HETEROCYCLIC AROMATIC

COMPOUNDS
 A heterocyclic compound is a cyclic
compounds in which the ring atoms are of two
more different elements
Some heterocyclic aromatic compounds:
OH
CH2CHCOOH CH2CH2N(CH3)2
NH2

N N
H H

tryptophan psilocin
An amino acid A hallucinogen in
Psilocybe mushrooms
 Organic Nomenclature

1) The ring systems of common heterocyclic aromatic

compounds have individual names.
N N

N O S N S
H H
pyrrolle furan thiophene imidazole thiazole

N
N N N
pyridine pyrimidine quinoline isoquinoline
 N N

N N N
H H
indole purine

2) The numbering of three representative heterocycles

follows:
4
4 3 4 3
5 3 N N

6 2 5 2 5 2
N S N
1 1 H
1
pyridine thiazole imidazole
3) When a heterocycles contains only one heteroatom,
Greek letters may also be used to designate ring
position. The carbon atom adjacent to the heteroatom
is the  carbon. The next carbon is the  carbon. The
next carbon in line, if any, is .

   

   
N N
H
pyridine pyrrolle
 Pyridine, a Six-Membered Aromatic
Heterocycle

H H

or sp3-hybridized
carbon
N N O
pyridine pyran

aromatic not aromatic

Of the common six-membered heterocycles, only

the nitrogen heterocycles are stable aromatic
compounds
 Properties of pyridine

Each ring atom contributes one  electron

Unshared electrons in sp2 orbital

+ +

+ - - +
N : 1. Containing a planar, six
- + + -
membered ring consisting of
- - five carbons and one nitrogen.
The lowest-energy 
molecular orbital in 2. Each of these ring atoms is sp2
pyridine hybridized and has one
electron in a p orbital.
3. Pyridine contains an electronegative nitrogen,
therefore it is polar.
4. Because nitrogen is more electronegative than
carbon, the rest of the pyridine ring is electron-
deficient (the ring carry a partial positive charge)

E+ attack on ring not favoured

+
N
-
A pyridine ring therefore has a low reactivity toward
electrophillic substitution compared with benzene.
5. Besides, pyridine forms a cation with many Lewis
acids.

e- deficient + + more e- deficient

N N+
- _
FeBr3

6. Pyridine does not undergo Friedel-Crafts

alkylations or acylations, and coupling with
diazonium salts. But it undergoes bromination by
free-radical path.
 Br Br Br
Br2
+
300o
N N N
pyridine 3-bromopyridine 3,5-dibromopyridine
(37%) (26%)

7. The nitrogen in pyridine contains an unshared pair

of electrons in an sp2 orbital. This pair of electrons
can be donated to a hydrogen ion.
8. Like amines, pyridine is basic. The basicity of
pyridine (pKb = 8,75) is less than that of aliphatic
amines (pKb =  4) because the unshared
electrons are in an sp2 orbital instead of an sp3
orbital.
 +
NH Cl-

HCl
Pyridinium chloride
N:

pyridine
CH3I SN2 +
NCH3 I-

N-methylpiridinium iodide
9. Like that of benzene, the aromatic ring of pyridine
is resistant to oxidation. Side chains can be
oxidized to carboxyl groups under conditions that
leave the ring intact.

CH3 COOH
KMnO4, H2O, H+

N N
Nucleophillic Substitution on the Pyridine Ring
A benzene ring substituted with EWG undergoes
aromatic nucleophillic substitutions.
NO2 NO2

NH3
O2N Cl O2N NH2

1-chloro-2,4-dinitrobenzene 2,4-dinitroaniline

Pyridine has a nitrogen which is withdrawing

electron density from the rest of the ring. Pyridine
undergoes aromatic nucleophillic substitutions
Substitution proceeds most readily at the 2-position,
followed by the 4-position, but not at 3-position.
2-position

NH3
heat
N Br N NH2

2-bromopyridine 2-aminopyridine

4-position Cl NH2

NH3
heat
N N
4-chloropyridine 4-aminopyridine
 Mechanism for substitution at 2-position
(favored)
:NH3

-H+ major contributors

N
.. Br

..- ..-
NH2 NH2 NH2
..
N N
.. N
.. ..-
Br Br Br
Resonance structures for intermediate

-Br-

N
.. NH2
The intermediate for 2-substitution is stabilized by
the contribution of the resonance structure in which
nitrogen carries the negative charge.
Substitution at the 3-position goes through an
intermediate in which the nitrogen cannot help
stabilize the negative charge.
The intermediate for 3-substitution is of higher
energy; the rate of reaction going through this
intermediate is slower.
Benzene itself (with no substituents) does not undergo
nucleophillic substitution. This reaction does occur with
pyridine if an extremely strong base such as lithium reagent
or amide ion (NH2-) is used.

