Theoretical Studies of the In-Solution Isomeric Protonation of Non-Aromatic Six-Member Rings with Two Nitrogens

Abstract

For exploring the preferred site for hydrogen bond formation, theoretical calculations have been performed for a number of six-member, non-aromatic 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.

Theoretical Calculations on the Conformational/Tautomeric Equilibria for Small Molecules in Solution

“…Accurate theoretical prediction of the free energy of hydration for a molecule is, however, challenging. The gas-phase term could be reliably predicted; the protonation energy and gasphase basicity were successfully calculated recently for a few molecules [41,42] applying satisfactorily high-level of energy calculations and by assuming ideal gas behavior. By combination of the classical limit expression for the translational, rotational energy and entropy and using the rigid-rotor/harmonic oscillator approach, [43] good agreement with experimental values was reached.…”

“…The counterion effect becomes nearly negligible only at about R = 12 Å. Recent studies suggest, however, that a free chloride counterion would wander in the solution and takes sometimes a hydrogen bond with the cation, whereas the cation -anion distance may increase temporarily even to about 14 Å in a dilute solution [37,41,42,112].…”

“…Ratios of differently protonated species for six-member aliphatic heterocycles with two nitrogen atoms in different ring positions were calculated in water and dichloromethane [42]. Calculated IEF-PCM/ B3LYP/aug-cc-pvtz and IEF-PCM/ QCISD(T)/cc-pvtz relative free energies predict the same preference for the compared species.…”

Theoretical study of the gauche–trans equilibrium with and without an intramolecular hydrogen bond for +H3NCH2CH2X systems (X = OH, NH2, COO−) in solution

“…For details of the methodology applied, see also recent papers. [25][26][27] Using the BOSS 4.8 package, 28 the all-atom OPLS-AA 12-6-1 pair-potential 29,30 was applied, and the 12-6 Lennard-Jones parameters were taken from the program's library. The atomic charges were fitted to the IEF-PCM/B97D/aug-cc-pvtz molecular electrostatic potential, generated on the basis of the solute's electron distribution polarized by the solvent, by means of the CHELPG procedure.…”

“…Previous studies indicated, however, that the ion and the counterion stay generally close to each other in a slightly polar solvent, and maintain a fairly stable hydrogen-bonded ion-pair. 26,39 Thus a bonded Cl À Á Á Á + H 3 NCH 2 CH 2 NH 2 model was optimized in chloroform. This is the other extreme structure for an ion-pair compared with the fully dissolved and separated model.…”