Electrophilic substitution in pyrrole, furan and thiophene
E
X
H
+
E
+
X
E
X+
H
H
+
preferred substitution
X1
2
3
E+
X
+
X
+
H
H
H
X = O, NH, or S
H
E
Examples:
H
N
H
acetic anhydride
N
H
NO2
HNO3, 20 oC
N
+
50%
O
acetic anhydride,
BF3,
CH3COOH
15% NO2
O
O
20 oC
50%
S
acetic anhydride
S
HNO3, 20 oC
70%
NO2
S
+
5%
NO2
Furan is able to act as a diene in the reactions of cycloaddition
O
O
O
+
O
O
O
O
O
90% H H
The Fisher synthesis of indoles
N
O
Indole
H
N
HN
H
2
+
Polyphosphoricacid
CH
3
N
+
N
H
3
H 2-Phenylindole
4. Chemistry of pyridine
Electrophilic substitution in pyridine
Pyridine is less active, than benzene toward electrophilic agents, because nitrogen is
more electronegative, than carbon and acts like an electron withdrawing substituent,
including the meta-directing effect.
Example:
NO2
HNO3
H3 C
N
CH3
H2SO4
H3 C
N
CH3
81%
Nucleophilic substitution in pyridine
The presence of nitrogen enables pyridine to react with nucleophilic agents, like an
electron withdrawing substituents enables benzene to participate in such reactions,
including the ortho-directing effect.
1. NaNH2, heat
N
2. H2O
+
N
70%
H2N
-
HN
-
H2N
-
H
N
H2N
H
N
+
NaOH
H2O
NH2
CH
H2
N
-
HC
H2N
H
N
+
HN
H
The most contributing structure
N
-
H
Another example:
PhLi
heat
N
+
LiH
N
50%
These reactions require very strong nucleophiles and heat, because H- is a very weak
leaving group. In ortho- or para-substituted pyridines nucleophilic substitution
proceeds much easier.
NaOCH3
N
Cl
CH3OH
+
N
OCH3
95%
NaCl
Tautomerism of 2-pyridones
NaNO2, H+, H2O
N
NH2
2-Aminopyridine
N
N
OH
2-Hydroxypyridine
N
O
H
2-Pyridone (aromatic)
NH
H
2-Pyridoneimine
Unlike phenol, 2-hydroxypyridine prefers the carbonyl form (2-pyridone), because
the isomerisation does not break aromaticity. However, 2-aminopyridine is the
preferred isomer due to the strong conjugation between electron donating
amino-group and electron withdrawing pyridine ring and weaker conjugation in
2-pyridoneimine
Pyridinium salts
Methylpyridinium iodide
CH3I
+
N
N
-
I
%
CH
3 98
O
H H
H
OH +
NH2
+
N
O
O
NH2
+
N
R
R
Body's oxidizing agent
Body's reducing