Computational estimation of the acidities of purines and indoles

  • Kara L. Geremia
  • Paul G. SeyboldEmail author
Original Paper
Part of the following topical collections:
  1. Tim Clark 70th Birthday Festschrift


Purines and related compounds are central ingredients in the genetic code and form the structural framework for many drugs and other bioactive compounds. A key feature of these compounds is their acidity, as expressed by their pKa values. For a proper understanding of the behaviors of these compounds, it is important to have a theoretical means for estimating their acidities. Here we present a quantum-chemical quantitative structure–activity relationship (QSAR) study of these compounds aimed at estimating the aqueous pKa values of purines and related compounds based on the energy differences in solution ΔE(H2O) between the parent compounds and their dissociation products. This method was applied to both the cation → neutral (pKa1) and neutral → anion (pKa2) dissociations of the compounds. Computations were performed using density functional theory at the B3LYP/6–31 + G** level with the SM8 aqueous solvent model. Good-quality QSAR regression equations were obtained for both dissociations using the ΔE(H2O) descriptor. These equations were applied to estimate missing pKa values for compounds in this category, and should also be applicable to the acidities of other related heterocyclic compounds.


Purines Indoles Acidities pKa Density functional theory QSAR 



  1. 1.
    Rosemeyer H (2004) The chemodiversity of purine as a constituent of natural products. Chem Biodivers 1:361–399Google Scholar
  2. 2.
    Alongi KA, Shields GC (2010) Theoretical calculations of acid dissociation constants. Ann Rep Comput Chem 6:113–138Google Scholar
  3. 3.
    Zevatskii YE, Samoilov DV (2011) Modern methods for estimation of ionization constants of organic compounds in solution. Russ J Org Chem 47:1423–1444Google Scholar
  4. 4.
    Seybold PG (2012) Quantum chemical QSPR estimation of the acidities and basicities of organic compounds. Adv Quantum Chem 64:83–104Google Scholar
  5. 5.
    Shields GC, Seybold PG (2014) Computational approaches for the prediction of pK a values. CRC, Boca RatonGoogle Scholar
  6. 6.
    Seybold PG, Shields GC (2015) Computational estimation of pK a values. WIREs Comput Mol Sci 5:290–297.
  7. 7.
    Ho J (2014) Predicting pK a in implicit solvents: current status and future directions. Aust J Chem 67:1441–1460Google Scholar
  8. 8.
    Liptak MD, Gross KC, Seybold PG, Feldgus S, Shields GC (2002) Absolute pK a determinations for substituted phenols. J Am Chem Soc 124:6421–6427Google Scholar
  9. 9.
    Ho J, Coote ML (2011) First-principles prediction of acidities in the gas and solution phase. WIREs Comput Mol Sci 1:649–660Google Scholar
  10. 10.
    Adam KR (2002) New density functional and atoms in molecules method of computing relative pK a values in solution. J Phys Chem A 106:11963–11972Google Scholar
  11. 11.
    Thapa B, Schlegel HB (2015) Calculations of pK a’s and redox potentials of nucleobases with explicit waters and polarizable continuum solvation. J Phys Chem A 119:5134–5144Google Scholar
  12. 12.
    Katritzky AR, Lobanov VS, Karelson M (1995) QSPR: the correlation and quantitative prediction of chemical and physical properties from structure. Chem Soc Rev 279–287Google Scholar
  13. 13.
    Tropsha A (2010) Best practices for QSAR model development, validation, and exploitation. Mol Inf 29:476–488Google Scholar
  14. 14.
    Cherkasov A, Muratov EN, Fourches D et al (2014) QSAR modeling: where have you been? Where are you going to? J Med Chem 57:4977–5010Google Scholar
  15. 15.
    Liao C, Nicklaus MC (2009) Comparison of nine programs predicting pK a values of pharmaceutical substances. J Chem Inf Model 49:2801–2281Google Scholar
