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Effect of methyl substituents in the reactivity of methylxanthines

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Abstract

The methylxanthines have attracted interest due to the changes on their biological activities and physicochemical properties in terms of the number and position of the methyl groups present in the xanthine moiety. We report a theoretical study of the influence of the methyl substituent in the basicity and reactivity of xanthine and its methylated derivatives. Our results provide that when the xanthine increases the number of methyl substituents, the gas phase basicity increases (reactivity to proton increases), and the global hardness decreases. The result is in agreement with the maximum hardness principle (MHP) that states, “at equilibrium, chemical systems are as hard as possible” (Pearson, R.G., J. Chem. Educ., 1987, 64, 561–567, and Parr R.G., Chattaraj P.K., J. Am. Chem. Soc. 1991, 113, 1854–1855).

Xanthine and its methyl derivatives

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References

  1. Katritzky AL, Ramsden CHA, Scriven EFV, Taylor RJK, Jones RCF (2008) Comprehensive heterocyclic chemistry III A review of the literature 1995–2007. Ring systems with at least two fused heterocyclic five-or six-membered rings with no bridgehead heteroatom, Elsevier, UK, Vol. 10, pp 525

  2. Rein D, Lotito S, Holt RR, Keen CL, Schmitz HH, Fraga CG (2000) Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. J. Nutrition. https://doi.org/10.1093/jn/130.8.2109S

  3. Ramiro-Puig E, Castell M (2009) Cocoa: antioxidant and immunomodulator. Br. J. Nutr. https://doi.org/10.1017/S0007114508169896

  4. Stadler RH, Fay LB (1995) Antioxidative reactions of caffeine: formation of 8-oxocaffeine (1,3,7-trimethyluric acid) in coffee subjected to oxidative stress. J. Agric. Food Chem. 43:1332–1338

    Article  CAS  Google Scholar 

  5. Rosemeyer H (2004) The chemiodiversity of purine as a constituent of natural product. Chem. Biodivers. https://doi.org/10.1002/cbdv.200490033

  6. Monteiro J, Alves M, Oliveira P, Branca M (2016) Structure-bioactive relationships of methylxanthines: trying to make sense of all promises and the drawbacks. Molecules. https://doi.org/10.3390/molecules21080974

  7. Pobudkowska A, Domanska U, Kryska JA (2014) The physicochemical properties and solubility of pharmaceuticals-methylxanthines. J Chem Thermodynamics 79:41–48

    Article  CAS  Google Scholar 

  8. Zlatkov AB, Peikov PT, Momekov GC, Pencheva I, Tsvetkova B (2010) Synthesis, stability and computational study of some ester derivatives of theophylline-7-acetic acid with antiproliferative activity. Der Pharma Chemica 2:197–210

    CAS  Google Scholar 

  9. Chapman RA, Miller DJ (1974) Structure–activity relations for caffeine: a comparative study of the inotropic effects of the methylxanthines, imidazoles and related compounds on the frog’s heart. J. Physiol. https://doi.org/10.1113/jphysiol.1974.sp010726

  10. Eleftheriadis E, Kotzampassi K, Koufogiannis D (1998) Modulation of intravariceal pressure with pentoxifylline: a possible new approach in the treatment of portal hypertension. Am. J. Gastroenterol. 93:2431–2435

    Article  CAS  Google Scholar 

  11. Salihović M, Huseinović Š, Špirtović-Halilović S, Osmanović A, Dedić A, Ašimović Z, Završnik D (2014) DFT study and biological activity of some methylxanthines. Bull Chem Thechnol Bosnia Herzegovina 42:31–36

    Google Scholar 

  12. de Almeida AL, Barbosa LP, Santos RL, Martins JBL (2016) Chemical reactivity indices of the caffeine molecule. Rev Virtual Quim 2:483–492 Xenobiotica Vol 17

    Article  Google Scholar 

  13. Ho T-L, Ho HC, Hamilton LD (1978) Biochemical significance of the hard and soft acids and bases principle. Chem. Biol. Interact. 23:65–84. https://doi.org/10.1016/0009-2797(78)90042-X

    Article  CAS  PubMed  Google Scholar 

  14. Pearson RG (1987) Recent advances in the concept of hard and soft acids and bases. J. Chem. Educ. 7:561–567

    Article  Google Scholar 

  15. Parr RG, Chattaraj PK (1991) Principle of maximum hardness. J. Am. Chem. Soc. 113:1854–1855

    Article  CAS  Google Scholar 

  16. Pearson RG (1993) The principle of maximum hardness. Acc. Chem. Res. 26:250–255

    Article  CAS  Google Scholar 

  17. Gázquez JL, Martínez A, Méndez F (1993) Relationship between energy and hardness differences. J. Phys. Chem. 97:4059–4063

    Article  Google Scholar 

  18. Ho T-L (1975) The hard soft acids bases (HSAB) principle and organic chemistry. Chem. Rev. 75:1–20. https://doi.org/10.1021/cr60293a001

