Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin

Abstract

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: N,N-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+G(d,p)}, the most stable structures correspond to the conjugated, push-pull, system (NR)(NH)C═N-C(═NH)NH (R = H, CH), 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 C═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)C(═NH)-NH-C(═NH)NH of biguanides, in which the two C═NH groups are separated by NH. This less stable form of biguanides binds Li 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.

Purine tautomeric preferences and bond-length alternation in relation with protonation-deprotonation and alkali metal cationization

“…For imidazole, they have been recently revised [91]. The revised experimental LiCA (213.2 kJ mol −1 [91]) is close to that predicted at the G3 and G3B3 levels (211.9 and 212.0 kJ mol −1 , respectively, see in Table 2), and it is not very different from that estimated at the DFT level (216.9 kJ mol −1 [91]). Unfortunately, the revised experimental LiCB (172.3 kJ mol −1 [91]) seems to be too low in comparison to the G3-and G3B3-calculated values.…”

“…Generally, bidentate adducts have smaller Gibbs energies than monodentate ones in the gas phase [77,91,92]. The lowest G value at the DFT level (Table S5 in SM) possesses the bidentate adduct P739M + , formed from the neutral minor tautomer P7 with the lithium or sodium cation (Chart 2).…”

“…High stability of bidentate metal cation adducts has also been reported for other neutral bases containing more than one Nbasic sites, e.g., biguanide, metformin, imeglimin, and histamine. [77,91,92]. In the case of the purine monoanion P − , the N sites can also interact with a metal cation, and monodentate or bidentate adducts can be formed as in the case of neutral purine.…”

“…In the literature, one can find the experimental LiCA or LiCB for imidazole (Im) and also MCA and MCB (M + = Li + , Na + , K + ) for pyrimidine (Pym), determined by different methods (equilibrium, kinetic, and threshold dissociation energy methods) [74,76,100,101]. For imidazole, they have been recently revised [91]. The revised experimental LiCA (213.2 kJ mol −1 [91]) is close to that predicted at the G3 and G3B3 levels (211.9 and 212.0 kJ mol −1 , respectively, see in Table 2), and it is not very different from that estimated at the DFT level (216.9 kJ mol −1 [91]).…”

“…5 Linear tendencies between the HOMED values estimated at the DFT level for lithium and sodium cation adducts of purine NH tautomers Fig. 4 Variations of the HOMED indices estimated at the DFT level when proceeding from the two isolated constituting heterocycles to the bicyclic purine in the favored deprotonated (a), neutral (b), and protonated (c) forms equilibria for tautomeric compounds containing CC and CN bonds [77,91,103]. Analogous relation takes place in the case of neutral purine (P).…”