Theoretical treatment of multiple site reactivity in large molecules

The method of electrostatic potentials is generalized via a double perturbation theory to describe the simultaneous attack of a large molecule by two or more charged species. The interaction term is found to reproduce accurately the full “super-molecule” calculation. The scheme is illustrated by treating the diprotonation of adenine and N7-methyladenine. For adenine, the most stable diprotonated species is found to be the N1, N7 combination, while the N3, N9 couple is predicted for the N7 substituted derivative if N3 is the first protonation site.