This document provides information on various heterocyclic compounds. It discusses the definition and importance of heterocyclic chemistry. It then summarizes the structure, properties, synthesis, reactions and applications of several important 5-membered and 6-membered heterocyclic compounds that contain one or two heteroatoms such as oxygen, nitrogen, sulfur. These include furan, pyrrole, thiophene, pyridine, pyrimidine, quinoline, isoquinoline, indole, pyrazine, and pyrazole.

1. Pharmaceutical
Chemistry

2. HETEROCYCLIC
CHEMISTRY
Unit No. 6

3. HETEROCYCLIC CHEMISTRY
Branch of organic chemistry which deals with
synthesis, properties and applications of
Heterocycles is called as heterocyclic
chemistry.

4. HETEROCYCLIC COMPOUNDS
• Have five or six membered carbon ring with
atleast one hetero atom as a member of ring.
• The common hetero atoms present in the
carbon ring are oxygen (O), nitrogen (N) and
sulphur (S), which are:
– Relatively stable
– Show aromatic character
– Contain conjugated double and single bonds

5. NOTE
• There are a number of heterocyclic rings
which are easily opened and do not easily
possess any aromatic properties e.g. ethylene
oxide, - and -lactones etc. These are not
considered to be heterocyclic compounds.

6. IMPORTANCE
• The importance of heterocyclic compounds is apparent
from variety of compounds that occur naturally or
they’re prepared on a commercial state by the dye or
drug industry.
• They are important building blocks for new materials
possessing interesting electronic, mechanical or
biological properties.
• Many of these compounds fulfill important
physiological functions in plants and animals thus the
carbohydrates may be classified as o-heterocycles
whereas nucleic acids and some amino acids, peptides
and proteins possess nitrogen containing ring system.

7. Five Membered Heterocyclic
Compounds
• One Heteroatom in Ring:
• Two Hetero-atoms in Ring:
• Other Examples include Iso-oxazole, Thiazole
and Isothiazole etc.

8. Six Membered Heterocyclic
Compounds
• One Heteroatom in Ring:
– Other Examples are usually derivatives of pyridine
e.g. Methyl pyridine and 2-Hydroxypyridine etc.
• Two Hetero-atoms in Ring:

9. Condensed Heterocyclic
Compounds
• Condensed Five Membered Heterocyclic
Compounds:
• Condensed Six Membered Heterocyclic
Compounds:

10. FURAN
(Oxole)
Five Membered Heterocyclic
Aromatic Compound
C4H4O

11. Structure
• Oxygen as hetero atom.
• All ring atoms in furan (4C + 1O) are sp2
hybridized.
• Possesses resonance.
• Less aromatic than benzene.

12. Physical Properties
• Most reactive among five membered heterocyclic
compounds
• Flammable
• Highly volatile liquid
• Colorless
• Boiling point is 31.40C
• Odour of chloroform
• Less dense than water
• Insoluble in water
• Soluble in most organic solvents such as alcohol, ether
and chloroform etc

13. Preparation
• Distillation of pine wood:

14. • Dehydration of succinaldehyde with P2O5 or
H2SO4:
• Oxidation of 1,3-Butadiene:

15. Chemical Properties
• Reduction Reactions
• Electrophilic Substitution Reactions
– Position 2
– Rarely at Position 3 or 5

17. • Gatterman Koch Reaction:
• Formation of Pyrrole and Thiophene:

18. Applications / Uses
• Nitrofurazone (Furacin) - anti-bacterial agent
• Nitrofurnatoin - anti-biotic in urinary tract
infection
• In anti-pyretic drugs.
• It forms many derivatives like furfural and
tetrahydrofuran (THF)

19. PYRROLE
(Azole)
Five Membered Heterocyclic
Aromatic Compound
C4H5N

20. Structure
• Nitrogen as hetero atom
• All ring atoms in furan (4C + 1N) are sp2
hybridized
• Possesses resonance
• It has less aromaticity than thiophene and is
more reactive than furan

21. Physical Properties
• It is a colorless, volatile liquid that darkens on the
exposure to air
• Weakly basic
• Boiling point is 1310C
• It is sparingly soluble in water but fairly soluble in
ethanol and ether
• Burning pungent taste
• Its smell resembles to chloroform
• It occurs in coal-tar and bone oil

22. Preparation
• From Pentose or furan
• From acetylene

23. • From Ammonium Mucate
• From Succinamide

24. Chemical Properties
• Electrophilic Substitution Reactions
• Diazotization
• Reimer-Thiemann Synthesis
• Reduction Reactions

25. • Electrophilic Substitution Reaction (Position 2
/ 5):

26. Applications / Uses
• Pyrrole is a constituent of anti-inflammatory drug
Tolmetin.
• It is present in drugs like (anti-depression) and Mirapex
(treatment against Parkinson’s disease).
• It is also used in anti-bacterial and anti-psychoticdrugs.
• It is used in drugs for the treatment of dyslipidimia and
in prevention of cardiac diseases.
• It is precursor of many biological molecules such as
porphyrin, hemoglobin, chlorophyll-A and vitamin B12.