    Article  CAS  Google Scholar 

  19. Romero M, Méndez F (2003) Is the hydrogen atomic charge representative of the acidity of parasubstituted phenols? J. Phys. Chem. A 107(22):4526–4530

    Article  Google Scholar 

  20. Ramírez R, García-Martínez C, Méndez F (2009) Influence of fluorine atoms and aromatic rings on the acidity of ethanol. J. Phys. Chem. A 113:10753–10758

    Article  Google Scholar 

  21. Gaussian 09, Revision A.02, Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam M, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2016) Gaussian, Inc., Wallingford, CT

  22. Dougherty D, Younathan E, Voll R, Abdulnur S, McGlynn S (1978) Photoelectron spectroscopy of some biological molecules. J. Electron Spectrosc. Relat. Phenom. https://doi.org/10.1016/0368-2048(78)85042-7

  23. Lifschitz C, Bergmann ED, Pullman B (1967) The ionization potentials of biological purines and pyrimidines. Tetrahedron Lett. 46:4583–4586

    Article  CAS  Google Scholar 

  24. Hush N, Cheung A (1975) Ionization potentials and donor properties of nucleic acid bases and related compounds. Chem. Phys. Lett. https://doi.org/10.1016/0009-2614(75)80190-4

  25. Slifkin M, Allison A (1967) Measurement of ionization potentials from contact charge transfer spectra. Nature 215:949–950

    Article  CAS  Google Scholar 

  26. Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A 6:3098–3100

    Article  Google Scholar 

  27. Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 7:5648–5652

    Article  Google Scholar 

  28. Lee C, Yang W, Parr RG (1988) Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 2:785–789

    Article  Google Scholar 

  29. Romero ML, Méndez F (2003) The local HSAB principle and bond dissociation energy of p-substituted phenol. J. Phys. Chem. A 30:5874–5875

    Article  Google Scholar 

  30. Parr RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press, New York

    Google Scholar 

  31. Levine IN (1996) Physical chemistry. McGraw-Hill, New York

    Google Scholar 

  32. Huang Y, Liu L, Liu S (2012) Towards understanding proton affinity and gas-phase basicity with density functional reactivity theory. Chem. Phys. Lett. 527:73–78

    Article  CAS  Google Scholar 

  33. Bahrami H, Tabrizchi M, Farrokhpour H (2013) Protonation of caffeine: a theoretical and experimental study. Chem. Phys. 415:222–227

    Article  CAS  Google Scholar 

  34. Hunter EPL, Lias SG (1998) Evaluated gas phase basicities and proton affinities of molecules: an update. J. Phys. Chem. Ref. Data 27:413–656. https://doi.org/10.1063/1.556018

    Article  CAS  Google Scholar 

  35. Feixas F, Matito E, Poater J, Solá M (2011) Understanding conjugation and hyperconjugation from electronic delocalization measures. J. Phys. Chem. A 115:13104–13113. https://doi.org/10.1021/jp205152n

    Article  CAS  PubMed  Google Scholar 

  36. Jarowski PD, Wodrich MD, Wanner CS, Schleyer PR, Houk KN (2004) How large is the conjugative stabilization of diynes? J. Am. Chem. Soc. 126:15036–15037

    Article  CAS  Google Scholar 

  37. Mullins JJ (2012) Hyperconjugation: a more coherent approach. J. Chem. Educ. 89:834–836

    Article  CAS  Google Scholar 

  38. Amador-Balderas JA, Ramírez RE, Méndez F, Meléndez Bustamante FJ, Richaud A (2018) Hyperconjugation enhances electrophilic addition to monocyclic monoterpenes: a Fukui function perspective. J. Mol. Model. 24:300. https://doi.org/10.1007/s00894-018-3825-2

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Acknowledgements

CC acknowledges the SNI-CONACyT, Mexico research assistant fellowship. Supercomputer time was provided by LSCVP-UAMI, México.

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Authors and Affiliations

  1. Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-534, 09340, México, D.F., México

    Cristina Coquis, Arlette Richaud & Francisco Méndez

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  1. Cristina Coquis
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  2. Arlette Richaud
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  3. Francisco Méndez
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Corresponding author

Correspondence to Francisco Méndez.

Additional information

This paper belongs to Topical Collection International Conference on Systems and Processes in Physics, Chemistry and Biology (ICSPPCB-2018) in honor of Professor Pratim K. Chattaraj on his sixtieth birthday

Electronic supplementary material

894_2018_3857_MOESM1_ESM.docx

Cartesian coordinates of the xanthine, methylxanthines, and their protonated species studied in this work are provided in the Electronic Supplementary Material. (DOCX 111 kb)

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Coquis, C., Richaud, A. & Méndez, F. Effect of methyl substituents in the reactivity of methylxanthines. J Mol Model 24, 331 (2018). https://doi.org/10.1007/s00894-018-3857-7

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