Annular tautomerism: experimental observations and quantum mechanics calculations

  • Aurora J. Cruz-Cabeza
  • Adrian Schreyer
  • William R. Pitt


The use of MP2 level quantum mechanical (QM) calculations on isolated heteroaromatic ring systems for the prediction of the tautomeric propensities of whole molecules in a crystalline environment was examined. A Polarisable Continuum Model was used in the calculations to account for environment effects on the tautomeric relative stabilities. The calculated relative energies of tautomers were compared to relative abundances within the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB). The work was focussed on 84 annular tautomeric forms of 34 common ring systems. Good agreement was found between the calculations and the experimental data even if the quantity of these data was limited in many cases. The QM results were compared to those produced by much faster semiempirical calculations. In a search for other sources of the useful experimental data, the relative numbers of known compounds in which prototropic positions were often substituted by heavy atoms were also analysed. A scheme which groups all annular tautomeric transformations into 10 classes was developed. The scheme was designed to encompass a comprehensive set of known and theoretically possible tautomeric ring systems generated as part of a previous study. General trends across analogous ring systems were detected as a result. The calculations and statistics collected on crystallographic data as well as the general trends observed should be useful for the better modelling of annular tautomerism in the applications such as computer-aided drug design, small molecule crystal structure prediction, the naming of compounds and the interpretation of protein—small molecule crystal structures.


Quantum mechanics Semiempirical Crystallographic data Chemical nomenclature Molecular modelling Chemical structure enumeration Tautomers Tautomeric equilibria 



AJCC thanks the Pfizer Institute for Pharmaceutical Materials Sciences for funding. WRP thanks UCB Celltech for funding his secondment to Professor Tom Blundell’s group. Thanks also to Dr Yvonne Martin for her encouragement and invitation to submit a paper in this subject area


