Experiment no-5

Green approach: Acetylation of primary amine

(Preparation of acetanilide)Acetanilide is an analgesic, which was formally known as Antifebrin, and is structurally similar

to acetaminophen (or Tylenol). However, unlike acetaminophen, acetanilide is toxic.

Acetanilide is prepared from aniline using an acetylation reaction.  Acetylation is often used to

place an acetyl protecting group on primary or secondary amines to reduce their reactivity

toward oxidizing agents or electrophiles. Anilidess are usually crystalline solids which can be a

help in purification by recrystallization. The melting points can be used for characterization and

identification of the corresponding compounds.

Conventional procedure to synthesize anilide from aniline is treating with acetic anhydride in

presence of pyridine in dichloromethane (DCM) as solvent or treating anilide with HCl, acetic

anhydride and sodium acetate (Scheme-1). In qualitative organic analysis this is a useful method

to prepare derivative of aniline. But any of the reagents are not eco-friendly. Instead of these

reagents we can follow a different route which is more environments friendly.

Scheme-1

Scheme-2: Mechanism for acetylation of aniline

In present we are very much concerned about environment. To save our world we should have

knowledge about Green chemistry, so now days Green Chemistry is an essential part of

Chemistry Curriculum.

“Green Chemistry” implies that the methods used during the experiment are environmentally

“friendly. It involves the development of synthetic methods that use nontoxic reagents, non-

harmful solvents and produce almost no wasteful by-products and thus causes the minimum

amount of pollution.

Conventional procedure to synthesize acetanilide:

Dissolve 500 mg of aniline in 14 mL of water. Aniline is immiscible in water and two layers

should be observed. Add 0.45 mL of concentrated hydrochloric acid and aniline hydrochloride

will be formed. Add acetic anhydride (0.6 mL) in aniline hydrochloride solution and

immediately add the sodium acetate solution [Sodium acetate (530 mg) dissolve in 3 mL of

water]. The solution becomes white as acetanilide precipitates. Cool the solution in an ice bath

and collect the solid acetanilide by vacuum filtration. Recrystallize from 95% ethanol - it may be

necessary to use a small amount of water.

Green approach for synthesis of anilide from aniline

Scheme-2

Mechanism

Chemicals Required:

Aniline – 20 mL (10.2 g)

Glacial acetic acid - 60 mL

Zinc dust - 1 g

Procedure:

Step-1: Take acetic acid (60 mL) in 250 mL round bottom flask. Add zinc dust (1 g) in acetic

acid (Inside hood) and stir it for 5 min. (see the note)

Step-2: Add aniline (20 mL) into that mixture.

Step-3: Attach with a reflux condenser and continue the heating for about 2 h at 80-90 ºC.

Step-4: Stop heating and cool it at RT.

Step-5: Add slowly 5 mL of cold water into the reaction mixture with stirring.

Step-6: Put the reaction mixture in ice bath. After 10-15 min you will observe formation of

shining crystals of acetanilide. If you are not getting any crystal, keep the container in freeze.

Next day shining crystals will form. (Alternative way: Take out half of your reaction mixture in a

beaker, cool it in ice bath. Add hexane dropwise and stir. If require you can add few ice crystal

into that mixture. You will see white ppt has started to form)

Step-7: Filter the crystals in Buchner funnel.

Step-8: White crystals can be re-crystallized in boiling water to get pure compound.

Step-9: Perform anilide functional group test to know whether it has formed or not.

Product analysis:

1. Check MP (Reported: 114 ºC)

2. Check IR and 1H NMR.

Why it is called Green?

In this protocol we can avoid the use of acetic anhydride, which is banned due to its utility in

narcotic business.

Note:1. Zinc dust should be cleaned with dilute HCl before the reaction because its surface can have

excessive oxide deposition.

Safety: Zn dust is stable in dry air. But reacts vigorously or explosively with water. Store in a cool dry place - keep containers tightly closed. Keep away from water. Avoid making dust. Wash thoroughly after handling. Avoid contact with skin and eyes. Avoid ingestion and inhalation.

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