Heterocyclic compounds Unit-III

1. HETEROCYCLIC
COMPOUNDS
Mr.P.S.Kore
Assistant Professor(Research Scholar)
Department of Pharmaceutical Chemistry
RCP, Kasegaon.
R.C.P. KASEGAON

2. Heterocyclic
compounds
Ring compounds with elements other than carbon
in the ring. The most common elements to appear
in heterocyclic compounds are oxygen, nitrogen
and sulfur.
The saturated heterocycles are similar to the
open chain analogues, ethers, amines and
sulfides.
The aromatic heterocycles are similar to other
aromatic compounds.
R.C.P. KASEGAON

3. Heterocyclic
Nomenclature
Replacementnomenclature (IUPAC
recommended 1957)
Lowest number assigned to the hetero atom with
the highest precedence: O > S > N
S
thiacyclobutane
O
NH
1-oxa-3-azacyclopentane
R.C.P. KASEGAON

4. Hantzsch-Widman
(1888)
Sr. No Hetero atom Symbol Prefix
01 Oxygen O Oxa
02 Sulphur S Thia
03 Selenium Se Selena
04 Nitrogen N Aza
05 Phosphorous P Phospha
06 Arsenic As Arsa
07 Antimony Sb Stiba
08 Bismuth Bi Bisma
09 Silicon Si Silia
Prefixes Used in Nomenclature of Heterocyclic
Compounds
R.C.P. KASEGAON

5. Hantzsch-Widman
(1888)
Ring No. Ring With Nitrogen Atom Ring WithoutNitrogen
Atom
Unsaturated Saturated Unsaturate
d
Saturated
3 -irine iridine irene irine
4 ete etidine ete etane
5 -ole olidine ole olane
6 -ine Perhydro in
e
in ane
7 -epine Perhydro e
pine
epin epane
Suffixes Used in Nomenclature of Heterocyclic
Compounds
R.C.P. KASEGAON

6. Nomenclature of Heterocyclic
Compounds
Name: Prefix + Stem + Suffix
In this nomenclature the nomenclature of heterocyclic compounds are
assignedby combining ‘prefix’ (that indicate the heteroatompresent)
with ‘stem’ (that indicate the ring sizeaswell asthesaturation and
unsaturation in the ring) and‘suffixes
Nomenclature of heterocyclic compound starts with the heteroatom
appears first
If more than two different hetero atoms are present in any
heterocyclic compound the prefixes are listed in Preceding order
If there are two or more than two hetero atoms of same types are
present in a heterocyclic compound they are indicated by di-, tri- etc.
Theposition of saturated atom is numerically indicated with prefix ‘H-’ as a
part of the name of the ring system
The size of a monocyclic ring (three to ten membered rings) is
indicated by stem. Thecommon ‘stem’nomenclature
R.C.P. KASEGAON

7. O S
* oxirane
ethylene oxide
oxacyclopropane
* thiirane
ethylene sulfide
thiacyclopropane
N
H
* aziridine
ethylene imine
azacyclopropane
N
H
N
N
diazirane
N
1-azirine
O
oxaziridine
oxazacyclopropane
You must know the *
names
R.C.P. KASEGAON

8. O S NH
N N
oxetane
oxacyclobutane
thietane
thiacyclobutane
azetidine
azacyclobutane
azete
azacyclobutadiene
1-azetine
1-azacyclobutene
R.C.P. KASEGAON

9. O
O
* furan
oxole
oxacyclopentandiene
S
* thiophene
thiole
thiacyclopentandiene
N
H
* pyrrole
O
1,3-dioxolane
1,3-dioxacyclopentane
O
* tetrahydrofuran
N
H
* pyrrolidine
azacyclopentane
R.C.P. KASEGAON

10. N N
N
H
N
N N
N
H
N
pyrazole
N
H
imidazole 1,2,4-triazole
O
oxazole
N
O
isooxazole
S
thiazole
R.C.P. KASEGAON

11. O O
O
O
N
H
N
H
H
N
O
4-hydropyran
O O
2-pyrone 4-pyrone
* 1,4-dioxane * piperidine piperazine
R.C.P. KASEGAON

12. N
N
N
N
N
N
N
O
pyridazine pyrimidine pyrazine
* pyridine
N
H
* morpholine
R.C.P. KASEGAON

13. 6
7
8
5
N
1
2
3
4
6
7
5
N 2
3
4
* quinoline
8 1
* isoquinoline
N
H
* indole
R.C.P. KASEGAON

