Electrophilic substitutions and HOMOs in azines and purines

The low reactivity of pyridine, pyridazine, pyrazine, pyrimidine, and purine toward electrophilic substitution reactions can be explained assuming a frontier orbitals control of the reaction. DFT study of the molecular orbitals of these molecules shows that the HOMOs of these substrates are not π orbitals. Furthermore, the change in the reactivity observed in pyridine-N-oxide, in activated pyrimidines, and in activated purines can be explained considering that, in this case, the HOMOs are π orbitals.