Structural features of neutral and protonated galanthamine: A crystallographic database and computational investigation

The conformational preferences and structural features of neutral and protonated galanthamine have been investigated experimentally, using data retrieved from the CSD and PDB databases, and theoretically, through various quantum chemical calculations: HF/6-31++G(d,p), MPWB1K/6-31++G(d,p) and MP2/6-311++G(2d,p). The main characteristics of galanthamine: (i) the axial or equatorial orientation of the N-methyl substituent; (ii) the hydroxyl and methoxy groups orientations; (iii) the tetrahydroazepine ring conformation, have been investigated. It is found that galanthamine must exist as a mixture of axial and equatorial N-methyl isomers, the tetrahydroazepine ring adopting a chair conformation and the methoxy group being in trans position with respect to the dihydrofuran ring. In both chemical forms (neutral and protonated), the intramolecular OH…O hydrogen bonding conformation is preferred. Structural features of galanthamine appear very similar in both the gas phase and the solid state, whatever its chemical form, a trend that indicates the rigid character of the molecule.