We have studied the mechanism of the reaction between the most stable and the most represented in literature tautomers of metformin and methylglyoxal by density functional theory calculations. Designed models included 16 explicit water solvent, which forms hydrogen bond networks around the reactants and intermediates molecules, facilitating intramolecular proton transfer in some steps of the reaction mechanism. The reaction takes place in five steps, namely: (1) formation of a dimethylguanide–guanylhydrazone–acetylcarbinol adduct, (2) formation of a zwitterionic triazepine derivative by ring closure, (3) dehydration of this intermediate, (4) an imine–enamine tautomerism, (5) an enol–keto tautomerism. The first step was found as the rate-determining step for the reaction, having the reaction an overall activation energy value of 9.7 kcal mol−1.
Bibliographical noteFunding Information:
The financial support of Govern de les Illes Balears (AAEE27/2014) is gratefully acknowledged. C.S.-C. is grateful to the Spanish Ministry of Foreign Affairs and Cooperation for the award of a MAE-AECI fellowship. We are grateful to Centro de cálculo de Computación de Galicia (CESGA) and the Centro de cálculo de Computación de Cataluña (CESCA) for allowing the use of their computational facilities.
© 2015, Springer-Verlag Berlin Heidelberg.
- DFT calculations
- Non-enzymatic glycation
- Triazepine derivatives
- α-Dicarbonyl compound