Theoretical studies of the in-solution isomeric protonation of non-aromatic six-member rings with two nitrogens.

For exploring the preferred site for hydrogen bond formation, theoretical calculations have been performed for a number of six-member, nonaromatic rings allowing for alternative protonation on the ring nitrogens. Gas-phase protonation studies for test molecules indicate that the B3LYP/aug-cc-pvtz and QCISD(T)(CBS) calculations approach the experimental values within about 1 kcal/mol with considerable improvement for relative enthalpies and free energies. Relative free energies calculated at the IEF-PCM/B3LYP/aug-cc-pvtz level predict favorable protonation on the tertiary rather than on the secondary nitrogen both in aqueous solution and in a dichloromethane solvent for saturated rings. Protonation on a nitrogen atom next to a C═C bond is disfavored due to a large increase in internal energy. Monte Carlo simulations considering a counterion and Ewald summation for the long-range electrostatic effects for a 0.1 molar model system predict ΔG(solv)/MC values generally less negative than from the IEF-PCM calculations. These results make the protonation on the tertiary nitrogen even more favored. The solute-solvent pair-energy distribution depends sensitively on the applied model. In conclusion, the freely moving anion has been considered as the most relevant model with overall neutrality for the system and applying the least restrictions.