Post on 13-Jan-2016
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