14. N
H
aziridine
O
oxirane
O
oxirene
N
H
1H-azirine
Classification of Heterocyclic
Compounds
1.Three membered heterocyclic ring
R.C.P. KASEGAON

15. 2.FIVE MEMBERED RING WITH ONE HETERO ATOM
N
H
1H-pyrrole
S
thiophene
O
furan
R.C.P. KASEGAON

16. 3.FIVE MEMBERED WITH 2 HETERO ATOM
N
N
H
1H-pyrazole
N
O
isoxazole
N
S
i s o t h i a z o l e
A. 1 AND 2
POSITION
N
N
H
1H-imidazole
N
O
o x a z o l e
N
S
t h ia z o l e
B. 1 AND 3
POSITION
R.C.P. KASEGAON

17. 4.FIVE MEMBERED RING WITH MORE THAN TWO
HETERO ATOM
N
N
N
H
1H -1,2,3-triazole
N
N
N
H
1H-1,2,4-triazole
N
N
N
HN
1H-tetrazole
N
N
O
1,2,4-oxadiazole
N
N
S
1,2,4-thiadiazole
N
N
O
1,3,4-oxadiazole
R.C.P. KASEGAON

18. 5.SIX MEMBERED RING WITH ONE HETERO ATOM
N
p y r i d i n e
N
H
piperidine
R.C.P. KASEGAON

19. 6.SIX MEMBERED RING WITH TWO HETERO ATOM
N
N
pyrimidine
N
N
pyrazine
N
N
py ridazine
R.C.P. KASEGAON

20. 7.FIVE MEMBERED HETEROCYCLIC RING FUSED WITH
BENZENE(BENZFUSED HETEROCYCLE)
N
H
1H-indole
R.C.P. KASEGAON

21. 8.SIX MEMBERED HETEROCYCLIC RING ATTACHED WITH
BENZENE
N
quinoline
N
isoquinoline N
acridine
R.C.P. KASEGAON

22. 9. SEVEN MEMBERED RING WIT ONE HETERO ATOM
N
H
N
N
H
AZEPI
NE
DIAZEPI
NE
R.C.P. KASEGAON

23. 10.BENZODIAZEPINES
N
N
H
R.C.P. KASEGAON

24. Calculationof “n”
Huckel Rule:
4n+2π
1 Double bond gives 2 πelectron and hetero atom contains 2
lone pair of electron.
Examples of hetero atom N, O,S etc
Hence Pyrrole, Furan, Thiophene
contains 6 π
Huckel
rule=4n+2 6
π=4n+2
4n=6-2
4n=4
N=4/4= 1
Hence
n=1
Huckel Rule: 4n+2
4(1)+2
Huckel rule = 6 π
electron
According to Huckel Rule Pyrrole, Furan and thiophene are aromatic
because it
1. Cyclic
2.Planner
3.Pressence alternate conjugate double bond
4. Follows huckel rule: means it satisfy 2, 6 π,10 π,14 π,18 π,22 π,26 π,
30 π
Aromaticity in Heterocyclic
compounds N O
furan
H
pyrrole
S
thiophene
Aromaticity in Heterocyclic
compounds
R.C.P. KASEGAON

25. Resonance
structure
N
H
N
H
Resonance of pyrrole
N
H
N
H
N
H
O O
Resonance of furan
O O O
S S
Resonance of Thiophene
S S S
R.C.P. KASEGAON

26. Comparison of Aromaticity
 Furan is less aromatic / Thiphene is more aromatic
The more electro negative atom holds lone pair of electron more tightly.
This will reduces delocalization(Aromaticity)
 Hence more electro negative atom decreases aromaticity and least
electro negative increases aromaticity. Oxygen is more
electronegative atom and sulphur is less electronegative atom
 Hence thiophene is more aromatic because of more delocalization,
more resonance energy.
R.C.P. KASEGAON

