Heterocyclic Rings
Pyridne, quinoline and isoquinoline
PyridnePyridine is a water -miscible liquid, b. p. 115 oC with an
unpleasant odourAn Excelent polar solvent, A base (pka = 5.23)Pyrrole is less basic than pyridine becuase the lone pair
of electrons in pyrrole is part of the aromatic ring, while that in pyridine is free.
NNH
:
Pyridine Pyrrole
N CH3 N
CH3
N
CH3
N
COOH
N
COOH
Picolines
N
N
H
CH3
nicotinic acid isonicotinic acid
Tobacco alkaloid (nicotine)Alkaloide (alkali like)
1) The Hantzsch Synthesis1,3-dicarbonyl compound + ammonia + aldehyde
CH3 O
MeO2C
CH3O
CO2Me
NH3
HAr
O
CH3 NH2
MeO2C
CH3O
CO2Me
Ar
H
NH2CH3
CH3
Ar
CO2MeMeO2C
ONH
Ar
CH3 CH3
CO2MeMeO2C
+
Conjugate addition (1,4-addition)
enamine enone
+
CH3 NH2
MeO2C
ArO
Cl
H
NH2CH3
Ar
Cl
CO2MeMeO2C
O
NCH3 Ar
MeO2C
+
Conjugate addition (1,4-addition)
enamine enone
Unsymetrical pyridine can be prepared from different enamines and enones
2) Reaction of Ammonia + 1,5-diketone
O O
NH3
NH
N
Oxidation
3) Diels-Alder Reaction
NO
X
N
X
N
R
Ph
CO2H
CO2H N
R
Ph
CO2H
CO2H
N
CF3
N
CF3
N
CF3
+-H2O
+
+400 oC heat
-H2
N
COOR
Tos N
COOR
Tos N
N
Ph
N
Ph
Ph
Ph
Ph
PhO
PhPh
PhPh
+ [O]
+heat
- CO
4) Kroehnke Synthesis
Chemistry of Pyridine
N N
CH3
N
N
N
R O
N
R Cl
O
CH3I+
I-
+Cl-
A good acylating agent
N N
O
R OOH
O
PX3
N
NHO3, H2SO4
N
O
NO2
PX3
N
NO2
N
O
NH2
PX3
N
NH2
+
-
Use of N-Oxides
+
-
+
-
H2 / Pd
Electrophilic SubstitutionPyridine is million times less reactive than benzene
Nitration (less than 5%, Chlorination in moderate yield, Bromination in a good yield)3-position is usually attacked preferably
ChiChibabin Reaction (Nucleophilic Substitution)
N N NH2
H
Na+
N NH2
NaNH2
-
-NaH
Quinoline and Isoquinoline
NN
12
3
44'56
78 8' 1
2
3
44'56
78 8'
Quinoline Isoquinoline
Quinoline Skraup Synthesis
O
NH2 NH
O
N
Aniline + Glecerol + H2SO4 quinoline
O
NH2 NH
O
N
Doebner-von Millar
+
Combes Synthesis
RO
O
RNH2 N R
R
H
O
NO2
R
O R2 N
R
R2+
Base1)
2) Reduction
Friedlaender Synthesis
Isoquinoline Synthesis, Bischler-Napierlaski
NH2
MeO
MeO
R Cl
O
NH
MeO
MeO
R
O
MeO
MeON
R
MeO
MeON
R
POCl3
Pd
Pictet-Spengler Synthesis
NH2
R H
O
N
R
MeO
MeONH
R
H+
Pomeranz-Fritsch Synthysis
OR
H
O
H2NCH2CH(OEt)2
ORN
OEtEtO
H
ORN
H2SO4
Chemistry of Quinoline and Isoquinoline Nucleophilic Substitution (ChiChibabin Reaction)
N
N
NaNH2
NaNH2
N NH2
N
NH2
N
N
KOH
KOH
N OH
N
OH
NH
O
NH
O
225 o
C
225 o
C
Electrophilic SubstitutionOccurs at the 5- or 8-positions, or both
Quinoline N-Oxides can be nitrated at the 4-position or photoisomerize as follows