Organic Chemistry

706 CHAPTER 17 Carbonyl Compounds I

17.16 Acid-Catalyzed Hydrolysis of Amides

When an amide is hydrolyzed under acidic conditions, the acid protonates the car-

bonyl oxygen, increasing the susceptibility of the carbonyl carbon to nucleophilic at-

tack. Nucleophilic attack by water on the carbonyl carbon leads to tetrahedral

intermediate I, which is in equilibrium with its nonprotonated form, tetrahedral inter-

mediate II. Reprotonation can occur either on oxygen to reform tetrahedral intermedi-

ate I or on nitrogen to form tetrahedral intermediate III. Protonation on nitrogen is

favored because the group is a stronger base than the OH group. Of the two pos-

sible leaving groups in tetrahedral intermediate III ( and ), is the weak-

er base, so it is expelled, forming the carboxylic acid as the final product. Since the

reaction is carried out in an acidic solution, will be protonated after it is expelled

from the tetrahedral intermediate. This prevents the reverse reaction from occurring.

Let’s take a minute to see why an amide cannot be hydrolyzed without a catalyst. In

the uncatalyzed reaction, the amide is not protonated. Therefore, water, a very poor

nucleophile, must attack a neutral amide that is much less susceptible to nucleophilic

attack than a protonated amide would be. In addition, the group of the tetrahedral

intermediate is not protonated in the uncatalyzed reaction. Therefore, is the

group expelled from the tetrahedral intermediate—because is a weaker base than

—which reforms the amide.

An amide reacts with an alcohol in the presence of acid for the same reason that it re-

acts with water in the presence of acid.

OH

CH 3 C

OH

NH 2

tetrahedral intermediate in

uncatalyzed amide hydrolysis

OH

CH 3 C

OH

NH 3

+

tetrahedral intermediate in

acid-catalyzed amide hydrolysis

• NH
  2

HO-

HO-

NH 2

C

O

C

tetrahedral intermediate I

tetrahedral intermediate III

tetrahedral intermediate II

OH

+

+

+

+

+

CH 3 NH 2 CH 3 NH 2

H 2 O

OH

+ +

+

CH 3 O− CH 3 OH

NH 4 NH 3

OH

OH OH 2

H−OH 2

CH 3 CNH 2

OH

OH

CH 3 CNH 2

OH

OH

H−OH 2

CH 3 CNH 3

mechanism for acid-catalyzed hydrolysis of an amide

+

C

O

C

+

H

NH 3

HO- NH 3 NH 3

NH 2

Tutorial:

Conversions between

carboxylic acid derivatives

An acid catalyst increases the
reactivity of a carbonyl group.

An acid catalyst can make a
group a better leaving group.