27. Basicity
Furan is more basic and thiophene is least basic or not
basic.
Furan contains Oxygen and it pulls Lone pair of electron as
oxygen is more electro negative atom. Hence less
delocalization of
πelectron or lone pair of electron. Electro negativity will
localized and it is more basic
Thiophene contains sulphur which is less electro negative
and it pulls of πelectron or lone pair of electron slowly.
Hence more delocalization. Hence thiophene is least basic
or not basic R.C.P. KASEGAON

28. Orbital structure of Pyrrole
The delocalization of lone pair of nitrogen in pyrrole
through conjugation also suggests that the pyrrole
molecule should have planar geometry.
This is only possible when the orbital's of carbon and
nitrogen in pyrrole are sp2- hybridized.
The unhybridized p-orbital of nitrogen contains lone
pair of electrons.
Two sp2- hybridized orbital's of nitrogen atom forms -bond
with two carbon atoms of the ring .
third sp2- hybridized orbital of nitrogen atom forms -bond
with
hydrogen atom.
Similarly each sp2- hybridized carbon forms two -bonds
with neighbouring carbon atoms and one -bond with
hydrogen atom
R.C.P. KASEGAON

29. Orbital
structure
R.C.P. KASEGAON

30. Orbital
structure
R.C.P. KASEGAON

31. Comparison stability and
reactivity
S
thiophene
O
furan
N
H
1H-pyrrole
Electronegativity order: O>N>S
Stability order
<
<
Reactivity order:
S
thiophene
O
furan
N
H
1H-pyrrole
> >
1. Oxygen has more
electro negativity hence
they have capacity to
pull electron more than
N and S
2. Hence furan acquire less
resonance stabilization
than pyrrole and
thiphene
3. Thiphene is stable
hence thiphene is
very reactive than
pyrrole and furan.
R.C.P. KASEGAON

32. CO NTEN T
Properties, synthesis, reactions & medicinal uses of…
R.C.P. KASEGAON

33. Properties
1. Aromaticity
PYRRO
LE
R.C.P. KASEGAON

34. Properties
1. Aromaticity
PYRRO
LE
R.C.P. KASEGAON

35. Properties
PYRRO
LE
R.C.P. KASEGAON

36. Physical properties of Pyrrole
Pyrrole is colorless liquid, BP 131°C
Rapidly turns brown on exposure to air.
Its odour is like chloroform and pyrrole sparingly soluble in water
but dissolves in ethanol and ether
Chemical properties of
Pyrrole Pyrrole is a weak
base(pKa=3.4)
R.C.P. KASEGAON

37. Chemical properties of
Pyrrole
N
+ HCl
N
H
H
Pyrrole is weak base(pKa=3.4) It reacts with dil. HCl to give crystalline hydrochloride
reason for basic character is presence of lone pair of electron on nitrogen atom
O2
Polymerisation
Brown Resin
Cl
Pyrrole hydrochloride
H
Pyrrole
Pyrrole is also weak acid(pKa=15). It reacts with KOH to form pyrrole potassium.
Reason for acidic character resonance structure shown positive charge on nitrogen
because electron density on nitrogen decreases while delocalization of lone pair of
electron
N
+ KOH
N
H
Pyrrole
K
Pyrrole potassium
+ H2O
R.C.P. KASEGAON

38. Basicity of
Pyrrole
From experimental studies it is observed that the pKb values of pyrrole,
pyridine and Piperidine are ~14, ~8.7 and ~2.7, respectively. Pyrrole is the
weakest base among these three heterocyclic bases
the lone pair of electron on nitrogen atom exists in the sp2 hybridized
orbital of nitrogen and participates in the delocalization, hence does not
freely available to cause the basic character of pyrrole.
the lone pair of electron on nitrogen atom of pyridine also exists in the sp2
hybridized orbital; however, it does not participate in the delocalization and
available freely to cause the basic character.
 In case of Piperdine, the lone pair of electron of nitrogen atom lies in
sp3 hybridized orbital of nitrogen .
These electrons are less tightly bonded with nucleus. Therefore, these
electrons are readily available for protonation. Thus, piperidine is the
strongest base among the three.
<
<
N
H
1H-pyrrole
N
pyridine
N
H
piperidine
R.C.P. KASEGAON

