julius_Axelrodhttp://chemicalland21.com/lifescience/phar/ACE