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