39. PYRRO LE
Synthesis
1. FromAcetylene
Mixture of Acetylene and ammonia passed over red
hot tube
CH CH
+ N
H
1H-pyrrole
CH CH
Acetylene
NH3
Ammonoia
R.C.P. KASEGAON

40. PYRRO LE
Synthesis
2. From AmmoniumMucate
Ammonium mucate heated with glycerol at
200°C
HO
OH
HO
H
H4NOOC
H
COONH4
OH
Ammonium Mucate
Glycerol
HO
H H
OH
H H
HO
H
HOOC
H
COOH
OH
Mucic acid
+ 2NH3
+ 4H2O +2CO2
N
H
Pyrrole
R.C.P. KASEGAON

41. PYRRO LE
Synthesis
3. Succinimide
Succinimide heated with Zn
Dust
C
CH2
H2C
C
N
H
N
H
O O
H H
OH
HO
Zn
Succinimide
(Keto)
Succinimide
(Enol)
N
H
Pyrrole
+ 2ZnO
R.C.P. KASEGAON

42. PYRRO LE
Synthesis
4. Succinic dialdehyde (Pal-Knor Synthesis
Succinic dialdehyde warmed with
ammonia
HC
CH2
H2C
CH
O O
H H
NH3
Succinic
dialdehyde
ENOL
N
H
Pyrrole
+ 2H2O
OH HO
R.C.P. KASEGAON

43. + NH3
PYRRO LE
Synthesis
5. From Furans
Mixture of Furan and ammonia passed steam over
aluminium oxide
catalyst at 480°C-490°C
Al2O3
Steam
+ H2O
O
furan
N
H
1H-pyrrole
R.C.P. KASEGAON

44. PYRRO LE
Synthesis
6.Paal-Knorr synthesis.
2,5 hexandione heated with Ammonium carbonate to form
pyrrole
C
CH2
H2C
C
O
H H
NH3
O
2,5 hxanedione ENOL
N
H
Pyrrole
+ 2H2O
OH HO
CH3
3
H C
CH3
H3C CH3
3
H C
R.C.P. KASEGAON

45. Synthesis
6. Paal-Knorr synthesis
PYRRO LE
R.C.P. KASEGAON

46. Synthesis
7. Hantzsch Pyrrole synthesis
PYRRO LE
R.C.P. KASEGAON

47. Synthesis
7. Hantzsch Pyrrole synthesis
PYRRO LE
R.C.P. KASEGAON

48. Synthesis
8. Knorr synthesis
PYRRO LE
R.C.P. KASEGAON

49. Synthesis
8. Knorr synthesis
Mechanism
PYRRO LE
R.C.P. KASEGAON

50. Reactions
1. Electrophilicsubstitution
PYRRO LE
R.C.P. KASEGAON

51. substitution reaction
Reactions
1. Electrophilic substitution
Pyrrole undergoes electrophilic
at 2nd position
PYRRO LE
R.C.P. KASEGAON

52. Reactions
1. Electrophilicsubstitution
PYRRO LE
R.C.P. KASEGAON

53. Mechanism
CH3 C
O
O NO2
+ CH3COOH
CH3
O
C O + NO2
Step-I generation of electrophile(NO2
+)
O O
CH3 C O C CH3 + HNO3
Step--II- Attack of electrophile on C2 of pyrrole to form resonance stabilisedstructure
N
H
+ NO2
N
H
NO2
+
H
N
H
H
NO2
N
H
H
NO2
Step-III- Deprotonation by acetate anion to form stable pyrrole
N
H
NO2
+
H
+
O
O C CH3
2
N
H
Pyrrole
NO + CH3COOH
R.C.P. KASEGAON

54. Reactions
2. Reduction
PYRRO LE
R.C.P. KASEGAON

55. Reactions
3. Reimer Tiemannreaction
PYRRO LE
R.C.P. KASEGAON

56. Reactions
PYRRO LE
R.C.P. KASEGAON

57. PYRRO LE
+ CH3ONa + CH2I2
N
H
Pyrrole
+ 2NaI + CH3COOH
N
Pyridine
Reactions:
Ring expansion reaction
Pyrrole treated with sodium methoxide and methylene iodide
to form
pyridine
R.C.P. KASEGAON