.. - 100o
+ : NH2 no reaction

.. -
+ : NH2 100o -H2O
+ OH-
-H2 .. -
N N NH N NH
.. 2
..
2-aminopyridine
(70%)

+ Li 100o + LiH
N N
2-phenylpyridine (50%)
In the reaction of pyridine with NH2-, the initial product is the
anion of 2-aminopyridine. The free amine is obtained by
treatment with water.
Step 1

.. - .. -
H H H
N ..
.. N
.. - N
.. N
.. - NH NH ..
: NH2 .. 2 .. 2 NH
.. 2
Resonance structures for intermediate

-
+ H
..
loss of H-
+ H2
N N H ..-
.. H N
.. NH
..
Step 2 (treatment with H2O)

+ H2O + OH-
..- ..
N
.. NH N
.. NH2

2-aminopyridine
 Quinoline and Isoquinoline

Quinoline is a fused-ring heterocycle that is similar

in structure to naphthalene, but with a nitrogen at
position 1. Isoquinoline is the 2-isomer.
5 4
6 3
or
7 2
N N
8 1 quinoline

5 4
6 3
or N
7 N2
8 1 isoquinoline
 Properties of Quinoline and Isoquinoline

1. Both quinoline and isoquinoline contain a pyridine

ring fused to a benzene ring. The nitrogen ring in
each of these compounds behaves somewhat like
the pyridine ring.
2. Both compounds are weak bases (pKb = 9,1 and
8,6 respectively)

3. Both compounds undergo electrophillic

substitution more easily than pyridine, but in
position 5 and 8 (on the benzenoid ring, not on
the dactivated nitrogen ring)
The position of substitution are determined by
intermediates similar to those in naphthalene
substitution reactions. NO2

HNO3
+
H2SO4
N 0o N N
5-nitroquinoline (52%)
quinoline NO2
NO2 8-nitroquinoline (48%)

HNO3
+
N H2SO4 N N
0o
5-nitroisoquinoline (90%)
isoquinoline NO2
8-nitroisoquinoline (10%)
4. Like pyridine, the nitrogen-containing ring of either
quinoline or isoquinoline can undergo
nucleophillic substitution. The position of attack
is  to the nitrogen in either ring system, just as it
is in pyridine.
1) NH2-
2) H2O
N N NH2
quinoline 2-aminoquinoline

1) CH3Li
2) H2O N
N

isoquinoline
CH3
1-methylisoquinoline
 Pyrrole, a Five-Membered Aromatic
Heterocycle
1)For a five-membered ring heterocycle to be
aromatic, the heteroatom must have two electrons
to donate to the aromatic  cloud.
2)Pyrrole, furan, and thiophene all meet this
criterion and therefore they are aromatic.

.. .. ..
N
H
..
O S
..
pyrrolle furan thiophene
3)Unlike pyridine and the amines, pyrrole (pKb = 
14) is not basic under the usual conditions.

+
+H No stable cation
..
N
H

WHY ?
One  electron
from each carbon Two  electrons
from nitrogen
H + + H
- -
+ +
H
- + N- H
-
H

In five-membered ring, the minimum electrons

needed for aromaticity is six.
The four carbons of pyrrole each contribute one
electron. While, the nitrogen atom in pyrrole must
contribute two electrons (not just one as in pyridine)
to the  molecular orbital and three electrons in 
bonds to two ring carbons and to a hydrogen.
 Consequently, all five bonding electrons of the
nitrogen are used in bonding.
The pyrrole nitrogen does not have unshared
electrons and is not basic.

electron rich
e- deficient + -
.. partially negative

N + N
- .. H
The pyrrole ring has six
 electrons for only five
ring carbon
 Electrophillic Substitution on the Pyrrole Ring

- the ring is electron rich

.. and partially negative
+ N
H

The carbons are active toward electrophillic

substitution but has low reactivity toward
nucleophillic substitution. (this reactivity is opposite
to that of pyridine)
 SO3
Pyridine SO3H
N
H
2-pyrrollesulfonic acid (99%)

N
H
HNO3
pyrrolle NO2
(CH3CO)2O
o N
5 C H
2-nitropyrrolle (80%)

Electrophillic substitution occurs principally at the

2-position of the pyrrole ring. WHY ?
2-Nitration (favored)

+NO2+ Three resonance structures

..
N
H
+
H H H

.. + .. +
N N N
NO2 H NO2 H NO2
H
Resonance structures for intermediate

-H+ NO2
..
N
H
3-Nitration ( not favored)

Only two resonance structures

+NO2+
..
N
H H H NO2

NO2 NO2
-H+
+ ..
.. +
N
N N H
H H

Resonance structures for intermediate

 Porphyrins
The porphyrin ring system is a biologically
important unit found in heme, the oxygen-carrying
component of hemoglobin; in chlorophyll, a plant
pigment; and in cytochromes, compounds involved
in utilization of O2 by animals.

..
N
H
N.. .. N
H
N
..

porphyrin
The pyrrole hydrogens in the porphyrin ring system
can be replaced by a variety of metal ions. The
product is a chelate, a compounds or ion in which a
metal ion is held by more than one bond from the
original molecule.

..
N
Planar and
N: Fe :N
resonance-stabilized
N
..
 HOOCH 2CH2C CH3

..
HOOCH 2CH2C N CH3

N: Fe :N

H3C N
.. HC CH2

H2C CH CH3

heme