  16. 16.
    Dearden JC, Rotureau P, Fayet G (2013) QSPR prediction of physico-chemical properties for REACH. SAR QSAR Environ Res 34:279–318Google Scholar
  17. 17.
    Henderson JF (1978) The position of the glycosidic bond in purine nucleosides: the conservative influence of a convention of chemical nomenclature. Ann Sci 35:299–323Google Scholar
  18. 18.
    Pullman B, Pullman A (1971) Electronic aspects of purine tautomerism. Adv Heterocycl Chem 13:77–159Google Scholar
  19. 19.
    Katritzky AR, Karelson M (1991) AM1 calculations of reaction field effects on the tautomeric equilibria of nucleic acid pyrimidine and purine bases and their 1-methyl analogues. J Am Chem Soc 113:1561–1566Google Scholar
  20. 20.
    Podolyan Y, Gorb L, Leszczynski J (2000) Protonation of nucleic acid bases. A comprehensive post-Hartree–Fock study of the energetics and proton affinities. J Phys Chem A 104:7346–7352Google Scholar
  21. 21.
    Shukla MK, Leszczynski J (2013) Tautomerism in nucleic acid bases and base pairs: a brief overview. WIREs Comput Mol Sci 3:637–649.
  22. 22.
    Marenich AV, Olson RM, Kelly CP, Cramer CJ, Truhlar DG (2007) Self-consistent reaction field model for aqueous and nonaqueous solutions based on accurate polarized partial charges. J Chem Theory Comput 3:2011Google Scholar
  23. 23.
    Lindstrom PJ, Mallard WG (eds) () NIST Chemistry WebBook: NIST Standards Reference Database Number 69. National Institute of Standards and Technology, Gaithersburg. Accessed 15 May 2015
  24. 24.
    Gross KC, Seybold PG (2001) Substituent effects on the physical properties and pK a of phenol. Int J Quantum Chem 85:569–579Google Scholar
  25. 25.
    Zhang S, Baker J, Pulay PA (2010) Reliable and efficient first principles-based method for predicting pK a values. 2. Organic acids. J Phys Chem A 114:432–442Google Scholar
  26. 26.
    Seybold PG (2015) Quantum chemical estimation of the acidities of some inorganic oxoacids. Mol Phys 113:232–236Google Scholar
  27. 27.
    Gross KC, Seybold PG (2000) Substituent effects on the physical properties and pK a of aniline. Int J Quantum Chem 80:1107–1115Google Scholar
  28. 28.
    Hollingsworth CA, Seybold PG, Hadad CM (2002) Substituent effects on the electronic structure and pK a of benzoic acid. Int J Quantum Chem 90:1396–1403Google Scholar
  29. 29.
    Seybold PG (2015) Quantum chemical estimation of the acidities of some inorganic nitrogen acids. Mol Phys 114:389–393Google Scholar
  30. 30.
    Bruice PY (2014) Organic chemistry, 7th edn. Pearson, New YorkGoogle Scholar
  31. 31.
    Dufour N, Dartiguenave Y, Dartiguenave M, Lebuis A-M, Bélanger-Gariépy F, Beauchamp A (1990) Crystal structures of 7-azaindole, an unusual hydrogen-bonded tetramer, and of two of its methylmercury(II) complexes. Can J Chem. 68:193–201Google Scholar
  32. 32.
    Catalán J, Pérez P, del Valle JC, de Paz JLG, Kasha M (2004) H-bonded N-heterocyclic base-pair phototautomerizational potential barrier and mechanism: the 7-azaindole dimer. Proc Natl Acad Sci USA 101:419–422Google Scholar
  33. 33.
    Pogozhev D, Baudron SA, Hosseini MW (2011) From insertion of rhodium acetate paddlewheels into functionalized 7-azaindole hydrogen-bonded dimers to infinite architectures. Dalton Trans 40:7403–7411Google Scholar
  34. 34.
    Koyama T, Wakisaka A (1997) Molecular self-assembly composed of aromatic hydrogen-bond donor–acceptor complexes. J Chem Soc Faraday Trans 21:3813–3817Google Scholar
  35. 35.
    Ogston AG (1935) The constitution of the purine nucleosides. Part III. Potentiometric determination of the dissociation constants of methylated xanthines. J Chem Soc 1376–1379Google Scholar
  36. 36.
