heterocyclic chemistry six-membered aromatic heterocyls: pyridine (azine)

Heterocyclic Chemistry


N

OS

Six-Membered Aromatic

Heterocyls: Pyridine (Azine)

Heterocyclic ChemistryHeterocyclic Chemistry

PYRIDINE- Structure and Aromaticity

Pyridine is a six membered heterocyclic compound Pyridine is a six membered heterocyclic compound with molecular formula of Cwith molecular formula of C66HH55N N and it is obtained from and it is obtained from

coal tar.coal tar. IIt t may be formally derived from the structure of may be formally derived from the structure of benzene through the exchange of one ring carbon for benzene through the exchange of one ring carbon for a a spsp2 hybridized nitrogen2 hybridized nitrogen a nitrogen. a nitrogen. Pyridine is Pyridine is an aromatic compound,an aromatic compound, however,however, the the nitrogen’s lone pairnitrogen’s lone pair of electrons of electrons is in an sp2 orbital orthogonal to the p orbitals of the ring, therefore it is is not involved in maintaining aromaticity bnot involved in maintaining aromaticity but it is available to react with protons thus pyridine is basic


Pyridine can be represented as a resonance Pyridine can be represented as a resonance hybrid of the following structures.hybrid of the following structures.

PYRIDINE- Structure and AromaticityPYRIDINE- Structure and Aromaticity


Pyridine (Azine): Introduction

Due to the greater electronegativity of nitrogen (relative to carbons) it tends to withdraw the electron density from carbon atoms at positions 2, 4 and 6 which therefore acquire partial positive charges while the N atom acquires partial negative charge while the carbons at positions 3 and 5 remain neutral.


1- 1- Common Strategy ‘’5 + 1’’Common Strategy ‘’5 + 1’’


Synthesis of Pyridine

From 1,5-dicarbonyl compounds:From 1,5-dicarbonyl compounds:

O ONH H

NH4OAc


2- 2- Bönnemann Bönnemann cyclization:cyclization:


3- 3- Hantzsch Synthesis:Hantzsch Synthesis:

O

OEt

O O

H HOEt

O

O

++NH

EtO

O

OEt

O

HNO3

[O]

NH3

Ethylacetoacetate -dicarbonyl cpd

dihydropyridine drivative 1) KOH 2) CaO,

N

O O

N

EtO

O

OEt

O

N

CH

CH

+ NHC +CH

CH

red hot tube



NH

+ CHCl3 KOH

N

Cl

Pyrrole

C

N+

N

CN CN - H2

N

CN300 C°

1,3-butadiene

4- 4- From pyrrole:From pyrrole:

5- 5- By Diels Alder reactionBy Diels Alder reaction


Basicity of pyridineBasicity of pyridine Pyridine is Pyridine is a weak basea weak base; ; since lone pair is in since lone pair is in

an span sp2 2 hybrid orbital. Is the conjugate acid hybrid orbital. Is the conjugate acid aromatic? aromatic?

It undergoes many reactions typical of amines such as reaction with Bronsted acids such as chromic acid and hydrobromic acid.

N NH

Br

Br2

NH

Br3

+ HBr

Pyridinium salt


Basicity of pyridineBasicity of pyridineCompared to pyrrole, pyridine is much stronger baseCompared to pyrrole, pyridine is much stronger base this is due to the nitrogen lone pair is not involved in maintaining the aromaticity thus it free for protonation, however, in pyrrole the lone pair on the N atom is already involved in the aromatic array of p electrons. Protonation of pyrrole on N atom results in loss of aromaticity and is therefore unfavorable.

Compared to imidazole, pyridine is less basic Compared to imidazole, pyridine is less basic this is this is due to the on protonation the + ve charge can be due to the on protonation the + ve charge can be delocalized over two nitrogen atoms while in case of delocalized over two nitrogen atoms while in case of pyridine it is delocalized over the ring which interrupt pyridine it is delocalized over the ring which interrupt aromatcity.aromatcity.


