Ab initiostudy of tautomerism and of basicity center preference in histamine, from gas phase to solution—comparison with experimental data (gas phase, solution, solid state)

Tautomeric and basicity center preferences for isolated neutral and monoprotonated histamine were studied by means of ab initiocalculations (HF, MP2 and DFT). The polarizable continuum model (PCM) was applied to the study of the variations of the tautomeric and basicity center preferences in histamine on going from the gas phase to aqueous solution. Twelve solvents of different polarities (from n‐heptane to water) were chosen and calculations were performed for geometries optimized at the HF/6–31G* level. In low‐polarity solvents and in the gas phase the protonation site is identical. A change of the preferred site of protonation takes place in solvents containing heteroatoms (except tetrachloromethane). Under the same conditions, a variation of the tautomeric preference in the monocation occurs. The ring N2‐protonated form (ImH+)—favored in gas phase—is also preferred in non‐polar solvents (n‐heptane, benzene, tetrachloromethane). The ImH+form becomes less important in more polar solvents. In such a case, the chain N3‐protonated form (AmH+‐T1) predominates. For the neutral histamine, solvation has a relatively small influence on the relative energies (variations are less than 1 kcal mol−1), and does not change the tautomeric preference (HA‐T2). Calculated basicity parameters were compared with those obtained experimentally in the gas phase and in aqueous solution. In the gas phase, the experimental (‘macroscopic’) basicity parameter (PA) is close to the ‘microscopic’ PAcalculated for the gaucheconformation. In aqueous solution, the microscopic pKaorder is similar to that of the Eprotcalculated for the transconformation. In the solid state, both forms of histamine (neutral and monoprotonated) prefer the transconformation. Some exceptions occur for complexes with metals. Copyright © 2003 John Wiley & Sons, Ltd.