58. PYRRO LE
+ NH2OH + C2H5OH
N
H
Pyrrole
CH CH
Reactions:
Ring Opening reaction
Pyrrole treated with hot ethanolic hydroxyl amine undergo ring
opening
reaction and to get dioxime of succindialdehyde
H2C CH2
NOH NOH
Succindialdehyde
R.C.P. KASEGAON

59. Medicinal uses
PYRRO LE
R.C.P. KASEGAON

60. Properties
1. Aromaticity
FU RA N
R.C.P. KASEGAON

61. Furan
Slightl
y
Furan is colorless liquid , bp 32°C with chloroform like
smell. soluble in water but soluble in organic solvent
It is weak base and form unstable salt with mineral acid. This
salt may
produce to brown resin or undergo hydrolysis to form
succindialdehyde
+ HCl
O
Cl
O2
Polymerisation
Brown Resin
H
O
O
H H
Succindialdehyde
Furan hydrochloride
O
Furan
R.C.P. KASEGAON

62. Properties
1. Aromaticity
FU RA N
R.C.P. KASEGAON

63. FU RA N
Synthesis
1. Paal-Knorr synthesis of furan
C C O
O
3
CH H3C
H H
-H2O
O
3
H C CH3
2,5 Dimethyl furan
H+ /HCl
CH CH
R.C.P. KASEGAON

64. CH CH
C C O
O
3
CH H3C
ACID
HC CH
C C OH
HO
3
CH H3C
2
-H O
O
H3C CH3
H H
KETO
hexane-2,5-dione
ENOL
(2E,4E)-hexa-2,4-diene-2,5-diol
2,5 Dimethyl furan
FU RA N
Synthesis
1. Paal-Knorr synthesis of furan
Mechanism:
R.C.P. KASEGAON

65. Synthesis
2. Feist – Benary Synthesis
FU RA N
R.C.P. KASEGAON

66. Synthesis
2. Feist – Benary Synthesis
Mechanism
FU RA N
CH
COOC2H5
C
O CH3
H HC
COOC2H5
C
HO CH3
+
HC
C
CH3
CH3
O
C
COOC H
2 5
C
HO CH3
HC
C
CH3
Cl
CH3
O
H
COOC2H5
CH
H3C OH
C
C
CH3
Cl
CH3
HO
O
C2H5OOC
H3C
CH3
CH3
HC
-HCl, H2O
H
ethyl 2,4,5-trimethylfuran-3-carboxylate
ethyl 3-oxobutanoate
Cl
3-chlorobutan-2-one
R.C.P. KASEGAON

67. FU RA N
Synthesis
3. From carbohydrate
Step-I Distillation of CH with Sulphuric acid
Step-II: Catalytic Decomposition of furfural in
steam
H
COH
H
OH
OH
H
O
H
OH
H H
H/H2SO4
O
C
O
H
-3H2O, -H2
CaO, steam
O
furan
R.C.P. KASEGAON

68. FURAN
Synthesis:
4. From Mucic acid:Dry distillation of Mucic acid and
heating of to get furan
HO
H
OH
H
HO
H
HOOC
H
COOH
OH
Mucic acid
Dry Distill
-3H2O, -CO2
O
Furoic acid
O
Furan
-CO2
COOH
R.C.P. KASEGAON

69. FURAN
O
Furoic acid
O
Furan
-CO2
COOH
C
O
Furfural
Synthesis:
5. From Oxidation Furfural: Oxidation of furfural with
potassium dichromate to give furoic acid and subsequent
decarboxylation at 200-300°C
O
H
[O]
K2Cr2O7
R.C.P. KASEGAON

70. FURAN
Ag2O
Steam
C
O
Furfural
Synthesis:
6. From Decarboxylation Furfural: Decarboxylation of
furfural in steam in the presence of silver oxide catalyst
O
H
O
furan
+ CO
R.C.P. KASEGAON

71. FURAN
Synthesis:
7. From Succinic dialdehyde: Pal-Knor synthesis
Dehydration of succinic dialdehyde by heating with
P2O5
HC
CH2
H2C
CH
O
O O
H H
P2O5
Succinic
dialdehyde
ENOL
Furan
+ H2O
OH HO
R.C.P. KASEGAON

72. Reactions
1. Electrophilic substitution
furan undergoes electrophilic substitution reaction at
2n
d
position
FU RA N
R.C.P. KASEGAON

