Tautomeric and conformational equilibria of tyramine and dopamine in aqueous solution

The protonation macro- and microconstants have been measured for tyramine at three temperatures using potentiometry combined with UV spectroscopy. The experimentally determined zwitterion/neutral tautomerization equilibrium constant for tyramine in aqueous solution decreases with increasing temperature from log k(z) = 1.03 at T = 287 K to log k(z) = 0.39 at T = 310 K. Using the van't Hoff isochore, the tautomerization enthalpy was calculated as -9.3 to -13.4 kcal mol(-1) in the indicated temperature range. Theoretical calculations on the solvent effects have been performed using the PCM polarizable continuum dielectric solvent approach at the B3LYP/6-31G* level, and by performing Monte Carlo simulations utilizing the free energy perturbation method. The applied PCM approach, including B3LYP/6-311++G** and MP2/6-31G* single point calculations, as well, consistently favours the neutral form in aqueous solution both for tyramine and dopamine. In contrast, Monte Carlo simulations predict solvent effects that are too large and favour the zwitterionic form both for tyramine and dopamine. Neither method can predict the experimental finding that the prevalent tautomer is the zwitterion for tyramine but is the neutral form for dopamine in aqueous solution. The Monte Carlo results could be improved by finding new, appropriate net atomic charges. The present charge sets derived by fits to the PCM/B3LYP/6-31G* and PCM/B3LYP/6-311++G**//PCM/B3LYP/6-31G* molecular electrostatic potentials provide structures for the zwitterionic solutes that are too polar.