So you think you understand tautomerism?

  • Roger A. Sayle


It appears so simple at first glance, “tautomers are isomers of organic compounds that readily interconvert, usually by the migration of hydrogen from one atom to another”. If a chemist can describe the problem so succinctly, one might question why the complication of tautomerism remains a considerable challenge to cheminformatics and computer-assisted drug design. With a half-century of experience with representing molecules in computers, and almost limitless modern computational power, the problem should have been solved by now. The unfortunate answer is that the frustration and inconvenience of a database search failing to find matches due to differences in the tautomeric forms of the query and registered compounds is but the tip of an iceberg. Prototropic tautomerism, the movement of hydrogens around a molecule, is but just one aspect of an interconnected web of complications. These include mesomerism, aromaticity, protonation state, stereochemistry, conformation, polymerization, photostability, hydrolysis, metabolism and EOCWR (explodes on contact with reality). The common theme is that valence theory, which underlies all modern chemical informatics systems, is an approximate theoretical model for representing molecules mathematically, and, as with all models, it has limitations and domains of applicability. In the physical environments that chemists care about, small organic molecules are often dynamic, existing in multiple equivalent or interconvertible forms. A single connection table can at best represent a snapshot or sample from these populations. Although partial algorithmic solutions exist for handling the most common cases of tautomerism, this perspective hopes to argue that the underlying problems perhaps make tautomerism more complex than it might first appear.


Tautomer Tautomerism Mesomerism Protonation state Enumeration Resonance Aromaticity 



The author would like to acknowledge the patient mentoring on the complex subject of tautomers from Peter Taylor, Peter Kenny and John Bradshaw. I’d also like to thank Evan Bolton, Andrew Grant, Ben Ellingson, Jack Delany, Geoff Skillman, Jens Sadowski, Hugo Kubinyi and Yvonne Martin for many interesting and enlightening discussions and numerous perplexing tautomeric examples.


  1. 1.
    Lewis GN (1916) J Am Chem Soc 38(4):761CrossRefGoogle Scholar
  2. 2.
    Baker JW (1934) Tautomerism. Van Nostrand, New YorkGoogle Scholar
  3. 3.
    Elguero J, Marzin C, Katritzky AR, Linda P (1976) Advances in heterocyclic chemistry. Supplement 1: The tautomerism of heterocycles. Academic Press, New YorkGoogle Scholar
  4. 4.
    Martin YC (2009) J Comput-Aided Mol Des 23:693–704CrossRefGoogle Scholar
  5. 5.
    Pauling L (1939) The nature of the chemical bond. Cornell University Press, New YorkGoogle Scholar
  6. 6.
    Sayle R, Skillman G (2002) Hooked on protonics. American Chemical Society Fall Meeting Boston 2002. Accessed 3 Mar 2010
  7. 7.
    Labute P (2005) J Chem Inf Model 45(2):215–221CrossRefGoogle Scholar
  8. 8.
    Lexichem Manual, Version 2.0. OpenEye Scientific Software, Santa Fe, New Mexico. Accessed 3 Mar 2010
  9. 9.
    Sayle R, Nicholls A (2006) J Comput-Aided Mol Des 20:191–208CrossRefGoogle Scholar
  10. 10.
    Taylor P (1998) Tautomeric preference: survey and guidelines. Lecture notes. Los Alamos National Laboratories (LANL), Los Alamos, NM, USAGoogle Scholar
  11. 11.
    Stocks M, Alcaraz L, Griffen E (2007) On medicinal chemistry. Sigma Aldrich, St LouisGoogle Scholar
  12. 12.
    Perez GV, Perez AL (2000) J Chem Ed 77(7):910–914CrossRefGoogle Scholar
  13. 13.
    Pearlman RS (2005) System and method for providing a canonical structural representation of chemical compounds. United States Patent Application 20050125210(A1)Google Scholar
  14. 14.
    Pearlman RS (2005) System and method for identifying structures of a chemical compound. United States Patent Application 20050159900(A1)Google Scholar
  15. 15.
    IUPAC (1996) Basic terminology of stereochemistry, IUPAC Recommendations. Pure and Appl Chem, 68(12):2193–2222. Accessed 3 Mar 2010
  16. 16.
    Oellien F, Cramer J, Beyer C, Ihlenfeldt W-D, Selzer PM (2006) J Chem Inf Model 46(6):2342–2354CrossRefGoogle Scholar
  17. 17.
    Kenny PW, Sadowski J (2004) In: Oprea TI (ed) Chemoinformatics in drug discovery. Wiley-VCH, Weinheim, pp 271–285Google Scholar
  18. 18.
    Milletti F, Storchi L, Sforna G, Cross S, Cruciana G (2009) J Chem Inf Model 49(1):68–75CrossRefGoogle Scholar
  19. 19.
    Trepalin SV, Skorenko AV, Balakin KV, Nasonov AF, Lang SA, Ivashchenko AA, Savchuk NP (2003) J Chem Inf Comput Sci 43(3):852–860Google Scholar
  20. 20.
    Ting A, McGuire R, Johnson AP, Green S (2000) J Chem Inf Comput Sci 40(2):347–353Google Scholar
  21. 21.
    Mockus J, Stobaugh RE (1980) J Chem Inf Comput Sci 20(1):18–22Google Scholar
  22. 22.
    Sayle R, Delany J (1999) In: innovative computational applications: the interface of library design, bioinformatics, structure-based drug design and virtual screening. IIRG publishers, San Franciso. Accessed 3 Mar 2010
  23. 23.
    QuacPac Manual: Tautomers. Version 1.3.1. OpenEye Scientific Software, Santa Fe, New Mexico. Accessed 3 Mar 2010
  24. 24.
    Pipeline Pilot Chemistry Collection: Advanced Chemistry User Guide (2008) Accelrys, San Diego, CaliforniaGoogle Scholar
  25. 25.
    Moran D, Sukcharoenphon K, Puchta R, Schaefer HF III, Schleyer PR, Hoff CD (2002) J Org Chem 67(25):9061–9069CrossRefGoogle Scholar
  26. 26.
    Allen FH (2002) Acta Crystallogr B58:380–388Google Scholar
  27. 27.
    Gilson MK, Gilson HSR, Potter MJ (2003) J Chem Inf Comput Sci 43(6):1982–1997Google Scholar
  28. 28.
    Katritzky AR, Pozharskii AF (2000) Handbook of heterocyclic chemistry. Pergamon Elsevier, AmsterdamGoogle Scholar
  29. 29.
    Valters RE, Flitsch W (1985) Ring-chain tautomerism. Plenum Press, New YorkGoogle Scholar
  30. 30.
    Altshuler DL, Dickson WB, Vance JT, Roberts SP, Dickinson MH (2005) Proc Natl Acad Sci 102(50):18213–18218CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.NextMove SoftwareSanta FeUSA

Personalised recommendations