73. Reactions
1. Electrophilicsubstitution
FU RA N
R.C.P. KASEGAON

74. Reactions
1. Electrophilicsubstitution
FU RA N
R.C.P. KASEGAON

75. Reactions
2. Reduction
FU RA N
R.C.P. KASEGAON

76. Reactions
3. Diels-Alder reaction
FU RA N
R.C.P. KASEGAON

77. Reactions
3. Diels-Alder reaction
FU RA N
R.C.P. KASEGAON

78. FU RA N
+ NH3
Reactions
4. Pyrrole synthesis
Mixture of Furan and ammonia passed steam over aluminium oxide
catalyst at 480°C- 490°C
Al2O3
Steam
+ H2O
O
furan
N
H
1H-pyrrole
R.C.P. KASEGAON

79. FU RA N
Reactions
5. Ring Opening reaction
When furan treated with methanol and HCl,Furan undergoes ring opening
reaction to form diacetal succindialdehyde
C
CH2
H2C
C
O
O O
Diacetyl Succinic
dialdehyde
Furan
3
+
+ 2CH OH 2 HCl
H3CO OCH3
R.C.P. KASEGAON

80. Medicinal uses
FU RA N
R.C.P. KASEGAON

81. Properties
1. Aromaticity
TH IOPH EN E
R.C.P. KASEGAON

82. TH IOPH EN E
Thiophene is a colorless liquid, bp 84°C it is
insoluble in water.
Thiophene does not shows any basic properties. It
more stable to acid than pyrrole or furan.
Thiophene does not undergo Diels –Alder reaction
R.C.P. KASEGAON

83. Properties
1. Aromaticity
TH IOPH EN E
R.C.P. KASEGAON

84. Properties
1. Aromaticity
TH IOPH EN E
R.C.P. KASEGAON

85. Synthesis
1. Paal-Knorr synthesis of thiophene
TH IOPH EN E
R.C.P. KASEGAON

86. Synthesis
1. Paal-Knorr synthesis of furan
Mechanism
TH IOPH EN E
R.C.P. KASEGAON

87. Mechanism
CH CH
C O
O C
3
CH H3C
ACID
HC CH
C C OH
HO
3
CH H3C
2
-H O
S
H3C CH3
H H
KETO
hexane-2,5-dione
ENOL
(2E,4E)-hexa-2,4-diene-2,5-diol
2,5 Dimethyl Thiphene
P2S5
R.C.P. KASEGAON

88. Synthesis
2. From sod. succinate
TH IOPH EN E
R.C.P. KASEGAON

89. Synthesis
3. Hinsberg Synthesis
TH IOPH EN E
R.C.P. KASEGAON

90. THIOPHENE
4. From Acetylene:
Mixture of acetylene and hydrogen sulphide passed over
aluminium oxide at 400°C
CH CH
CH CH
S
+
Acetylene
Hydrogen sulphide
H
H
S
thiophene
Al2O3
R.C.P. KASEGAON

91. THIOPHENE
5. From Furoic acid:
Distillation of furoic acid with barium
sulfide.
O
C OH + BaS + BaCO3
O
Furoic acid
S
Thiophene
R.C.P. KASEGAON

92. THIOPHENE
6. From n-butane:
Reaction of n-butane with sulphur in the gas phase at
650°C.
+ 4S
650°c
H2C CH2
CH3 CH3
n- Butane
S
Thiophene
+ 3H2S
R.C.P. KASEGAON

93. Reactions
1. Electrophilic substitution
thiophene undergoes electrophilic substitution reaction at 2nd
position
TH IOPH EN E
R.C.P. KASEGAON

94. Reactions
1. Electrophilicsubstitution
TH IOPH EN E
R.C.P. KASEGAON

95. Reactions
1. Electrophilicsubstitution
TH IOPH EN E
R.C.P. KASEGAON

96. Reactions
2. Reduction
TH IOPH EN E
R.C.P. KASEGAON

97. Reactions
3. Reaction with organo lithium
TH IOPH EN E
R.C.P. KASEGAON

98. Medicinal uses
TH IOPH EN E
R.C.P. KASEGAON

99. Medicinal uses
TH IOPH EN E
R.C.P. KASEGAON