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 &s ON i N N.UN x? x’ x X=0,S, NH 1,3-Azole 1,2-Azole 1,2,5-Oxadiazoles 1,2,5-Thiadiazole 1/2.3-Triazole N-\ N-N N=N ay 1 - a Ne NH Sv Pa Vv ero Tetrazole 1,2,4-Triazole —_1,3,4-Oxadiazole 1'3.4-ThiadiazoleChemical Reactivity of Azoles 1- The additional SP?-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 7-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. 1,2-azoles We : /f additional SP* N 3: x additional SP? N 1,3-azoles On the other hand, the additional SP? N atom has an inductive electron-withdrawing effect and can provide stablization to negatively charged intermediate.Ce Be Gy 28> Cm Protons can add to nitrogen atom number 3 of 1,3-azoles as the case in pyridine. Imidazole is a moderately strong base but NF oS m< O>& H the other azoles are weak bases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: Q>GH> 9 ee e N GSR ne ‘ys > ch > Se Reactivity towards E*Polyazoles and Imidazoles exhibit also annular tautomerism of the ring that not involved in the z-electron system. pees = Me gee Om aR Ga (3: = (s N H a pyrazole Imidazole B R R y a Ef N: oN: SNH aN 4 Wu yo 8 N N 3-alkyl pyrazole 5-alkyl pyrazole 4-alkyl pyrazole 5-alkyl pyrazole Re oA < yy, Ae Y 3(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 a ne te Electrophilic substitution in pyridine occurs mainly at position 3- and compared to pyridine. 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.deactivated correspond 4 N3 iy to pyridine ee 1 most strongly activated by Z R Oe ee3- Electrophilic substitution with imdazole in acidic strong media either fail completely as Fridel-Craft's reaction or proceed with difficulty at C-4. ates On =N tard 4 ee Ob. he abhor especially stable highly unstable because the +ve charge is adjacent to SP? N E. E. acd oS ub |» @ " en eo especially stable atcn & _N =N — Ghee ohhe Ode especially stable highly unstable sixtet nitrogen Itis 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.= De ———_—— | yl Br yor H Fridel Craft i, no reaction OWN. HNOs / HzS0, a po Pa a os N H Hot oleum et nnn ] We H feo AN, Cl N Bee ea N strong base N g H4 wi 1 *z ® w x™ Fu | uw x’, x? eo ~Nucleophilic substitution reactions NaNHp / 150°C YN ON, Cy ras: MeONa / MeOH & se Pr = \>och;N i 1 oO Coser « CG CHs HC io HC HC, xs NH, / 75°C I} —_> HC on HC oe Ph Ph’ N PhNH, Phun L> od Lwin g 0 Phi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 v \N N H u N N H Br. Br Br / aq. NaOH a Br ee H