Heterocyclic Chemistry

Heterocyclic Chemistry

N

OS

5-Membered rings with two

heteroatoms

Imidazole and Pyrazole

Heterocyclic Chemistry

IntroductionIntroduction

Replacing a CH group in the pyrrole ring with a Replacing a CH group in the pyrrole ring with a nitrogen atom can give rise to two compounds : nitrogen atom can give rise to two compounds : pyrazole and imdazole.pyrazole and imdazole.

Only one nitrogen atom can contribute two Only one nitrogen atom can contribute two electrons to the aromatic sextet. It is the nitrogen electrons to the aromatic sextet. It is the nitrogen with the hydrogen (black in color) and it is described with the hydrogen (black in color) and it is described as pyrrole-like nitrogen. While the second nitrogen as pyrrole-like nitrogen. While the second nitrogen which has no hydrogen (green) is described as which has no hydrogen (green) is described as pyridine-like. pyridine-like.

The lone pair on pyrrole-like nitrogen is delocalized The lone pair on pyrrole-like nitrogen is delocalized round the ring while that on the pyridine-like nitrogen round the ring while that on the pyridine-like nitrogen is localized in spis localized in sp22 orbital on nitrogen. Thus these orbital on nitrogen. Thus these compounds have properties intermediate between compounds have properties intermediate between those of pyrrole and pyridine.those of pyrrole and pyridine.

Heterocyclic Chemistry

Physical Properties of Imidazole and Physical Properties of Imidazole and PyrazolePyrazoleImidazole and pyrazole are water soluble solids and Imidazole and pyrazole are water soluble solids and

insoluble in aprotic solvent.insoluble in aprotic solvent. They have very much higher boiling point:256 and They have very much higher boiling point:256 and 187 °C respectively, this difference is due to imidazole 187 °C respectively, this difference is due to imidazole has an extensive hydrogen bonding than pyrazole has an extensive hydrogen bonding than pyrazole thus imidazole molecules can exist as oligommers, consequently more energy is required to break these bonds to bring the molecules from one phase to another. On the other hand pyrazole molecules can form dimers only thus lesser energy is required to break these molecules.

pyrazole molecules as a dimerimidazole molecules as a polymer

NN

H N

N

H NN

N

N

H

N

NH

Heterocyclic Chemistry

Physical Properties of Imidazole and Physical Properties of Imidazole and PyrazolePyrazole

N-subsituted imidazole and pyrazole have lower boiling and melting points than the unsubstituted compounds due to inability to form H-bonds.

BasicityBasicity

Imidazole is a stronger base than pyrazole or pyridine and of course pyrrole. Thus imidazole and pyrazole are more stabilized than pyrrole in acidic medium.

Basicity order: Imidazole > Pyrazole > Pyridine > pyrrole

This can be explained as follows:i) Pyrrole is not basic because the lone pair on the

only nitrogen is needed to complete the aromatic pi system and protonation if occurs at all occurs at carbon rather than on nitrogen and the resulting cation is not aromatic.

Heterocyclic Chemistry

BasicityBasicity

ii) Pyridine its l.p. is not involved in maintaining aromaticity thus available for protonation and it only has one nitrogen on which to stabilize the positive charge

iii) Both of imidazole and pyrazole have two nitrogen atoms and on protonation the positive charge can be delocalized over them. However, pyrazoles are much weaker bases than imidazoles. This difference is due to the fact that the positive charge in pyarzolium ion is less delocalized than in the imidazolium ion

Heterocyclic Chemistry

Basicity

Generally E.D.G groups on the ring increase the basicity Generally E.D.G groups on the ring increase the basicity while E.W.G. decrease it.while E.W.G. decrease it.

N-methyl imidazole is more basic than imidazole itself.N-methyl imidazole is more basic than imidazole itself. However, N-methylpyrazole is less basic than pyrazole However, N-methylpyrazole is less basic than pyrazole

which can be attributed to steric hindrance effect which which can be attributed to steric hindrance effect which cause difficulty in accessing the lone pair of electron by cause difficulty in accessing the lone pair of electron by the proton.the proton.

