A proton-ionizable ester crown of 3,5-disubstituted 1H-pyrazole able to form stable dinuclear complexes with lipophilic phenethylamines

A convenient synthesis of the proton-ionizable crown 3 is reported that uses dibutyltin oxide. In acetonitrile, the reaction of 3 (LH2) with phenethylamine and homoveratrylamine (molar ratio 1:2) affords solid dinuclear complexes [LH2]2RNH(2) (4a,b), which spectroscopic (FAB-MS, IR, H-1 and C-13 NMR) data point toward a strong participation of the pyrazole nitrogens in the amine complexation. In DMSO-d(6) solution, a C-13 MMR study demonstrates the formation in situ of analogous neutral 4a-d[LH2]2RNH(2) or charged 5a-d[L2-]2RNH(3)(+) dinuclear complexes by reaction of 3 [LH2] or 3'[L2-]2Na(+) with RNH2 (phenethylamine, homoveratrylamine, dopamine, and norepinephrine) or their RNH3+Cl- salts, respectively. Differences between the structure of complexes 4 and 5 have been evaluated by taking the homoveratrylamine derivatives 4b and 5b as models. An H-1 and C-13 NMR study (by raising the temperature) and measurements of intermolecular NOE effects (from NOESY and ROESY spectral demonstrate that both complexes behave as prototropic isomers showing different conformations. By increasing the ionic strength, the 4b isomer structure becomes similar to that of 5b. The molecular modeling (GenMol software) of 4a-d and 5a-d shows that the assemblage in which both amine molecules are on the same side of the crown is the more stable. Lipophilic amines afford more stable complexes than hydrophilic ones and charged species are much more stable than the neutral ones.