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Tautomeric and basicity center preferences for isolated neutral and monoprotonated histamine were studied by means of ab initio calculations (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’ PA calculated for the gauche conformation. In aqueous solution, the microscopic pKa order is similar to that of the Eprot calculated for the trans conformation. In the solid state, both forms of histamine (neutral and monoprotonated) prefer the trans conformation. Some exceptions occur for complexes with metals. Copyright © 2003 John Wiley & Sons, Ltd.

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.

Relative energies were calculated at different semi-empirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initio levels (RHF/STO-3G//STO-3G, RHF/STO-4G//STO-4G, RHF/3-21G//3-21G, RHF/6-31G//6-31G, RHF/6-31G*//6-31G, RHF/6-31G*//6-31G*, RHF/6-31 ++ G**//6-31G*, RHF/6-311 ++ G**/6-31G*, RHF/6-31G**//6-31G**, RHF/31 ++ G**//6-31 ++ G**, MP2/6-31G*//6-31G* and MP2/6-31G**//6-31G**) for so-called ‘essential’ (trans) and ‘scorpio’ (gauche) conformations of the neutral and monoprotonated histamine tautomers. For the monocationic forms, the polarizable continuous model was applied to geometries optimized at the RHF/6-31G* level. The comparison shows that, generally, both types of calculation (semi-empirical and ab initio) predict the same tautomeric preference for the conformations of histamine and its monoprotonated cation when not interacting with the environment, i.e. for conditions corresponding to the gas phase. For the monocation, the ring N-aza protonated form (ImH⁺) is favoured in the gas phase for both conformations (trans and gauche); this is contrary to water solution, where the chain N-amino (AmH⁺-T1) predominates. This difference results mainly from the high polarizability of the imidazole ring in the gas phase which is strongly reduced in solution. Some ‘discrepancies’ are only observed for neutral histamine, for which the relative energy is close to zero. Good agreement of results predicted by various methods can result from the fact that in histamine the proton is transferred between atoms of the same element (nitrogen). Copyright © 2001 John Wiley & Sons, Ltd.

Relative energies were calculated at different semi‐empirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initiolevels (RHF/STO‐3G//STO‐3G, RHF/STO‐4G//STO‐4G, RHF/3‐21G//3‐21G, RHF/6‐31G//6‐31G, RHF/6‐31G*//6‐31G, RHF/6‐31G*//6‐31G*, RHF/6‐31 ++ G**//6‐31G*, RHF/6‐311 ++ G**/6‐31G*, RHF/6‐31G**//6‐31G**, RHF/31 ++ G**//6‐31 ++ G**, MP2/6‐31G*//6‐31G* and MP2/6‐31G**//6‐31G**) for so‐called ‘essential’ (trans) and ‘scorpio’ (gauche) conformations of the neutral and monoprotonated histamine tautomers. For the monocationic forms, the polarizable continuous model was applied to geometries optimized at the RHF/6‐31G* level. The comparison shows that, generally, both types of calculation (semi‐empirical and ab initio) predict the same tautomeric preference for the conformations of histamine and its monoprotonated cation when not interacting with the environment, i.e. for conditions corresponding to the gas phase. For the monocation, the ring N‐aza protonated form (ImH+) is favoured in the gas phase for both conformations (transand gauche); this is contrary to water solution, where the chain N‐amino (AmH+‐T1) predominates. This difference results mainly from the high polarizability of the imidazole ring in the gas phase which is strongly reduced in solution. Some ‘discrepancies’ are only observed for neutral histamine, for which the relative energy is close to zero. Good agreement of results predicted by various methods can result from the fact that in histamine the proton is transferred between atoms of the same element (nitrogen). Copyright © 2001 John Wiley & Sons, Ltd.