N Acetylation: The Acetylation of Aniline

Introduction

In an earlier experiment, we saw that the oxygen atom in an alcohol or

phenol could be acetylated with acetic anhydride or acetyl chloride. These are
examples of acylation reactions that produce acetate esters. If we substitute
nitrogen plus an H (to account for the trivalent N), for oxygen in an alcohol we get
an amine. For example, ethanol would become ethylamine. Likewise, the
substitution of NH for O in phenol makes aniline, a primary aromatic amine.
Figure 1 shows the structural relationships among these compounds. In these
structures, nitrogen requires two hydrogen atoms to satisfy its trivalence.

CH3CH2OH CH3CH2NH2
ethanol ethanamine
ethyl alcohol ethylamine

OH NH2

phenol aniline

Figure 1. Alcohols and amines.

Though the compounds in Figure 1 differ in some properties (e.g., ethanol is

a neutral compound, phenol is a weak acid, and ethylamine and aniline are weak
bases), they can all serve as nucleophiles because of the pair of non-bonding
electrons on the heteroatom. Thus, all of these compounds react similarly with
acetic anhydride or acetyl chloride. As we have seen before, acetic anhydride is
formed by heating (i.e., pyrolysis) of acetic acid. Two molecules of acetic acid lose
one molecule of water to form one molecule of the anhydride. When two
molecules join by the loss of a small molecule such as water, the reaction is called
a condensation reaction. Acetic anhydride is formed by a condensation reaction
between two acetic acid molecules as shown in Figure 2.

Lab 10 1
 O O O

2 CH3COH CH3COCCH3 + H2O
acetic acid acetic anhydride

Figure 2. Preparation of acetic anhydride.

Mechanism of Acetylation of Aniline

Figure 3 shows the mechanism of N acylation, using acetic anhydride as the
acylating agent and aniline as the substrate.

O- O
O O
CH3C O CCH3
NH2 CH3COCCH3 NH2
+
acetic anhydride

aniline transfer di-ion

of H+

O H
OH O
O
CH3C -O CCH3
CH3C O CCH3
NH +
NH acetate

O O
N CCH3 + HOCCH3
H
acetanilide acetic acid

Figure 3. Mechanism of N acylation.

The product of an acetylation of an amine is an acetamide, which is an
analog of an acetate ester. When the amine is aniline, the acetamide is called

Lab 10 2
acetanilide. Thus, amides contain a nitrogen atom next to a carbonyl group.
Compounds that contain a heteroatom next to a carbonyl group are acids or acid
derivatives. Amides are acid derivatives. Acid derivatives are composed of an acid
part and a second part, which depends on the heteroatom and overall structure. For
example, esters are a combination of an acid and an alcohol, and amides are a
combination of an acid and an amine. Both esters and amides are acid derivatives
because they both contain an acid part. The acidic hydrolysis of acid derivatives
produce the acid and the other part. Basic hydrolysis produces the acid salt and the
other part. The salt must be acidified to produce the acid. Thus, amides, esters, acyl
halides, and anhydrides are all acid derivatives because hydrolysis of them yields
an acid.

Figure 4 shows the acid hydrolysis of four derivatives of acetic acid, acetamide,
ethyl acetate, acetyl chloride and acetic anhydride. Acetic acid is a product in each
case, because acetic acid is the acid part of each starting compound. The second
part depends on the starting material. For example, acetamide yields ammonia,
ethyl acetate yields ethanol, acetyl chloride yields hydrogen chloride, and acetic
anhydride yields acetic acid.

Lab 10 3
 O
O HOH
CH3CNH2 CH3COH + NH3
H+
acetamide acetic acid ammonia
an amide

O O
HOH
CH3COCH2CH3 CH3COH + HOCH2CH3
H+
ethyl acetate acetic acid ethanol
an ester an alcohol

O O
HOH
CH3CCl CH3COH + HCl
H+
acetyl chloride acetic acid hydrochloric acid
an acyl chloride
or acid chloride

O O
O O HOH + CH COH
CH3COH 3
CH3COCCH3 H+
acetic acid acetic acid
acetic anhydride

Figure 4. Hydrolysis of acid derivatives.

Lab 10 4
Procedure

1. Tare a 25-mL Erlenmeyer flask on a microanalytic balance.

2. Carefully transfer 0.46-g aniline to the Erlenmeyer flask.

3. Take the Erlenmeyer flask to your bench; add 10 drops of concentrated

hydrochloric acid, HCl, to the flask.

4. Add 10-mL distilled water to the Erlenmeyer flask and mix the contents.

5. Prepare a solution of sodium acetate (NaOAc) by dissolving 0.5-g anhydrous

sodium acetate in 3-mL distilled water in a small beaker.

6. Add, in quick succession, 15 drops of acetic anhydride and the solution from
Step 5 to the 25-mL Erlenmeyer flask.

7. Swirl the Erlenmeyer flask to mix the contents and place it in an ice-water bath.

8. Acetanilide will crystallize from the solution. When the crystallization is

complete, filter the crystals on a Bchner funnel.

9. Weigh the dry crystals and then show them to the instructor.

10. Clean and return all glassware to the storages areas. Check the balance area.
Return any chemicals to their original locations and turn off all balances.

Lab 10 5
 Questions N Acetylation

Last name____________________________, First name_____________________

1. Draw structures of isopropylamine, propanamide, sec-butyl alcohol, and propyl

acetate.

2. Write an equation for the preparation of propanoic anhydride, starting with

propanoic acid.

3. Write an equation for the preparation of propanoyl chloride, starting with

propanoic acid.

Write complete chemical equations for the reactions between each of the
following pairs of compounds.

4. 2-Nitrophenol plus acetic anhydride.

5. Butanol plus acetic anhydride.

6. 4-Bromoaniline plus acetic anhydride.

Lab 10 6
7. Phenol plus propanoyl chloride.

8. Acetic anhydride plus water in an acidic medium.

9. Aniline plus acetyl chloride.

10. Acetanilide plus aqueous sodium hydroxide.

Lab 10 7