Nomenclature of hetero cyclic compounds, classification of heterocyclic compounds, Reactivity, aromaticity, orbital picture, stability, resonance energy, resonance structure, basicity, method of preparation, reaction and medicinal uses of Pyrrole, furan and thiophene

1. Unit III
Heterocyclic Compounds
Mr. Mote G.D
ADCBP, Ashta

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.

3. Heterocyclic Nomenclature
Replacement nomenclature (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

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

5. Hantzsch-Widman (1888)
Ring No. Ring With Nitrogen Atom Ring Without Nitrogen
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

6. Name: Prefix + Stem + Suffix
Nomenclature of Heterocyclic Compounds
In this nomenclature the nomenclature of heterocyclic compounds are
assigned by combining ‘prefix’ (that indicate the heteroatom present)
with ‘stem’ (that indicate the ring size as well as the saturation 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.
The position 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. The common ‘stem’ nomenclature

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

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

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

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

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

12. N
N
N
N
N
N
N N
H
O
pyridazine pyrimidine pyrazine
* pyridine * morpholine

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

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

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

16. 3.FIVE MEMBERED WITH 2 HETERO ATOM
N
N
H
1H-pyrazole
N
O
isoxazole
N
S
isothiazole
A. 1 AND 2 POSITION
N
N
H
1H-imidazole
N
O
oxazole
N
S
thiazole
B. 1 AND 3 POSITION

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

18. 5.SIX MEMBERED RING WITH ONE HETERO ATOM
N
pyridine
N
H
piperidine

19. 6.SIX MEMBERED RING WITH TWO HETERO ATOM
N
N
pyrimidine
N
N
pyrazine
N
N
pyridazine

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

21. 8.SIX MEMBERED HETEROCYCLIC RING ATTACHED WITH
BENZENE
N
quinoline
N
isoquinoline N
acridine

22. 9. SEVEN MEMBERED RING WIT ONE HETERO ATOM
N
H
N
N
H
AZEPINE
DIAZEPINE

23. 10.BENZODIAZEPINES
N
N
H

24. Calculation of “n”
Huckel Rule: 4n+2π
1 Double bond gives 2 π electron 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
H
O
furan
pyrrole
S
thiophene
Aromaticity in Heterocyclic compounds

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

26. Comparison of Aromaticity
26
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.

27. Basicity
27
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
π electron 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 π electron or lone pair of electron slowly. Hence more
delocalization. Hence thiophene is least basic or not basic

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

29. Orbital structure

30. Orbital structure

31. Comparison stability and reactivity
N
H
O S
thiophene
furan
1H-pyrrole
Electronegativity order: O>N>S
Stability order
<
<
Reactivity order:
N
H
O S
thiophene
furan
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.

32. CO NTEN T
Properties, synthesis, reactions & medicinal uses of…

33. Properties
1. Aromaticity
PYRRO LE

34. Properties
1. Aromaticity
PYRRO LE

35. Properties
PYRRO LE

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)

37. Chemical properties of Pyrrole
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
N
H
+ HCl
N
H
H
Cl
O2
Polymerisation
Brown Resin
Pyrrole hydrochloride
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
H
+ KOH
N
K
Pyrrole Pyrrole potassium
+ H2O

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 N N
H
<
<
1H-pyrrole pyridine
piperidine

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

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

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

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

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

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

45. Synthesis
6. Paal-Knorr synthesis
PYRRO LE

46. Synthesis
7. Hantzsch Pyrrole synthesis
PYRRO LE

47. Synthesis
7. Hantzsch Pyrrole synthesis
PYRRO LE
47

48. Synthesis
8. Knorr synthesis
PYRRO LE
48

49. Synthesis
8. Knorr synthesis
Mechanism
PYRRO LE
49

50. Reactions
1. Electrophilic substitution
PYRRO LE
50

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

52. Reactions
1. Electrophilic substitution
PYRRO LE
52

53. Mechanism
CH3 C
O
O C
O
CH3 + HNO3
CH3 C
O
O NO2
+ CH3COOH
CH3 C
O
O + NO2
Step-
I generation of electrophile(NO2
+
)
Step-
-II-
Attack of electrophile on C2 of pyrrole to form resonance stabilised structure
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 C
O
CH3
N
H
NO2
Pyrrole
+ CH3COOH

54. Reactions
2. Reduction
PYRRO LE
54

55. Reactions
3. Reimer Tiemann reaction
PYRRO LE
55

56. Reactions
PYRRO LE

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

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

59. Medicinal uses
PYRRO LE
59

60. Properties
1. Aromaticity
FU RA N
60

61. Furan
Furan is colorless liquid , bp 32°C with chloroform like smell. Slightly
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
O
+ HCl
O
Cl
O2
Polymerisation
Brown Resin
H
O
O
H H
Succindialdehyde
Furan hydrochloride
Furan

62. Properties
1. Aromaticity
FU RA N
62

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

64. Synthesis
1. Paal-Knorr synthesis of furan
FU RA N
64
CH CH
C C O
O
CH3
H3C
ACID
HC CH
C C OH
HO
CH3
H3C
ENOL
KETO
-H2O
O
H3C CH3
H H
hexane-2,5-dione (2E,4E)-hexa-2,4-diene-2,5-diol
2,5 Dimethyl furan
Mechanism:

65. Synthesis
2. Feist – Benary Synthesis
FU RA N
65

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

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

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
COOH
O
Furoic acid Furan
-CO2

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

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

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

72. Reactions
1. Electrophilic substitution
furan undergoes electrophilic substitution reaction at
2nd position
FU RA N
72

73. Reactions
1. Electrophilic substitution
FU RA N
73

74. Reactions
1. Electrophilic substitution
FU RA N
74

75. Reactions
2. Reduction
FU RA N
75

76. Reactions
3. Diels-Alder reaction
FU RA N
76

77. Reactions
3. Diels-Alder reaction
FU RA N
77

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

79. Reactions
5. Ring Opening reaction
FU RA N
79
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
+ CH3OH + HCl
2 2
H3CO OCH3

80. Medicinal uses
FU RA N
80

81. Properties
1. Aromaticity
TH IOPH EN E
81

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

83. Properties
1. Aromaticity
TH IOPH EN E
83

84. Properties
1. Aromaticity
TH IOPH EN E
84

85. Synthesis
1. Paal-Knorr synthesis of thiophene
TH IOPH EN E
85

86. Synthesis
1. Paal-Knorr synthesis of furan
Mechanism
TH IOPH EN E
86

87. Mechanism
CH CH
C C O
O
CH3
H3C
ACID
HC CH
C C OH
HO
CH3
H3C
ENOL
KETO
-H2O
S
H3C CH3
H H
hexane-2,5-dione (2E,4E)-hexa-2,4-diene-2,5-diol
2,5 Dimethyl Thiphene
P2S5

88. Synthesis
2. From sod. succinate
TH IOPH EN E
88

89. Synthesis
3. Hinsberg Synthesis
TH IOPH EN E
89

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

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

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

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

94. Reactions
1. Electrophilic substitution
TH IOPH EN E
94

95. Reactions
1. Electrophilic substitution
TH IOPH EN E
95

96. Reactions
2. Reduction
TH IOPH EN E
96

97. Reactions
3. Reaction with organo lithium
TH IOPH EN E
97

98. Medicinal uses
TH IOPH EN E
98

99. Medicinal uses
TH IOPH EN E
99