1. Pharmaceutical Organic ChemistryBy
Dr. Mehnaz Kamal
Assistant Professor
Pharmaceutical Chemistry
Prince Sattam Bin Abdulaziz University

2. Heterocyclic Chemistry

3. Heterocyclic Chemistry
Five-membered Heterocycles
Pyrrole, Furan and Thiophene

4. 1-To identify types of five membered heterocyclic compounds
2- To know sources of five membered heterocyclic
3-To know syntheses of five membered heterocyclic compounds compounds
4-To understand chemical reactions of five membered heterocyclic compounds

5. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
The main reason for the study of pyrrole came from the work on the structure of haem; the blood respiratory pigment, and the chlorophyll; the green photosynthetic pigment of plants.
Thiophene and its derivatives occurs in petroleum.
Furan occurs widely in secondary plant metabolites, especially in terpenoids.
Unsubstituted pyrrole, furan, and thiophene are usually obtained from petroleum.

6. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Pyrrole, furan and thiophene are colorless liquids of boiling points 126o, 32o, and 84o respectively.
Pyrrole has a relatively high boiling point as compared to furan and thiophene, this is due to the presence of intermolecular hydrogen bonding in pyrrole.

7. Structure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity
Pyrrole furan and thiophene are aromatic because:
they fulfill the criteria for aromaticity, the extent of delocalization of the nonbonding electron pair is decisive for the aromaticity, thus the grading of aromaticity is in the order of:
Furan < Pyrrole < Thiophene < Benzene this order is consistent with the order of electronegativity values for oxygen (3.44), nitrogen (3.04) and thiophene (2.56).
The order of aromaticity
Benzene > Thiophene > Pyrrole > Furan

8. Structure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity
2) They tend to react by electrophilic substitution due appearance of –ve charge on carbon atoms due to delocalization as shown in the following resonance structures

9. Structure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity
3- Electrons not available for protonation—hence not basic
4- 6  electrons over 5 ring atoms ….. Electron rich… so more reactive than benzene towards electrophilic substitution.
The order of reactivity is:
Pyrrole > Furan > Thiophene > Benzene

10. Structure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity
5- The pattern of reactivity with Electrophilic reagents.
Aromatic compounds ……. By substitution
addition followed by proton loss
[ onium intermediate ]
Order of reactivity : Pyrrole > Furan > Thiophene > Benzene

11. Structure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity ne
6-The order of aromaticity
Benzene > Thiophene > Pyrrole > Furan
In case of Thiophene [S] donate & accept electrons…… so
delocalization as complete as benzene
In case of Pyrrole [N] -Diene-like character CH2=CH-CH=CH2
In case of Furan [O] electronegativity more …. Diene-like character CH2=CH-CH=CH2

12. Evidences of aromatic character in pyrrole
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Evidences of aromatic character in pyrrole
It tends to react by electrophilic substitution

13. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
3) Its exceptional lack of basicity and strong acidity as a secondary amine compared to the aliphatic analog (pyrrolidine). This can be explained on the basis of participation of N lone pair in aromatic sextet (see the resonance structures)
So Its weak acid not basic as the secondary amines
Lone pair of N is involved in  cloud and not
Available for sharing with acids
thus the dipole moment of pyrrole compared with pyrolidine is reverted and thus protonation occurs at carbons not at N

14. Sources & Synthesis A) Sources Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Sources & Synthesis
A) Sources
Pyrrole & Thiophene …. Coal Tar
Pyrrole ring …. Porphyrin system…..
Chlorophyll & Hemoglobin
Furan ….. Decarbonylation of Furfuraldehyde …….
Oat hulls, corn cobs or rice hulls
Oat hulls
corn cobs
rice hulls

15. B) Synthesis Hetero-Monocyclic Compounds Thiophene
A. Five-membered Rings with one Heteroatom
B) Synthesis
Thiophene
Pyrrole
Furan

16. Reactions of pyrrole Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Vilsmier Rex
Acetylation
HNO3 +Ac2o
Sulfonation
Reduction
Nitration

17. Reactions of Pyrrole Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
with carbene
Halogenation

18. Reactions of Furan Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Acetylation
Vilsmier Rex
Sulfonation
Nitration

19. Reactions of Thiophene
Hetero-Monocyclic Compounds
Reactions of Thiophene
A. Five-membered Rings with one Heteroatom
Sulfonation
Acetylation
Nitration
Halogenation

20. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Five Membered Heteroaromatic Rings
Containing 2X , at least one nitrogen
1,3-Azoles
1,2-Azoles
Thiazole [ 1,3-thiazole]
Oxazole [ 1,3-oxazole]
Imidazole [ 1,3-diazole]
Isothiazole [ 1,2-thiazole]
Isoxazole [ 1,2-oxazole]
Pyrazole [ 1,2-diazole]

21. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Five Membered Heteroaromatic Rings
Containing 2X , at least one nitrogen
Aromaticity & Basicity
Strong base, due to the greater electron releasing capacity of the two nitrogen's
Importance of the ring
Building blocks as Histidine and Histamine
It exist in two tautomeric forms …..

22. Fused Five Membered Heteroaromatic Rings With one X
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Fused Five Membered Heteroaromatic Rings With one X

23. Fused Five Membered Heteroaromatic Rings With one X
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Fused Five Membered Heteroaromatic Rings With one X
Indole
Fischer Synthesis
Basicity of Indole
Not basic because lone pair is delocalized and contributed to the Aromatic system

24. Indole Hetero-Monocyclic Compounds
Fused Five Membered Heteroaromatic Rings With one X
A. Five-membered Rings with one Heteroatom
Indole
It undrego Electrophilic Subistitution at Position 3

25. Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Vilsmier Rex
Reaction with carbene

26. Fused Five Membered Hetero aromatic Rings
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Fused Five Membered Hetero aromatic Rings
With two X
Benzimidazole …
In Vit B12 : Commercially as an parasiticide