The low reactivity of pyridine, pyridazine, pyrazine, and pyrimidine towards electrophilic substitution reactions can be explained assuming a frontier orbitals control of the reaction. In fact, 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 can be explained considering that, in this case, the HOMO is an aromatic orbital.