27. THIOPHENE
(Thiopyran)
Five Membered Heterocyclic
Aromatic Compound
C4H4S

28. Structure
• Sulphur as hetero atom
• All ring atoms in thiophene are sp2 hybridized
• It is a resonance hybrid

29. Physical Properties
• Colorless liquid
• Boiling point 840C
• Odour is similar to that of benzene
• Insoluble in water but soluble in organic solvent
• More reactive than benzene
• Occurs in coal-tar and shale oils (rock)
• Boiling point is close to that of benzene so it is
difficult to separate it from the benzene fraction
obtained from coal-tar

30. Preparation
• It can be obtained by heating disodium
succinate with phosphorous trisulphide.
• It can be prepared by the high temperature
reaction of sulphur with butane.

31. • Thiophene may be prepared by passing a
mixture of acetylene and hydrogen sulphide
through a tube containing alumina at 4000C.
2C2H2 + H2S → C4H4S + H2

32. Chemical Properties
• Desulphurization:
Catalytic reduction of thiophene with Ni catalyst
results in the removal of sulphur to form n-
butane.
Thiophene + H2 + Ni (Catalyst) → CH3 (CH2)2CH3 + NiS
• Reduction:
On reduction with sodium amalgam and ethanol,
it is converted into tetrahydro-thiophene.

33. • Electrophilic Substitution Reactions (at position 2,
rarely at 5)

34. Note
• Derivatives:
• Derivatives of thiophene may be prepared
by heating 1, 4-diketone with phosphorous
trisulphilde.
• Condensed Structures:
• A number of condensed thiophene
systems are known e.g.
(Dibenzothiophene) (Benzothiophene)

35. Applications / Uses
• Thiophenes are important heterocyclic
compounds that are widely used as building
blocks in many agrochemicals and
pharmaceuticals.
• The benzene ring of a biologically active
compound may often be replaced by a
thiophene without loss of activity. This is seen
in examples such as NSAID lornoxicam, the
thiophene analogue of piroxicam.

36. PYRIDINE
(Azine)
Six Membered Heterocyclic
Aromatic Compound
C5H5N

37. Structure
• Pyridine has nitrogen as hetero atom
• All ring atoms in thiophene are sp2 hybridized.
• It is Iso-electronic and analogous to benzene
• It is a resonance hybrid

38. Physical Properties
• Discovered by Anderson in 1851
• Boiling point is 1150C
• Occurs in coal-tar (0.1%) and in bone oil
• Disagreeable smell
• Miscible with water
• Basic liquid
• Crystallizes in orthorhombic system

39. Synthesis

40. Chemical Properties
• Electrophilic Substitution Reaction
• Nucleophilic Substitution Reaction
• Reduction
• Oxidation
• Formation of Salts
Note:
Pyridine is stable and it is not easily oxidized at
carbon. It undergoes substitution rather than
addition. It shows negative inductive (electron
withdrawn) and negative mesomeric effect.

41. • Electrophilic (Position 3), Nucleophilic (Position 2,
rarely 4) Substitution Reactions

42. • Reduction
• Salt Formation: Pyridine is basic proton). It
reacts with strong acids to form salts.

43. Pyridine Derivatives
• Mono-methyl pyridines are called Picolines.
• Di-methyl pyridines are called Lutidines.
• Tri-methyl pyridines are called Collidines.

44. Applications / Uses
• It is used in formation of Pyridium
(structure) that is a pain reliever
and is given in urinary tract infection.
• It is used in formation of Imidazole [1, 2-a]
pyridine (anti-inflammatory) and Nexium
(used in acid reflex problem).
• It acts as a catalyst in the formation of
Grignard reagent and solvent in the
estimation of active hydrogen.

45. PYRIMIDINE
(1, 3-Diazine)
Six Membered Heterocyclic
Aromatic Compound with Two Heteroatoms
C4H4N2

46. Properties
• Liquid
• Boiling point 1240C
• Among diazines, it is most important closely
related to pyridine and certain characteristic
properties increase in it.
• Two electron withdrawing nitrogen in 1, 3-
relationship is present.
• Ring carbon atoms are more deactivated
towards electrophilic attack than pyridine.
• Its nucleus occurs in purines, nucleic acid
synthesis and barbiturates.

47. • Synthesis
• Derivatives
Pyrimidines are derivative of many biological
compounds such as cytosine, uracil and
thymine.

48. Uses / Applications
• Sulfadiazine (synthetic anti-bacterial drug)
• Sulfamerazine (its anti-bacterial ring is less
potent than sulfadiazine)

49. QUINOLINE
(2, 3-Benzo-pyridine)
Condensed Six Membered Heterocyclic
Aromatic Compound with One Heteroatom
C9H7N

50. Structure
• Bicyclic heterocyclic compound having a
benzene ring fused with a pyridine ring at 2, 3-
position.
• It could be considered as naphthalene in
which one CH in 2-position has been replaced
by nitrogen.
• The official name of quinoline is 1-
Azanapthalene.

