Heterocyclic compounds contain at least one heteroatom such as nitrogen, oxygen, or sulfur in their cyclic structure. Some common heterocycles discussed include pyrrole, furan, thiophene, pyridine, piperidine, indole, quinoline, and isoquinoline. Heterocyclic compounds are important because many natural products and drugs contain heterocyclic rings. Pyridine is aromatic according to Hückel's rule but does not undergo electrophilic aromatic substitution. Pyrrole and indole undergo electrophilic substitution preferentially at certain positions. Common heterocycle syntheses discussed include the Hantzsch pyridine synthesis and Fischer-Indole synthesis.

1. Heterocyclic Chemistry
CHEM320
2016

2. Heterocyclic compounds
• Why are they important to mankind?
• Names of commonly encountered heterocyclic
compound
• Shape and stability of heterocyclic compounds
• Reactions of aromatic heterocyclic compounds
• Synthesis of aromatic heterocyclic compounds

3. Heterocyclic compounds of interest
O
O
H3C
N
CO2CH3
Cocaine
O
O
O
O
O
Artemisinin
HO
O
HO
N
CH3
H
Morphine
N
O
H
N
O
H
Indigo
N
N
H
Nicotine

4. Some common heterocycles
N
H
Pyrrole
N
H
Pyrrolidine
O
Furan
S
Thiophene
N
Pyridine
N
H
Piperidine

5. N
H
Indole
(benzo[b]pyrrole)
N
Quinoline
N
Isoquinoline

6. Aromaticity
• Hückel’s rule
– Planar cyclic polyenes containing 4n+2 -electrons
should show added stability
N
N
H

7. N
Pyridine

8. • Benzene
– Each atom bonded to H
– Perfect hexagon
– Electrodensity evenly distributed around ring
• Pyridine
– N more electronegative than C
– C-N bonds slightly shorter than C-C
– electrodensity higher on N
– N-atom not bonded to H, but has lone pair electrons
– Lone pair oriented in same plane as ring
– Can donate lone pair (Lewis base)
– Aromaticity is retained when one or more of CH is
replaced by N

9. Pyrrole
• Resonance hybrids
• Dipole moment of pyrollidine vs pyrrole

10. Revise
• Electrophilic aromatic substitution
• Nucleophilic aromatic substitution (SNAr)

11. • Pyrrole
• Aromaticity is achieved by sharing four p-
electrons and 2 lone pair electrons from N
• Can no longer donate lone pair electrons
• Aromaticity is retained when one or more
CH’s is replaced by N’s

12. Electrophilic aromatic substitution of
pyrrole
• Pyrrole, furan and thiophene are more
reactive than benzene towards because they
are better able to stabilize the positive charge
on the carbocation intermediate
• Reactivity towards electrophilic aromatic
substitution:
• Pyrrole > furan > thiophene > benzene

14. Pyridine
Pyridine does not undergo electrophilic
substitution:
•Aromatic electrophilic substitution on pyridine
is not a useful reaction.
•Avoid nitration, sulfonation, halogenation, and
Friedel–Crafts reactions on simple pyridines.

15. Nucleophilic substitution of pyridines:
• Acidity of methylpyridines:
N Br N
Br
N
Br
N CH3 N
CH3
N
CH3

17. • Pyridine N-oxides are reactive towards both electrophilic and
nucleophilic substitution at C-2, C-4 and C-6
• Pyridine N-oxides can be transformed back into pyridines by
treatment with PCl3

19. Bromination and Oxidation of
Substituted Pyridine

20. Pyridine synthesis

21. Hantzsch pyridine synthesis

22. Mechanism???

23. Indoles
• Part of amino acid tryptophan
• Part of drugs like indomethacin
• Form skeleton of indole
alkaloids such as LSD and
strychnine – biologically active
compound from plants

24. Indoles
• Electrophilic substitution: Pyrrole reacts with
electrophiles at all positions, but prefer 2- and
5-positions, while indole prefers the 3-position
Why??

26. Vilsmeier formylation reaction:

27. Fischer-Indole synthesis

30. Summary