Hetero-cyclic compounds unit III as per PCI syllabus for second year B pharmacy students. It covers all the details regarding Furan, Pyrrole and Thiophene ring

1. Heterocyclic
Compounds
Mr.P.S.Kore
Assistant Professor(Research Scholar)
Department of Pharmaceutical Chemistry
RCP, Kasegaon.

2. Contents
o INTRODUCTION
o CLASSIFICATION
o NOMENCLATURE
o PYROLE (SYTHESIS AND PREPARATION)
o FURAN (SYTHESIS AND PREPARATION)
o THIOPHENE (SYTHESIS AND PREPARATION)

3. PYRROLE
o Structure: The molecular formula of pyrrole is C4H5N. It is
a five member ring with one hetero atom N.
o Structure of Pyrrole is,
N
H
N
+
1H-pyrrole
N
H
N
+
H
N
+
H
N
+
H
N
+
H
+ + + +
..
..
.. ..
..
1 2 3 4 5
Resonating structures:

4. PYRROLE
o Synthesis: Pyrrole may be synthesized by the following
methods.
o 1. From succinimide: Succinimide on distillation with zinc
dust gives pyrrole.
o 2. From Acetylene: When a mixture of ammonia and
acetylene is passed through a red hot tube, Pyrrole is
formed.
N
H
O O N
H
O
H OH N
H
+2ZnO
Zn dust
Heat
Intrermediate Pyrrole
Succunimide
N
H
+H2O
P
yrrole
2
CH
CH
+ NH3
Red hot
tube
Acetylene

5. PYRROLE
o 3. From furan: Pyrrole is mfg by passing a mixture of furan,
ammonia and steam over heated alumina at 753-763 K.
O
N
H
+H2
Steam, Al 2O3
Pyrrole
Furan
753
-
763 K
+ NH3

6. PYRROLE
o Physical Properties:
o 1. Colorless liquid.
o 2. B.P 1310c.
o 3. Slightly soluble in water but totally misible with ether and
ethanol.
o Chemical properties:
o Pyrrole undergoes electrophillic substitution at the 2-position.
Attack of the electrophile at 3-position in pyrrole leads only
two resonance structures.
o Three resonance strutures are possible for the intermediate
produced by attack at 2-position.
o 2-position is more stable as compare to 3-position.

7. Mechanism of reaction
o Pyrrole, Thiophene and Furan undergoes electrophillic substitution
reaction preferably at position 2.
o The mechanism takes place in three steps.
o
1, Step I: Form
ation of electrophile
E
-Nu E
+
+ :Nu
-
E
lectrophile
Nulceophile
2.Step II: Formation of carbocation intermediate
+
X
..
E
+ slow
X
E
H
X E
H
X
E
H
.. .. +
3.Step III: Loss of a proton.
C
-
X
E
H
+ :NU
- Fast
X
E
.. + H-Nu
X= may be NH(Pyrrole), O (Furan) or S (Thiophene)

8. PYRROLE
N
H
..
E
+
N
H
H
E
.. +
N
+
H
E
H
+
N
H
..
E
+
N
H
H
E
..
N
H
H
E
+
+
+ N
+
H
E
H
+
N
H
E
Attack at positon 3
attack at postion 2

9. PYRROLE derivative synthesis
o 4. Paal-Knorr synthesis (from 1,4 diketone): This method involves the
reaction of diketone with ammonia or ammonium carbonate.
o Mechanism: Explain.
o 5. Hantzch Pyrrole synthesis: In this reaction condensation occur
between an alpha haloketone with a beta ketoester in the presence of
ammonia or a primary amine.
N
H
CH3
C
H3
2,5 DimethylPyrrole
C
H3 C C CH3
O
O
Hexane 2, 5 dione
NH3
or (NH4)2CO3
373 K(-2H2O)
N
H
CH3
C
H3
H5C2OOC
Ethyl 2,5 DimethylPyrrole
Ethyl Acetoacetate
COOC 2H5
C
H2
C
CH3
O + NH3 +
CH2Cl
C
CH3
O
apla chloroacetone
Heat +H2O + HCl
-3 carboxylate

