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!