1. Pyrrole can be synthesized by passing acetylene and ammonia through a hot tube or by heating succinimide with zinc dust. 2. Pyrrole undergoes electrophilic substitution preferentially at the 2-position and can be nitrated, sulfonated, halogenated, formylated, acetylated, alkylated, and undergo coupling reactions. 3. Pyrrole has important medicinal uses with derivatives such as atorvastatin and tolmetin containing pyrrole nuclei, and glimepiride, enalapril, and captopril containing pyrrolidine or pyrroline nuclei for treating conditions like high blood pressure, heart disease

1. Heterocyclic Compounds
Pyrrole
Synthesis,Reactions&MedicinalUses
Prof.Dr.P.Venkatesh
Jagan’s Institute of Pharmaceutical Sciences - Nellore
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N
H

2. Synthesis of Pyrrole
By passing a mixture of acetylene and ammonia through a red-hot tube.
By heating succinimide with zinc dust.
By warming succinic dialdehyde with ammonia.
+
CH
CH
+ NH3

HC
HC N
H
Acetylene Ammonia Pyrrole
N
H
O
O N
H
OH
HO
Zn

N
H
Pyrrole
Succinimide
O
O
Succinic dialdehyde
OH
HO
NH3
N
H
Pyrrole
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3. Characteristic Reactions of
Pyrrole
N
H
1
2
3
4
5
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4. 1.ElectrophilicSubstitution
The π-electron density at the carbon atom of the Pyrrole ring is very high (due to resonance) as
compared to that of benzene.
Hence Pyrrole is very reactive towards electrophiles.
The high reactivity is also due to the relatively stable structure (III) of the 2-substituted pyrrole.
In structure III every atom has an octet of electrons; nitrogen accommodates the positive
charge simply by sharing four pair of electrons.
N
H
E
H
..
+
N
H
E
H
..
+
N E
H
+
I II III
H
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5. Pyrrole undergoes electrophilic substitution preferentially at either of the 2-positions
followed by 3.
The predominance of 2-substituted product over 3 is because of the positive charge in the
transition state in 2-substituted product is delocalised over three atoms as compared to two
in 3-substituted product.
Thus, the intermediate from position-2 attack has less energy (more stable) than the
intermediate from position-3 attack.
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6. Electrophilic attack at position-2
Electrophilic attack at position-3
Position 3 is attacked only when both of the 2-positions are blocked
Electrophilic substitution reactions of pyrrole are not carried out in the presence of strong acids or reagents
which give rise to strong acids, because under such conditions pyrrole undergoes polymerisation.
N
H
.. + E
+
N
H
E
H
..
+
N
H
E
H
..
+
N E
H
+
N
H
E
..
- H+
More stable 2 - Substitution
product
H
N
H
.. + E
+
N
H
E
H
.. +
N
E
H
+
Less stable
- H+
N
H
E
..
3 - Substitution
product
H
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7. a. Nitration
Pyrrole can be nitrated by a cold solution of nitric acid in acetic anhydride.
b. Sulphonation
Sulphonated with sulfur trioxide in pyridine at about 100°C
N
H
Pyrrole
+ HNO 3 + (CH3CO) 2O
Nitric acid Acetic anhydride
10 °C
N
H
NO2
+ 2CH3COOH
2 - nitro pyrrole
Acetic acid
N
H
+ SO3
Sulfur
trioxide
Pyridine
100 °C N
H
SO3H
Pyrrole - 2- sulfonic acid
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8. c. Halogenation: Proceeds with great vigour and require careful control of reaction
conditions.
 Chlorination is carried out with sufuryl chloride in ether at 0°C
 Bromination with bromine in ethanol at 0°C
 Iodination with iodine in aqueous solution of potassium iodide
N
H
+ SO2Cl2
Sulfuryl Chloride
Ether
0 °C N
H
Cl
Cl
Cl
Cl
2, 3, 4, 5 - tetrachloro pyrrole
N
H
+ Br2
N
H
I
Br
Br
Br
2, 3, 4, 5 - tetrabromo pyrrole
Br
C2H5OH
0 °C
N
H
+ I2
aq.KI
N
H
I
I
I
I
2, 3, 4, 5 - tetraiodo pyrrole
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9. d. Formylation
 Gattermann reaction : Formylated by a mixture of hydrogen cyanide & hydrogen chloride in the
presence of Lewis acid catalyst.
 Vilsmeier reaction : Undergoes Vilsmeier reaction with DMF and Phosphorus oxychloride
 Reimer–Tiemann reaction : With Chloroform & caustic alkali
HCN - HCl
AlCl3
N
H
N
H
CHO
Pyrrole - 2 -carboxaldehyde
N
H
(CH3)2NCHO - POCl3
N
H
CHO
Pyrrole - 2 -carboxaldehyde
N
H
+ CHCl 3 + KOH
N
H
CHO
Pyrrole - 2 -carboxaldehyde
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10. e. Acetylation [Friedel-Crafts reaction] : Acetylated with acetic anhydride at 250°C
f. Alkylation: N-alkylation of pyrrole was readily achieved with primary alkyl halides
g. Coupling reaction: Undergoes coupling reaction with benzenediazonium chloride
N
H
+ CH3 - CO - O - CO - CH 3
N
H
CO - CH 3
+ CH3COOH
2 - acetyl pyrrole
Acetic anhydride

