Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Crystal Structure and Tautomerism Study of the Mono-protonated Metformin Salt

  • Wei, Xiaodan (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China) ;
  • Fan, Yuhua (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China) ;
  • Bi, Caifeng (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China) ;
  • Yan, Xingchen (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China) ;
  • Zhang, Xia (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China) ;
  • Li, Xin (Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China)
  • Received : 2014.05.09
  • Accepted : 2014.08.10
  • Published : 2014.12.20
Download PDF
⟨ Previous Next ⟩

Abstract

A novel crystal, the mono-protonated metformin acetate (1), was obtained and characterized by elemental analysis, IR spectroscopy and X-ray crystallography. It was found that one of the imino group in the metformin cation was protonated along with the proton transfer from the secondary amino group to the other imino group. Its crystal structure was then compared with the previously reported diprotonated metformin oxalate (2). The difference between them is that the mono-protonated metformin cations can be linked by hydrogen bonding to form dimers while the diprotonated metformin cations cannot. Both of them are stabilized by intermolecular hydrogen bonds to assemble a 3-D supermolecular structure. The four potential tautomer of the mono-protonated metformin cation (tautomers 1a, 1b, 1c and 1d) were optimized and their single point energies were calculated by Density Functional Theory (DFT) B3LYP method based on the Polarized Continuum Model (PCM) in water, which shows that the most likely existed tautomer in human cells is the same in the crystal structure. Based on the optimized structure, their Wiberg bond orders, Natural Population Analysis (NPA) atomic charges, molecular electrostatic potential (MEP) maps were calculated to analyze their electronic structures, which were then compared with the corresponding values of the diprotonated metformin cation (cation 2) and the neutral metformin (compound 3). Finally, the possible tautomeric mechanism of the mono-protonated metformin cation was discussed based on the observed phenomena.

Keywords

References

  1. Lu, L. P.; Zhang, H. M.; Feng, S. S.; Zhu, M. L. Acta Cryst. 2004, C60, o740.
  2. Thomas, L.; Russell, A. D.; Maillard, J. Y. J. Appl. Microbiol. 2005, 98, 533. https://doi.org/10.1111/j.1365-2672.2004.02402.x
  3. Denys, A.; Machlanski, T.; Bialek, J.; Mrozicki, S. Praeventivmedizin 1977, 164, 85.
  4. Tanzer, J. M.; Slee, A. M.; Kamay, B. A. Antimicrob. Agents Chemother. 1977, 12, 721. https://doi.org/10.1128/AAC.12.6.721
  5. (a) Pinelli, A.; Trivulzio, S.; Pojaga, G.; Rossoni, G. Pharmacol. Res. 1996, 34, 225. https://doi.org/10.1006/phrs.1996.0092
  6. (b) Pinelli, A.; Colombo, R.; Trivulzio, S.; Berti, F.; Tofanetti, O.; Caimi, B. R. Arzneim. Forsch. 1984, 34, 890.
  7. Bailey, P. J.; Pace, S. Coord. Chem. Rev. 2001, 214, 91. https://doi.org/10.1016/S0010-8545(00)00389-1
  8. (a) Rebek, J., Jr.; Angew. Chem. Int. Ed. 1990, 29, 245. https://doi.org/10.1002/anie.199002451
  9. (b) Amabilino, D. B.; Stoddart, J. F. Chem. Rev. 1995, 95, 2715.
  10. (c) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393. https://doi.org/10.1021/ar950199y
  11. (d) Harada, A.; Li, J.; Kamachi, M. Nature 1992, 356, 325. https://doi.org/10.1038/356325a0
  12. (e) Harada, A.; Li, K.; Kamachi, M. Nature 1994, 370, 126. https://doi.org/10.1038/370126a0
  13. Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312. https://doi.org/10.1126/science.1962191
  14. Albrecht, M. Naturwissenschaften 2007, 94, 951. https://doi.org/10.1007/s00114-007-0282-7
  15. Akai, N.; Ohno, K.; Aida, M. Chem. Phys. Lett. 2005, 413, 306. https://doi.org/10.1016/j.cplett.2005.07.101
  16. (a) Mahadevan, S.; Palaniandavar, M. Inorg. Chem. 1998, 37, 693. https://doi.org/10.1021/ic961066r
  17. (b) Kashanian, S.; Gholivand, M. B.; Ahmadi, F.; Taravati, A.; Hosseinzadeh Colagar, A. J. Spectrochim. Acta 2007, A67, 472.
  18. Carter, M. T.; Rodriguez, M.; Bard, A. J. J. Am. Chem. Soc. 1989, 111, 8901. https://doi.org/10.1021/ja00206a020
  19. Liu, C. L.; Zhou, J. Y.; Li, Q. X.; Wang, L. J.; Liao, Z. R.; Xu, H. B. J. Inorg. Biochem. 1999, 75, 233. https://doi.org/10.1016/S0162-0134(99)00037-9
  20. Bharatam, P. V.; Patel, D. S.; Iqbal, P. J. Med. Chem. 2005, 48, 7615. https://doi.org/10.1021/jm050602z
  21. SMART and SAINT, Area Detector Control and Integration Software. Siemens Analytical X-ray Systems, Inc. Madison, WI, 1996.
  22. Bruker AXS, SAINT Software Reference Manual. Madison, WI, 1998.
  23. Sheldrick, G. M. Acta Cryst. 2008, A64, 112.
  24. Brandenburg, K. DIAMOND, version 3.1D, Crystal Impact GbR, Born, Germany, 2006.
  25. Frisch, K. D.; Trucks, G. W.; Schlegel, H. B.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A. Gaussian 03, Revision A. 6. Gaussian, Inc. Pittsburgh, Pennsylvania, USA, 2003.

Cited by

  1. Enhanced Basicity of Push–Pull Nitrogen Bases in the Gas Phase vol.116, pp.22, 2016, https://doi.org/10.1021/acs.chemrev.6b00224
  2. Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations vol.120, pp.37, 2016, https://doi.org/10.1021/acs.jpca.6b04786
  3. Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin vol.121, pp.45, 2017, https://doi.org/10.1021/acs.jpca.7b09338
  4. Biguanides, anion receptors and sensors vol.53, pp.72, 2017, https://doi.org/10.1039/C7CC05012G
  5. Synthesis, characterization and crystal structure of a new organic salt of antidiabetic drug metformin resulting from a proton transfer reaction vol.1193, pp.None, 2014, https://doi.org/10.1016/j.molstruc.2019.05.040
  6. Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm vol.15, pp.6, 2014, https://doi.org/10.1371/journal.pone.0234571