Organic Chemistry

If the leaving groups at C-2 and C-4 are different, the incoming nucleophile will
preferentially substitute for the weaker base (the better leaving group).

PROBLEM 19

Compare the mechanisms of the following reactions:

PROBLEM 20

a. Propose a mechanism for the following reaction:

b. What other product is formed?

∆

N N O

H

KOH/H 2 O

+ −NH 2

N

Cl

+ Cl−

N

NH 2

+ −NH 2

Cl

+ Cl−

NH 2

N

Br

−NH

2

OCH 3

+

N

NH 2

Br−

OCH 3

+

∆

N

CH 3

CH 3 O−

Cl

+

N

CH 3

Cl−

OCH 3

+

∆

−N

2-position

most stable

most stable

N

−

− −

−

−

− −

−

N

N N

N

N

N N N

4-position

+ Y− 3-position

H

Y

H

Y

Y H

H

Y

H

Y

Y H

H

Y

H

Y

Y H

>Figure 21.3

Structures of the intermediates that

can be formed from the reaction of

a nucleophile with pyridine.

Section 21.10 Aromatic Six-Membered-Ring Heterocycles 905

Nucleophilic aromatic substitution of pyridine takes place at C-2 and C-4, because at-
tack at these positions leads to the most stable intermediate. Only when nucleophilic
attack occurs at these positions is a resonance contributor obtained that has the greatest
electron density on nitrogen, the most electronegative of the ring atoms (Figure 21.3).

slow

mechanism for nucleophilic aromatic substitution

fast

Y−

N

+

Z

Z−

N

+

N Z Y

Y

−

Pyridine undergoes nucleophilic

aromatic substitution at C-2 and C-4.

Pyridine is lessreactive than benzene to-

ward electrophilic aromatic substitution

and morereactive than benzene toward

nucleophilic aromatic substitution.