  1. 1.
    Katritzky AR, Lagowski JM (1963) Prototropic Tautomerism of Heteroaromatic compounds: I. General discussion and methods of study. Adv Heterocycl Chem 1:311–338CrossRefGoogle Scholar
  2. 2.
    Katritzky AR, Lagowski JM (1963) Prototropic Tautomerism of Heteroaromatic compounds: II. Six-membered rings. Adv Heterocycl Chem 1:339–437CrossRefGoogle Scholar
  3. 3.
    Katritzky AR, Lagowski JM (1963) Prototropic Tautomerism of Heteroaromatic compounds: III. Five-membered rings and one hetero atom. Adv Heterocycl Chem 2:1–26CrossRefGoogle Scholar
  4. 4.
    Katritzky AR, Lagowski JM (1963) Prototropic Tautomerism of Heteroaromatic compounds: IV. Five-membered rings with two or more hetero atoms. Adv Heterocycl Chem 2:27–81CrossRefGoogle Scholar
  5. 5.
    Minkin V, Garnovsk A, Elguero J, Katritzky A, Denisko O (2000) The Tautomerism of Heterocycles: Five-membered rings with two or more heteroatoms. Adv Heterocycl Chem 76:157–323CrossRefGoogle Scholar
  6. 6.
    Stanovnik B, Tiler M, Katritzky A, Denisko O (2001) The Tautomerism of Heterocycles. Six-membered heterocycles: Part 1, Annular Tautomerism. Adv Heterocycl Chem 81:253–303CrossRefGoogle Scholar
  7. 7.
    Stanovnik B, Tisler M, Katritzky A, Denisko O (2006) The Tautomerism of Heterocycles: substituent Tautomerism of six-membered ring Heterocycles. Adv Heterocycl Chem 91:1–134CrossRefGoogle Scholar
  8. 8.
    Elguero J, Katritzky A, Denisko O (2000) Prototropic Tautomerism of Heterocycles: Heteroaromatic tautomerism. General overview and methodology. Adv Heterocycl Chem 76:1–84CrossRefGoogle Scholar
  9. 9.
    Shcherbakova I, Elguero J, Katritzky A (2000) Tautomerism of Heterocycles: condensed five-six, five-five, and six-six ring systems with heteroatoms in both rings. Adv Heterocycl Chem 77:51–113CrossRefGoogle Scholar
  10. 10.
    Martin YC (2009) Let’s not forget tautomers. J Comput Aided Mol Des 23:693–704CrossRefGoogle Scholar
  11. 11.
    Alkorta I, Blanco F, Elguero J (2008) Application of Free-Wilson matrices to the analysis of the tautomerism and aromaticity of azapentalenes: a DFT study. Tetrahedron 64:3826–3836CrossRefGoogle Scholar
  12. 12.
    Alkorta I, Blanco F, Elguero J (2008) Heteropentalenes aromaticity: a theoretical study. J Mol Struct THEOCHEM 851:75–83CrossRefGoogle Scholar
  13. 13.
    Alkorta I, Elguero J, Liebman J (2006) The Annular Tautomerism of imidazoles and pyrazoles: the possible existence of nonaromatic forms. Struct Chem 17:439–444CrossRefGoogle Scholar
  14. 14.
    Allen F (2002) The cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr B 58:380–388CrossRefGoogle Scholar
  15. 15.
    Berman H, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov I, Bourne P (2000) The Protein Data Bank. Nucl Acids Res 28:235–242CrossRefGoogle Scholar
  16. 16.
    Hao MH, Haq O, Muegge I (2007) Torsion angle preference and energetics of small-molecule ligands bound to proteins. J Chem Inf Model 47:2242–2252CrossRefGoogle Scholar
  17. 17.
    Pitt W, Parry D, Perry B, Groom C (2009) Heteroaromatic rings of the future. J Med Chem 52:2952–2963CrossRefGoogle Scholar
  18. 18.
    Platonov MO, Samijlenko SP, Sudakov OO, Kondratyuk IV, Hovorun DM (2005) To what extent can methyl derivatives be regarded as stabilized tautomers of xanthine? Spectrochim Acta Part A Mol Biomol Spectrosc 62:112–114CrossRefGoogle Scholar
  19. 19.
    Alkorta I, Goya P, Elguero J, Singh SP (2007) A simple approach to the tautomerism of aromatic heterocycles. Natl Acad Sci Letts 30:139–159Google Scholar
  20. 20.
    Bruno I, Cole J, Edgington P, Kessler M, Macrae C, McCabe P, Pearson J, Taylor R (2002) New software for searching the Cambridge structural database and visualizing crystal structures. Acta Crystallogr B 58:389–397CrossRefGoogle Scholar
  21. 21.
    James CA, Weininger D, Delay J SMARTS.
  22. 22.
    Schreyer A, Blundell T (2009) CREDO: a protein–ligand interaction database for drug discovery. Chem Biol Drug Des 73:157–167CrossRefGoogle Scholar
  23. 23.
    Murzin AG, Brenner SE, Hubbard T, Chothia C (1995) SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247:536–540Google Scholar
  24. 24.
    Dalby A, Nourse J, Hounshell D, Gushurst A, Grier D, Leland B, Laufer J (1992) Description of several chemical structure file formats used by computer programs developed at Molecular Design Limited. J Chem Inf Comput Sci 32:244–255Google Scholar
  25. 25.
    Weininger D (1988) SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J Chem Inf Comput Sci 28:31–36Google Scholar
  26. 26.
    Idrissi MS, Senechal M, Sauvaitre H, Cotrait M, Garrigou-Lagrange C (1980) J Chim Phys 77:195Google Scholar
  27. 27.
    Claramunt RM, Lopez C, Garcia MA, Otero MD, Torres MR, Pinilla E, Alarcon SM, Alkorta I, Elguero J (2001) Untitled. New J Chem 25:1061–1068CrossRefGoogle Scholar
  28. 28.
    Bairoch A, Apweiler R, Wu C, Barker W, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin M, Natale D, O’Donovan C, Redaschi N, Yeh LS (2005) The universal protein resource (UniProt). Nucl Acids Res 33:D154–D159CrossRefGoogle Scholar
  29. 29.
    Alkorta I, Elguero J (2005) Theoretical estimation of the Annular Tautomerism of Indazoles. J Phys Org Chem 18:719–724CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Aurora J. Cruz-Cabeza
    • 1
  • Adrian Schreyer
    • 2
  • William R. Pitt
    • 2
    • 3
  1. 1.The Pfizer Institute for Pharmaceutical Materials ScienceThe Cambridge Crystallographic Data CentreCambridgeUK
  2. 2.Department of BiochemistryUniversity of CambridgeCambridgeUK
  3. 3.Department of Medicinal ChemistryUCB CelltechSloughUK

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