Protonation macro- and microconstants have been determined experimentally for the 4-aminophenol molecule and five hydroxy-substituted 2-phenylethylamines: tyramine, octopamine, dopamine, norepinephrine and epinephrine. In aqueous solution, 4-aminophenol is in the form of the neutral zero-net-charge tautomer, whereas (hydroxyphenyl)ethylamines exhibit tautomeric and conformational equilibria between the zwitterionic (zw) and the neutral (n) forms. The zw/n ratio was measured in the range of 0.09–7.43. No evident correlation has been found between the structural changes and changes in the zw/n values for this set of compounds. Polarizable continuum solvent calculations in the SCIPCM and PCM approximations and explicit solvent Monte Carlo simulations have been performed for theoretical investigation of tautomeric/conformational equilibria for the 4-aminophenol, tyramine and dopamine. Gas-phase and in-solution geometry optimizations were carried out mostly at the DFT/B3LYP/6-31G* level followed by B3LYP/6-311++G** single point calculations. All calculations found the neutral form as the stable one for the 4-aminophenol molecule in aqueous solution with an aniline-type amino group. Continuum solvent calculations underestimate the stability of the zwitterion relative to the neutral form for glycine and tyramine with an aliphatic amine group in the molecule. The calculated values are subject to a large basis set effect for tyramine. For explicit solvent calculations, an atomic charge set has been proposed where the charges were fitted to the molecular electrostatic potential calculated by using the self-consistent in-solution wave function. Using PCM/B3LYP/6-31G*-based atomic charges in Monte Carlo simulations, the preference of the zwitterionic tyramine was demonstrated. For reaching a better accord with the experimental free energy difference, corrections including intermolecular solute–solvent vibrational entropies are to be considered. Theoretical studies for the trans dopamine zwitterion predict the preference of the 4-OH form over the 3-OH isomer.
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