    Turner Jr A, Osol A (1949) The spectrophotometric determination of the dissociation constants of theophylline, theobromine, and caffeine. J Am Pharm Assoc 38:158–161Google Scholar
  37. 37.
    Kirkland JJ (1996) Stability of silica-based, monofunctional C18 bonded-phase column packing for HPLC at high pH. J Chromatogr Sci 34:309–313Google Scholar
  38. 38.
    Jarvinen K, Akerman S, Svarfvar B, Tarvainen T, Viinikka P, Raronen P (1998) Drug release from pH and ionic strength responsive poly(acrylic acid) grafted poly(vinylidenefluoride) membrane bags in vitro. Pharm Res 15:802–805Google Scholar
  39. 39.
    Reed AE, Weinstock RB, Weinhold F (1985) Natural population analysis. J Chem Phys 83:735–746Google Scholar
  40. 40.
    Randic’ M (1991) Resolution of ambiguities in structure–property studies by use of orthogonal descriptors. J Chem Info Comput Sci 31:311–325Google Scholar
  41. 41.
    Peterangelo SC, Seybold PG (2004) Synergistic interactions among QSAR descriptors. Int J Quantum Chem 96:1–9Google Scholar
  42. 42.
    Rossi RD (2003) What does the acid ionization constant tell you? An organic chemistry student guide. J Chem Ed 90:183–190Google Scholar
  43. 43.
    Serjeant EP, Dempsey B (1979) In: Ionization constants of organic acids in aqueous solution (IUPAC Chemical Data Series no. 23). International Union of Pure and Applied Chemistry, OxfordGoogle Scholar
  44. 44.
    Dean JA (1985) Lange’s handbook of chemistry, 13th edn. McGraw-Hill, New YorkGoogle Scholar
  45. 45.
    Adler T, Albert A (1960) Diazaindenes (“azaindoles”). Part 1. Ionization constants and spectra. J Chem Soc 1794–1797Google Scholar
  46. 46.
    Walba H, Isensee R (1960) Acidity constants of some arylimidizaoles and their cations. J Org Chem 26:2789–2791Google Scholar
  47. 47.
    Katritzky AR, Ramsden CA, Joule JA, Zhdankin VV (2010) Handbook of heterocyclic chemistry, 3rd edn. Elsevier, New YorkGoogle Scholar
  48. 48.
    Eicher T, Hauptmann S (2003) The chemistry of heterocycles: structures, reactions, synthesis, and applications, 2nd edn. Wiley-VCH, WeinheimGoogle Scholar
  49. 49.
    Sondheimer E, Covitz F, Marquisee MJ (1961) Association of naturally occurring compounds, the chlorogenic acid–caffeine complex. Arch Bioch Biophys 93:63–71Google Scholar
  50. 50.
    Spiller G (1998) Caffeine. CRC, Boca RatonGoogle Scholar
  51. 51.
    Albert A, Serjeant EP (1962) Ionization constants of acids and bases: a laboratory manual. Wiley, New YorkGoogle Scholar
  52. 52.
    Dawson R, Elliott D, Elliott W, Jones K (1986) Data for biochemical research, 3rd edn. Oxford University Press, OxfordGoogle Scholar
  53. 53.
    Milletto F, Storchi L, Goracci L, Bendels S, Wagner B, Kansey M, Cruciani G (2010) Extending pK a prediction accuracy: high-throughput pK a measurements to understand pK a modulation of new chemical series. Eur J Med Chem 45:4270–4279Google Scholar
  54. 54.
    Kulikowska E, Kierdaszuk B, Shugar D (2004) Xanthine, xanthosine and its nucleotides: solution structures of neutral and ionic forms, and relevance to substrate properties in various enzyme systems and metabolic pathways. Acta Biochim Pol 51:493–531Google Scholar
  55. 55.
    Fox JJ, Wempen I, Hampton A, Doerr IL (1958) Thiation of nucleosides. I. Synthesis of 2-amino-6-mercapto-9-β-D-ribofuranosylpurine (“thioguanosine”) and related purine nucleosides. JACS 80:1669–1675Google Scholar
  56. 56.
    Lide DR (ed) (2008) CRC handbook of chemistry and physics, 89th edn. CRC, Boca RatonGoogle Scholar
  57. 57.
    Paragi G, Kovacs L, Kupihar Z, Szolomajer J, Penke B, Guerra C, Bickelhaupt F (2011) Neutral and positively charged purine tetramer structures: a computational study of xanthine and uric acid derivatives. New J Chem 35:119–126Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of ChemistryWright State UniversityDaytonUSA

Personalised recommendations