Solvent-Induced Effects:  Self-Association of Positively Charged π Systems

Antimalarial cationic drugs, such as chloroquine (CQ) and ferroquine (FQ), form stable dimer structures not only in the solid state but also in solution. The short distances (3.3-3.5 A) observed between the positively charged quinolinium rings suggest that this self-association process is driven by pi/pi stacking interactions. Nevertheless, the strength of these dispersive forces is likely not sufficient to overcome the strong repulsive +/+ electrostatic effects. The question of the exact role of the environment, particularly the solvent, is clearly raised here. Characterization of these unconventional stabilizing nonbonding interactions which we have named +-pi/+-pi is therefore of great importance. In the present work, we describe theoretical calculations and NMR experiments undertaken to probe the nature and the strength of +-pi/+-pi interactions occurring upon self-association of FQ and CQ molecules in water.