1 research outputs found
Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin
Substituted
biguanides are known for their biological effect, and
a few of them are used as drugs, the most prominent example being
metformin (1,1-dimethylbiguanide, IUPAC name: <i>N,N</i>-dimethylimidodicarbonimidic diamide). Because of the presence of
hydrogen atoms at the amino groups, biguanides exhibit a multiple
tautomerism. This aspect of their structures was examined in detail
for unsubstituted biguanide and metformin in the gas phase. At the
density functional theory (DFT) level {essentially B3LYP/6-311+GÂ(d,p)},
the most stable structures correspond to the conjugated, pushâpull,
system (NR<sub>2</sub>)Â(NH<sub>2</sub>)ÂCî»NâCÂ(î»NH)ÂNH<sub>2</sub> (R = H, CH<sub>3</sub>), further stabilized by an internal
hydrogen bond. The structural and energetic aspects of protonation
and lithium cation adduct formation of biguanide and metformin was
examined at the same level of theory. The gas-phase protonation energetics
reveal that the more stable tautomer is protonated at the terminal
imino Cî»NH site, still with an internal hydrogen bond maintaining
the structure of the neutral system. The calculated proton affinity
and gas-phase basicity of the two molecules reach the domain of superbasicity.
By contrast, the lithium cation prefers to bind the less stable, not
fully conjugated, tautomer (NR<sub>2</sub>)ÂCÂ(î»NH)âNHâCÂ(î»NH)ÂNH<sub>2</sub> of biguanides, in which the two Cî»NH groups are separated
by NH. This less stable form of biguanides binds Li<sup>+</sup> as
a bidentate ligand, in agreement with what was reported in the literature
for other metal cations in the solid phase. The quantitative assessment
of resonance in biguanide, in metformin and in their protonated forms,
using the HOMED and HOMA indices, reveals an increase in electron
delocalization upon protonation. On the contrary, the most stable
lithium cation adducts are less conjugated than the stable neutral
biguanides, because the metal cation is better coordinated by the
not-fully conjugated bidentate tautomer