CHEMISTRY OF AZOLES Azoles 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: N X
X
N
N
X
N
X = O, S, NH 1,3-Azole
1,2-Azole
N N
N N H
N
1,2,4-Triazole
X X=O,S 1,3,4-Oxadiazole 1,3,4-Thiadiazole
1,2,5-Oxadiazoles 1,2,5-Thiadiazole 1,2,3-Triazole N N N NH Tetrazole
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. N X
N
additional SP2 N
1,2-azoles
additional SP2 N
X 1,3-azoles
On the other hand, the additional SP2 N atom has an inductive electron-withdrawing effect and can provide stablization to negatively charged intermediate.
N
N
-
Nu X
Z
Z
X
N
X
Nu Z
Nu
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
NH Z N
N N H
N
N H
X
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:
O
N H N N H
N H
S N
N S
O
N O
N
Reactivity towards E+
S
N
Polyazoles and Imidazoles exhibit also annular tautomerism of the ring that not involved in the π-electron system.
N N N H pyrazole
N
R
N
R
R N
N
3-alkyl pyrazole
N H Imidazole
R N H
NH
NH
N
5-alkyl pyrazole
3(5) alkyl pyrazole
NH
NH N H 4-alkyl pyrazole
N 5-alkyl pyrazole
4(5) alkyl pyrazole
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.
E
E
N 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.
4 5 Z 1 most strongly activated by Z
R
N3
deactivated correspond to pyridine
2
R N N H
NH N
3- Electrophilic substitution with imdazole in acidic strong media either fail completely as Fridel-Craft’s reaction or proceed with difficulty at C-4. N
at C-5
E
N H
N
N E
E
N H
N H
especially stable highly unstable because the +ve charge is adjacent to SP2 N
E N
E
E N
at C-4
N H
N H
N N H especially stable
at C-2
N H
N
N
N E
highly unstable sixtet nitrogen
N H
E
E N H especially stable
It is clear that E+ attack at C-2 and C-5 is not preferred because they yield three resonating structures, one or two of them are highly unstable. On the other hand, attack at C-4 gives 2 stable resonance structures). Thus E+ attack is preferred at C-4.
Br2
Br N Br
Fridel Craft
Br
N H
no reaction O2 N
N
N
HNO3 / H2SO4
N H
N H
Hot oleum
HO3S N N H
AN2 Cl strong base
N N H
N
N Ar
E
E
E X N X
X
X
N
N
E
N
X E
N
X E
N
Nucleophilic substitution reactions N
NaNH2 / 150oC
NH2
S N S
Br N
MeONa / MeOH S
OCH3
H N
N Br + N CH3
N H3C
H3C
Ph
N CH3
Cl Ph
N H3C
Br
N
N
H3C
NH3 / 75oC
N H3C
N
200oC
PhNH2
Ph
NH2 N CH3
N NHPh
O Ph
O
1,2-Azoles 1,2-Azoles are much less reactive than 1,3-azoles, not undergo electrophilic
substitution
in
acid
conditions.
Electrophilic
substitution occurs at position 4. Br Br2 / aq. AcONa N H N H
N
N Br
Br Br2 / aq. NaOH Br
N H
N