250 °C
CH3I
60 °C
N
H
N
CH3
high temp
N
H
CH3
+
N
H
CH3
N-methyl pyrrole 2 - methyl pyrrole 3 - methyl pyrrole
N
H
C6H5N2Cl
CH3COONa N
H
N = N - C 6H5
2- phenylazopyrrole
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11. h. Carboxylation
i. Reaction with Grignard reagent
N
H
+ CCl 4 + 4KOH
N
H
COOH
Pyrrole - 2 -carboxylic acid
N
H
+ CO2
N
H
COOH
Pyrrole - 2 -carboxylic acid
120 °C
Kolbe Schmitt reaction
N
H
CH3MgBr
N
MgBr
Pyrrole-N-magnesium bromide
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12. 2. Oxidation : Pyrrole oxidised by chromium trioxide in acetic acid
3 . Reduction: Zinc and acetic acid reduces Pyrrole to Pyrroline which may be further
reduced to Pyrrolidine by means of red phosphorus & hydriodic acid.
 Catalytic reduction reduces Pyrrole directly to pyrrolidine
N
H
+ 3 [O]
Cr2O3
CH3COOH N
H
O
O
Maleic imide
N
H
Zn
CH3COOH N
H
2, 5 - dihydropyrrole
(Pyrroline)
Red P
HI N
H
Pyrrolidine
N
H
H2 - Ni
200 °C N
H
Pyrrolidine
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13. 4. Mannich reaction: Pyrrole undergoes Mannich reaction to form 2-
dimethylaminomethyl pyrrole.
5. Ring expansion : Pyrrole when treated with sodium methoxide and
iodide undergoes ring expansion forming Pyridine.
N
H
+ CH2O +
Formaldehyde
NH(CH 3)2
Dimethylamine
N
H
CH2N(CH 3)2
2 -dimethylaminomethyl pyrrole
N
H
+ 2CH3ONa + CH2I2
Sodiummethoxide Methylene iodide
N
+ 2NaI + 2CH3OH
pyridine
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14. 6. Ring opening reaction:
 Pyrrole when treated with hot ethanolic hydroxylamine, undergoes ring
opening and produces dioxime of succindialdehyde.
N
H
+ NH2OH
C2H5OH

Hydroxylamine
NOH
HON
Succindialdoxime
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15. Medicinal Uses of Pyrrole
N
H
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16. Atorvastatin (Pyrrole nucleus)
Atorvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and
reduce the risk of cardiovascular disease including myocardial infarction and
stroke.
N CH(CH 3)2
C-NH
F
CH2 -CH2-CH-CH 2-CH-CH 2-COOH
OH OH
O
Atorvastatin
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17. Tolmetin (Pyrrole nucleus)
Tolmetin is a Non-steroidal anti-inflammatory drug (NSAID) used to treat
acute flares of various painful conditions and used for the long term
management of osteoarthritis, rheumatoid arthritis and juvenile arthritis.
O
H3C N CH2-COOH
C
CH3
Tolmetin
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18. Glimepiride (Pyrroline nucleus)
It is used to treat type-2 diabetes mellitus
N
CH3
H5C2
O
C-NH-CH 2-CH2
O
SO2-NH-C-NH CH3
O
Glimepiride
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19. Enalapril (Pyrrolidine nucleus)
Enalapril is used to treat high BP, congestive heart failure, kidney problems
caused by diabetes and to improve survival after a heart attack.
N
HOOC
C-CH-NH-CH-CH 2-CH2
CH3
COOC 2H5
O
Enalapril
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20. Captopril (Pyrrolidine nucleus)
Captopril used in the treatment of high BP, heart failure and used to prevent
kidney failure due to high BP & diabetes.
N
HOOC
C-CH-CH 2SH
CH3
O
Captopril
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