Organic Chemistry

Section 17.7 General Mechanism for Nucleophilic Acyl Substitution Reactions 685

A carboxylic acid derivative will undergo

a nucleophilic acyl substitution reaction,

provided that the newly added group in

the tetrahedral intermediate is not a

much weaker base than the group that

was attached to the acyl group in the

reactant.

All carboxylic acid derivatives

react by the same mechanism.

Movie:

Nucleophilic acyl substitution

An anhydride, however, cannot be converted into an acyl chloride because a chloride ion

is a weaker base than a carboxylate ion.

17.7 General Mechanism for Nucleophilic

Acyl Substitution Reactions

All carboxylic acid derivatives undergo nucleophilic acyl substitution reactions by the

same mechanism. If the nucleophile is negatively charged, the mechanism discussed

in Section 17.5 is followed: The nucleophile attacks the carbonyl carbon, forming a

tetrahedral intermediate. When the tetrahedral intermediate collapses, the weaker base

is eliminated.

If the nucleophile is neutral, the mechanism has an additional step. A proton is lost

from the tetrahedral intermediate formed in the first step, resulting in a tetrahedral in-

termediate equivalent to the one formed by negatively charged nucleophiles. This

tetrahedral intermediate expels the weaker of the two bases—the newly added group

after it has lost a proton or the group that was attached to the acyl group in the reactant.

( represents any species in the solution that is capable of donating a proton, and

represents any species in the solution that is capable of removing a proton.)

The remaining sections of this chapter cover specific examples of these general

principles. Keep in mind that all the reactions follow the same mechanism.There-

fore, you can always determine the outcome of the reactions of carboxylic acids and

carboxylic acid derivatives presented in this chapter by examining the tetrahedral

intermediate and remembering that the weaker base is preferentially eliminated

(Section 17.5).

R Y

C

OH

C

R

++H

O

RC

OH

H

+

2 O YY−

− O

RC

OH

B HB+

Y

−

removal of

a proton from

the tetrahedral

intermediate

neutral nucleophile

attacks the carbonyl

carbon

elimination of the

weaker base from the

tetrahedral intermediate

O O

≠B

HB+

−

negatively charged

nucleophile attacks

the carbonyl carbon

elimination of the

weaker base from the

tetrahedral intermediate

O

Y

H

−

++

O

RC

O

OH

YY−

OH

O

R

CC

R

an anhydride

RO

Cl− no reaction

R

C +

O

C

O

carboxylate ion

RO−

an acyl chloride

RCl

+

an anhydride

RO

Cl−

R

C +

O

C

O

C

O

C

O

The tetrahedral intermediate

eliminates the weakest base.