Basicity of pyridineBasicity of pyridineCompared to analogous aliphatic amines, pyridine is Compared to analogous aliphatic amines, pyridine is less basicless basic this is due to the nitrogen atom in pyridine this is due to the nitrogen atom in pyridine is is sp2 sp2 hybridized (more electronegative) and the lone hybridized (more electronegative) and the lone pair of electrons occupies an pair of electrons occupies an sp2sp2 orbital thus it is held orbital thus it is held more tightly by the nucleus than the lone pair of more tightly by the nucleus than the lone pair of electron in aliphatic amines with electron in aliphatic amines with sp3sp3 hybrdized N hybrdized N atom and the lone pair of electrons occupies an atom and the lone pair of electrons occupies an sp3sp3 orbital (less electronegative).orbital (less electronegative).

NNH

NH

NH

N> > >

Decreasing order of basicity


Chemical properties: Chemical properties: 1-Electrophilic substitution1-Electrophilic substitution

the negative pole in pyridine ring is at N while the positive pole is the negative pole in pyridine ring is at N while the positive pole is at carbon skeleton which is opposite to what happens in pyrrole.at carbon skeleton which is opposite to what happens in pyrrole.

This is due to the greater electronegativity of nitrogen (relative This is due to the greater electronegativity of nitrogen (relative to carbons) it tends to withdraw the electron density from carbon to carbons) it tends to withdraw the electron density from carbon atoms at atoms at positions 2, 4 and 6positions 2, 4 and 6 which therefore which therefore acquire partial acquire partial positive chargespositive charges while the N atom acquires partial negative while the N atom acquires partial negative charge and the charge and the carbons at positions 3 and 5 (carbons at positions 3 and 5 (ββ-position) remain -position) remain neutralneutral therefore these positions are therefore these positions are the most preferred for the most preferred for elctrophilic attack. elctrophilic attack.

N


Chemical properties: Chemical properties: 1-Electrophilic substitution1-Electrophilic substitution

Also as a consequence of electron deficiency on Also as a consequence of electron deficiency on pyridine ring , pyridine ring , pyridine is less reactive towards pyridine is less reactive towards electrophiles than pyrroleelectrophiles than pyrrole and benzene (it and benzene (it resembles highly deactivated benzene derivatives), resembles highly deactivated benzene derivatives), where it does not undergo Friedel-Craft’s alkylation where it does not undergo Friedel-Craft’s alkylation or acylation or coupling with diazonium salts.or acylation or coupling with diazonium salts.

Moreover, electrophilic substitution reactions of Moreover, electrophilic substitution reactions of pyridine require very harsh conditions (e.g. v. high pyridine require very harsh conditions (e.g. v. high temp.) to take place and are low yieldingtemp.) to take place and are low yielding . .


2-Pyridine as a nucleophile 2-Pyridine as a nucleophile (reactions on N atom)(reactions on N atom)

As a tertiary amine pyridine has nucleophilic properties thus it reacts with electrophiles:

N

HCl NH Cl

+-

Pyridinium chloride

CH3I

NCH3 I

+-

N-methyl pyridinium iodide

CH3COOOH

r.t.N

O

Pyridine-N-oxide


3-Nucleophilic substitution on 3-Nucleophilic substitution on carboncarbon

Pyridine is very reactive towards nucleophiles than benzene it resembles benzene having strong E.W.G due to the withdrawing effect of the electronegative N atom . AS appeared from the canonical structures of pyridine positions 2, 4 and 6 carry partial positive charges thus ncleophilic substitution proceeds readily at the 2-position followed by 4-position but not at the 3-position. Additionally, attack at positions 2, 4 or 6 results in resonance structure in which the negative charge is delocalized at N thus it is more preferred while attack at position 3 or 5 results in resonance structures in which the negative charge is delocalized over carbons only.