51. Physical Properties
• Colorless
• Hygroscopic liquid
• Boiling point is 2380C
• Present in coal-tar, bone oil, petroleum and shale
oil
• First isolated in 1834 and was first obtained from
alkaloid quinine by alkaline decomposition
• Disagreeable, pyridine-like odor
• It is soluble in water and completely miscible with
alcohol, ether and acetone

52. Synthesis
• Skraups Synthesis:
A mixture of aniline, glycerol and sulphuric acid is
heated in the presence if a mild oxidizing such as
nitrobenzene. The reaction being exothermic tends to
be violent and FeSO4 is used asmoderator.
• Friedlander’s Synthesis:
o-Amino benzaldehyde is condensed with
acetaldehyde in aq. NaOH.
• From Indole:
When methyl-lithium is added to Indole in methylene
dichloride solution, quinoline is produced by ring
expansion via the addition of chloromethylene.

54. Reactions

56. Uses / Applications
• Primaquine (synthetic anti-malarial drug)
• Cinchocaine (long acting local anesthetic drug)

57. • It is also used as a highly boiling basic solvent
in organic reactions.
• It is used in manufacture of dyes and
insecticides.
• It is used as solvent for resins and terpenes,
food colors, lake colors and salt free dyes.
• Over exposure to quinoline can cause injury to
cornea, retina and optic nerve.

58. ISOQUINOLINE
(4, 6-Benzopyridine)
Condensed Six Membered Heterocyclic
Aromatic Compound isomer to quinoline
C9H7N

59. Structure
• It is bicyclic heterocyclic compound having a
benzene ring fused with a pyridine isomer to
quinoline.
name of quinoline is 2-
• The official
Azanapthalene.

60. Physical Properties
• It is a colorless, oily solid or liquid.
• Its melting point is 230C and boiling point is
2340C.
• It is weakly basic and hygroscopic.
• It is penetrating and has unpleasant odour.
• It is insoluble in water and soluble in organic
solvents.

61. Synthesis
Bischler-Bapieralski Synthesis:

62. Chemical Properties
• Electrophilic at position 5 or 8 nucleophilic
substitution reactions at position 1 (like
quinoline).
• Protonate to form salts upon treatment with
strong acid such as HCl
• While it shows oxidation as:

63. Applications / Uses
• Paparerine HCl (USP) which acts as
spasmolytic (relax / bronchodilator) on
smooth muscles
• The Isoquinoline ring in natural components
derives from the amino acid tyrosine.
• It is used as viscosity adjustor and
intermediate in various chemical reactions.

64. INDOLE
(Benzopyrrole)
Bicyclic Six Membered Fused Ring
with Five Membered Nitrogen
containing Pyrrole Ring
C8H7N

65. Occurrence
• It was first isolated by Baeyer in 1866 from
degradation products of Indigo (C16H10O2N2).
• It occurs in coal-tar, jasmine flower and
orange blossoms.
• It is also present in human feces and has
intense fecal color.

66. Physical Properties
• Colorless solid
• Crystals
• Melting point 52.50C
• Strong fecal odour
• In dilute solutions, it has flowery odour
• It is soluble in hot water, alcohol and ether.

67. Synthesis
• Indole is widely distributed in the natural
environment and can be produced by a variety
of bacteria.
• Indole can be prepared from aniline.

68. • Fischer-Indole Synthesis (1866):
When phenyl-hydrazone of Pyruvic acid is
heated with zinc chloride catalyst it yields
indole-2-carboxylic acid which decarboxylates
to Indole.

69. Chemical Properties
• Chemically, it resembles pyrrole.
• It shows usual substitution reactions at
position 3 due to greater stabilization of
intermediate carbonium ion as compared to
that in 2-position.
• If both 2 and 6 positions are occupied,
substitution occurs at 6-position.

71. Uses / Applications
• It is used in preparation of Indomethacin (anti-
inflammatory analgesic)
.
• It is used in perfumery for the preparing
jasmine and orange blends.

72. PYRAZINE
(p-Diazine)
Six Membered Heterocyclic
Compound with two Hetero-atoms
C4H4N2
Other Names:
•Paradiazine
•1, 4-diazine
•Piazine
•1, 4-Diazabenzene

73. Physical Properties
• Pyrazine is present in white crystalline shape
with boiling point 1150C.
• It is soluble in water.
• It is readily reduced to piperazine.

74. Staedal-Rughmeimer Pyrazine
Synthesis
Pharmaceutical Applications
(Phenazine – anti-tumor, Anti-biotic, Diuretic activities)

75. PYRAZOLE
Five Membered Heterocyclic
Compound with Two Hetero-atoms /
Azoles
C3H4N2

76. Synthesis
Pharmaceutical Application /
Example
(Dipyron – Anti-Pyretic Drug)

77. “Abeautiful life does not just
happen; it is built daily by prayer,
humanity, sacrifice and hard work”
Composed By: Muhammad Muneeb
D16M137
Best of Luck!