CHEMISTRY OF AZOLESAzoles are five membered heterocycles having the ring nitrogen

and other heteroatomes or more than one nitrogen atom, there

is several types azoles as shown below:

NH

NN

X

NN

X = O , S1,2,4-Triazole 1,3,4-Oxadiazole

1,3,4-Thiadiazole

NHNN

N

Tetrazole

X

N

1,3-Azole

XN

1,2-Azole

XNN

1,2,5-Oxadiazoles1,2,5-Thiadiazole1,2,3-Triazole

X = O, S, NH

Chemical Reactivity of Azoles

The presence of addition SP2-N atom in the rings affects

the reactivity of these compounds as follow:1- The additional SP2-Nnitrogen atom has localized lone pair of

electrons which lies in a plane perpendicular to the plane of the ring

and available for protonation and electrophilic attack.

2- This lone pair of electrons causes a lowering in the energy levels of

the π-orbitals due to resonance and formation of two tautomeric forms.

This makes the E+ attack at C-atom less than in case of pyrrole, furan

and thiophene.

3- However, it is also electron attracting thus can stability –ve charge

making nucleophilic substitution easier.

The effect of introducing an additional nitrogen atom into pyrrole,

furan and thiophene is similar to introducing an electron

withdrawing substituent at that position. Thus in case of azoles,

electrophilic attack at carbon atoms is less easy than in

pyrrole, furan or thiophene.

XN

X

N

1,2-azoles 1,3-azoles

additional SP2 N

additional SP2 N

On the other hand, the additional SP2 N atom has an inductive

electron-withdrawing effect and can provide stablization to

negatively charged intermediate.

Z

NX

Nu-

Z

NX

Nu Z

NNuX

Protons can add to nitrogen atom number 3 of 1,3-azoles as

the case in pyridine. Imidazole is a moderately strong base but

the other azoles are weak bases

Z

NH

NH

N

NH

NX

N

In imidazole the inductive withdrawal by nitrogen number 1 is weak, so

imidazole is much stronger base than pyridine. The oxygen containing

heterocycles are the least basic because of the inductive effect of

oxygen. The order of reactivity is follow as:

NH

O S

NH

N

O

N

S

N

NH

NO

N SN

Reactivity towards E+

Polyazoles and Imidazoles exhibit also annular tautomerism of the

ring that not involved in the π-electron system.

NH

NN

NH

R R

NH

NN

NH

3-alkyl pyrazole 5-alkyl pyrazole

3(5) alkyl pyrazole

NH

N

N

NH

4-alkyl pyrazole 5-alkyl pyrazole

4(5) alkyl pyrazole

NH

N

N

NH

R R

pyrazole Imidazole

Electrophilic Substitution at Carbon of 1,3-Azoles

1,3-Azoles are less susceptible to electrophilic substitution than

pyrrole, furan and thiophene but much more reactive as

compared to pyridine.

N

EE

Electrophilic substitution in pyridine occurs mainly at position 3- and

5- whereas in furan, pyrrrole and thiophene at positions 2- or 5-. In

the other words, the additional N atom deactivates its vicinal position

in 1,3-azoles.

Z

N

1

2

34

5

deactivatedcorrespondto pyridine

most stronglyactivated by Z

NH

NR

N

NHR

3- Electrophilic substitution with imdazole in acidic strong media either fail

completely as Fridel-Craft’s reaction or proceed with difficulty at C-4.

It is clear that E+ attack at C-2 and C-5 is not preferred because they yield three resonatingstructures, one or two of them are highly unstable. On the other hand, attack at C-4 gives2 stable resonance structures). Thus E+ attack is preferred at C-4.

NH

N

NH

N

ENH

N

E

ENH

N

NH

NE E

NH

NNH

N

E ENH

N

E

NH

N

E

especially stable

especially stable

at C-5

at C-4

at C-2

highly unstable because the +ve charge is adjacent to SP2 N

highly unstable sixtet nitrogen

especially stable

NH

N

Br2

Fridel Craft

HNO3 / H2SO4

Hot oleum

NH

N

NH

N

NH

N

NH

N

Br

Br Br

O2N

HO3S

NN Ar

no reaction

strong base

AN2 Cl

N

X E

N

XE

N

XE

N

XE

N

X

E N

X

E

S

N

S

N

S

N

Br

NaNH2 / 150oCNH2

/ MeOHMeONaOCH3

Nucleophilic substitution reactions

N

N

N

N

N

N

BrN

Br

CH3

+

HN

H3C

200oC

H3C

H3C

CH3

NH3 / 75oC

N

N

NH2

H3C

H3C

CH3

O

NCl

Ph

Ph

PhNH2

O

NNHPh

Ph

Ph

1,2-Azoles are much less reactive than 1,3-azoles, not undergo

electrophilic substitution in acid conditions. Electrophilic

substitution occurs at position 4.

1,2-Azoles

NH

N

Br2 / aq. AcONa

NH

N

Br

Br2 / aq. NaOH

NH

N

Br Br

Br