Logo Division of Drug Synthesis
Department of Pharmaceutical Chemistry
Faculty of Life Sciences, University of Vienna
Logo Uni Wien

Heterocyclic Tautomerism

Heterocyclic systems being capable of tautomerism play important roles in biological processes (see, for instance, base pairing in the DNA molecule). Interesting systems with marked tautomeric behaviour are pyrazolones (2-pyrazolin-5-ones). In principle, for pyrazolones unsubstituted at pyrazole C-4, OH- (A), CH- (B) and NH-isomers (C) are possible (upper line), assigned as 1H-pyrazol-5-ols, 2,4-dihydro-3H-pyrazol-3-ones and 1,2-dihydro-3H-pyrazol-3-ones according to Chemical Abstracts nomenclature. In the case of 4-acyl congeners, which are popular chelating and extracting ligands for metal ions as well as educts for biologically active compounds, additional species (D, E, middle line) have to be considered as now the 4-substituent can participate to tautomerism and also stabilization by intramolecular hydrogen bonds may occur (A', D', Figure 1, lower line). Whereas in the solid state unambiguous results can be obtained on basis of X-ray crystallography, the situation in solution is much more complicated and the determination of the tautomeric composition can be very difficult.
In a series of publications we reported about investigations concerning the tautomeric behaviour of variously substituted pyrazolones in solution by application of modern NMR-methods such as NOE-spectroscopy or by the systematic analysis of 13C,1H spin coupling constants. The aim of these – ongoing - studies is also to understand the specific reactivity of such compounds, which we use as valuable building blocks for the construction of novel structures with potential biological activity (see next research focus).
Additional systems which are currently under investigation regarding their prototropic tautomerism are 4-substituted cinnolines (cinnolin-4-ol, cinnolin-4-thiol, 4-cinnolinamine, 4-hydrazinocinnoline) as well as the corresponding Phthalazine series.