10. Mechanism of reaction
o The electrophillic substution reaction in Pyrrole occurs at alpha or 2
position. If it is blocekd then substitution occurs at beta or 3 position.
o
N
H
N
H
I
I
I
I
N
H
NO 2
N
H
COCH 3
N
H
SO3H
N
H
Br
Br
Br
Br
Iodination
I2,KI
Nitration
HNO 3
Friedel crafts acylation
(CH3CO) 2O, SnCl 4
sulphonation
SO3, Pyridine
Bromination
Br2, C2H5OH
2,3,4,5-tetrabromo-1H-pyrrole
1H-pyrrole-2-sulfonic acid
2-nitro-1H-pyrrole
2,3,4,5-tetraiodo-1H-pyrrole
2 Acetyl Pyrrole
1H-pyrrole

11. Mechanism of reaction
N
H
1H-pyrrole
+ 3O
Cr 2O3, CH 3COOH
Oxidation: Pyrrole on oxidation w ith chromiuum trioxide
in acetic acid to give maleinimide.
N
H
O
O
N
H
1H-pyrrole
Zn, CH 3COOH
Reduction: Pyrrole on reduction w ith zinc and acetic acid it gives 3 pyrroline.
w hich on further catalytic reduction gives pyrrolidine (tetrahydropyrrole)
N
H
3 pyrroline
N
H
pyrrolidine

12. FURAN
o Structure: The molecular formula of Furan is
C4H4O. It is a five member ring with one hetero
atom O.
o Structure of Furan is,
O
Furan

13. FURAN
o Synthesis: Furan may be synthesized by the following
methods.
o 1. Furan synthesized from furfural obtained by acid-
hydrolysis of pentosans (C5-polysacharides)
(C5H8O4)n
H2O/H
+
CHO
(HOHC)
CH2OH
H2SO4
-3H2O
O
C
O
H
ZnO/Cr 2O3
-CO
O
Pentosans
Aldopentose Furfural Furan
3

15. FURAN
o Physical Properties:
o 1. Colorless liquid.
o 2. B.P 310c.
o 3. Insoluble in ether but soluble in organic solvents.
o Chemical properties:
o Furan undergoes electrophillic substitution at the 2-position..

16. Mechanism of reaction
o The electrophillic substution reaction in Furanoccurs at alpha or 2
position.
o
O
O
O
NO 2
O
C CH3
O
O
SO3H
O Br
Reduction
2H2 / Ni
Nitration
HNO 3
Friedel crafts acylation
(CH3CO) 2O, SnCl 4
sulphonation
SO3, Pyridine
Bromination
Br2, C2H5OH
2-bromofuran
2-nitrofuran
furan-2-sulfonic acid
tetrahydrofuran
acetic anhydride
2 acetylfuran
Furan

17. Thiophene
o Structure: The molecular formula of Thiophene is C4H4S.
It is a five member ring with one hetero atom S.
o Structure of Thiophene is,
S
thiophene

18. Thiophene
o Synthesis: 1. Thiophene may be prepared by heating
sodium succinate with phosphorous trisulfide.
o 2. By the high temperature reaction of sulfur with butane.
C
H2
C
H2
CO
CO
ONa
+
ONa
+
-
-
Sodiumsuccinate
P2S3
S
+ +
2NaPO 2S S
thiophene
C
H2
CH3
CH2
CH3 S
+
thiophene
+ 4S
600
0
C
3H2S
butane

19. Thiophene
o Physical Properties:
o 1. Colorless liquid.
o 2. B.P 840c.
o 3.Odour similar to benzene.
o 4. Insoluble in water but soluble in organic solvents.
o Chemical properties:
o Furan undergoes electrophillic substitution at the 2-position..

20. Mechanism of reaction
o The electrophillic substution reaction in Thiophene occurs at alpha or
2 position.
o
S
S
S
NO 2
S
C CH3
O
S
SO3H
S Br
Reduction
2H2 / Ni
Nitration
HNO 3
Friedel crafts acylation
(CH3CO) 2O, SnCl 4
sulphonation
SO3, Pyridine
Bromination
Br2, C2H5OH
thiophene
tetrahydrothiphene
2-nitrothiophene
2 acetyl thiophene
thiophene-2-sulfonic acid
2-bromothiophene