The geometries of various tautomers and rotamers of clonidine and rilmenidine in both anionic and protonated forms, were optimized using the two-layered ONIOM(B3LYP 6-311]G(d,p) : MNDO) method. The calculations showed that, in agreement with experiment, clonidine exists as the more stable imino tautomer. The tautomer containing the amino group is less stable by about 30 kJ mol~1. Rilmenidine also exists in two forms (amino and imino), the amino tautomer being more stable by 5 kJ mol~1. The computed stable conformation for the clonidine species is characterized by the phenyl and imidazolidine rings being perpendicular to each other. In the case of the rilmenidine tautomers and ionised forms, the oxazoline and dicyclopropyl moieties are in a mutual gauche conformation. In contrast to the parent neutral molecule of clonidine, ionization caused considerable geometric changes in the clonidine anions. The oxazoline derivative of rilmenidine is by about 50È60 kJ mol~1, a weaker acid than the imidazoline derivative clonidine. The primary protonation sites are the imidazolidine and oxazoline parts of the drugs. Rilmenidine is slightly less basic than clonidine. The proton affinities of clonidine and rilmenidine were computed to be [999 and [996 kJ mol~1, respectively. The clonidine base was found to be substantially more lipophilic than the base of rilmenidine.

The geometries of various tautomers and rotamers of moxonidine in both anionic and protonated forms were optimized using the two-layered ONIOM(B3LYP 6-311+G(d,p):  AM1) method. The calculations showed that, in agreement with experiments, moxonidine exists in a more stable imino tautomer. The tautomer containing the amino group is less stable by about 19 kJ/mol. The computed stable conformation for the moxonidine species is characterized by the pyrimidine and imidazolidine rings being in the mutual gauche conformation to one another. In contrast to the parent neutral molecule of moxonidine, ionization caused considerable geometric changes in the anions compared to the neutral species. In the neutral form and anion of the parent drug, an intramolecular hydrogen bond stabilizes the structure and makes the most stable conformations more planar. The primary protonation site is the imidazolidine part of drug. The proton affinity of moxonidine was computed to be −1004 kJ/mol. The moxonidine base was found to be less lipophilic than the base of parent clonidine.

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