Orientation of nucleophilic Orientation of nucleophilic substitution in pyridinesubstitution in pyridine

N

+ NuN Nu

H

N Nu

H

N Nu

H

attack at C-2more preferred

-ve charge on N

NN

NuH

N

NuH

N

NuH

attack at C-4more preferred

+ Nu

-ve charge on N

N Nattack at C-3

+ Nu

NuH

N

Nu

H

N

NuH

-ve charge on C only


3- Nucleophilic Substitution 3- Nucleophilic Substitution reactionsreactions

i) i) The Chichibabin reaction The Chichibabin reaction


R can be o-, m-, or p- substituent

ii) Reaction with organometallic compounds lithium reagents

N

C4H9Li

N C4H9

+

Butyllithium

2-Butylpyridine


3-Nucleophilic substitution 3-Nucleophilic substitution ReactionsReactions

iii) Reaction with potassium iii) Reaction with potassium hydroxidehydroxide

N

KOH / 320 C

N O NH

OH

2-Pyridone2-Hydroxy pyridine

° keto-enol

tautomerism


4-Reduction Reactions4-Reduction Reactions


CH3CH2CH2CH2CH3 NH3

NH

N

NH

NH

1) L

iAlH 4

2) H+ , H

2O

Na/NH3

Birch reduction

H2 /Ni

HI, 30

0o C

+

1,4-Dihydropyridine

1,2-Dihydropyridine

piperidine


Derivative of pyridine: Derivative of pyridine: N-oxide pyridineN-oxide pyridine

Pyridine can be oxidized easily to N-oxide pyridine Pyridine can be oxidized easily to N-oxide pyridine by peracids.by peracids.

On the basis of dipole moment studies, N-oxide On the basis of dipole moment studies, N-oxide pyridine is considered as a resonance hybrid of the pyridine is considered as a resonance hybrid of the following structuresfollowing structures

N NO

AcOOHr.t. N-oxide pyridine

N

O

N

O

N

O

NO

N

ON

O

The -ve. charges appear at positions 2, 4 thus active towards

E+s.

The +ve. charges appear at positions 2, 4 thus active towards nucleophiles

NO


N-oxide pyridine

As appears from the previous canonical forms , there As appears from the previous canonical forms , there are positive and negative charges at positions 2 and 4 are positive and negative charges at positions 2 and 4 thus thus N-oxide pyridine isN-oxide pyridine is more activated for more activated for electrophilic and nucleophilic attackelectrophilic and nucleophilic attack at these positions at these positions than pyridinethan pyridine itself. itself.

N-oxide pyridines are very important intermediates N-oxide pyridines are very important intermediates for preparing pyridine derivatives that are difficult to for preparing pyridine derivatives that are difficult to prepare due to the easiness of removal of oxygen atom prepare due to the easiness of removal of oxygen atom by reduction.by reduction.

For instance, nitration of pyridine is very difficult For instance, nitration of pyridine is very difficult and low yielding reaction and it occurs at position 3, and low yielding reaction and it occurs at position 3, however using N-oxide pyridine will direct the nitration however using N-oxide pyridine will direct the nitration to position 4 and then the oxygen can be easily to position 4 and then the oxygen can be easily removed by reduction as shown in the following removed by reduction as shown in the following scheme. scheme.


Reactions of N-oxide pyridine

N N

O

CH3CO OOH, r.t.

HNO3 / H2SO4

N

NO2

6 %

N

O

NO2

PCl3

N

NO2

H2 / Pd / H+

N

NH2

300 C°

HNO3

SOCl2

N

O

Cl

+

N

O

Cl

or H2O2

heterocyclic chemistry six-membered aromatic heterocyls: pyridine (azine)

Documents

aromaticity pyridine

case of pyridine

pyridine azine slide

aromaticity b pyridine

aromaticity slide

nitrogen lone pair

basic slide

membered heterocyclic