Effect of substitution on basicity

N

NH

NH

N

N

N NN>

CH3CH3

<Basicity

Heterocyclic Chemistry

Acidity

Imidazoles unsubstituted in the 1-position are weak Imidazoles unsubstituted in the 1-position are weak acids. Its acidity is greater than that pyrrole and acids. Its acidity is greater than that pyrrole and equals that of pyrazole. equals that of pyrazole.

Electrophilic Aromatic Substitution Diazoles are Diazoles are less reactiveless reactive than 5-membered than 5-membered heterocycles with one heteroatom (pyrrole and its heterocycles with one heteroatom (pyrrole and its analogs) in electrophilic aromatic substitution due to analogs) in electrophilic aromatic substitution due to the inductive electron-withdrawing effect of the the inductive electron-withdrawing effect of the second heteroatom. second heteroatom.

However, they are more reactive than pyridine due However, they are more reactive than pyridine due to delocalization of the lone pair of electrons on the to delocalization of the lone pair of electrons on the N-N-atomatom make the C- atoms bear negative charges while make the C- atoms bear negative charges while in pyridine the N- atom exerts inductive electron in pyridine the N- atom exerts inductive electron withdrawing effect only.withdrawing effect only.

The orientation in pyrazole, is at the 4-positionThe orientation in pyrazole, is at the 4-position due due to the deactivation effect of the pyridine-like nitrogen.to the deactivation effect of the pyridine-like nitrogen.

Heterocyclic Chemistry

Electrophilic Aromatic Substitution

The orientation in imidazole, is at 5-positionThe orientation in imidazole, is at 5-position, due to the , due to the additional N-atom deactivates its vicinal positionsadditional N-atom deactivates its vicinal positions

However, if the position 5 is occupied the electrophiles However, if the position 5 is occupied the electrophiles will be directed to 4-position.will be directed to 4-position.

Pyrazole

NH

N

E+

4-substituted

NH

N

E

N

NH

N-like pyridine deactivate its vicinal positions

most strongly activated position

1

2

34

5

Heterocyclic Chemistry

Electrophilic Aromatic Substitution

NNH

Br2 / CHCl3N

NH

Br

NH

N

NH

N

HO3S

N

NH

N

NH

O2N

H2SO4 / SO3

100 C°

HNO3 / H2SO4

160 C°

Heterocyclic Chemistry

Electrophilic Aromatic Substitution

Diazocoupling:Diazocoupling:

Since it occurs with electron rich aromatic Since it occurs with electron rich aromatic compounds it occurs only with imidazole and compounds it occurs only with imidazole and activated pyrazole ( with EDG) activated pyrazole ( with EDG) in alkalinein alkaline medium.medium.

N

N

N

N

H

N=NPh

Ph N=N +Cl-

NN

NN

PhN2+ Cl

N=N-PhHOHO

H H

Heterocyclic Chemistry

Electrophilic Aromatic substitution

NN

CH3

BuLi RXN

N R

N

N

ph

N

N

ph

Li

ph

R

BuLiN

N

CH3

R

Li

N

NH

N

N

NNH

NN

Ac2O

COCH3

CH2N2

CO2CH3

H3C

CH3

H3C

CO2CH3

Acylation

Alkylation

Lithiation

Heterocyclic Chemistry

Reaction with oxidizing reagentsReaction with oxidizing reagents

N

NH

NH

NH

O2 / MeOH

O

MeO

MeO

Heterocyclic Chemistry

Synthesis of imidazole and pyrazole

a) Pyrazole:

b) Imidazole:

C CR'CR

O

+ NH2-NH2

N

NH

R

R'

R

O

O

R'

R

O NNH2

+ H2NNH2 NN

H1,3-diketone Hydrazine hydrate

R'

R

R'

Hydrazine hydrate

N

NPh

CCH3CN + PhCN

BuLi N

NH

Ph

N

N

H

OR

R1 OH

+ HCONH2

NHCHOR

R1 NHCHO

R

R1

-Hydroxy ketone

Foramide