Tautomerism and pKa behaviour of 1-hydroxypyrazoloquinolines and pyrazoloisoquinolines

The recently-synthesised novel heterocyclic isomers 3-hydroxy-3H -pyrazolo[3,4-c ]isoquinoline (1), 3-hydroxy-3H -pyrazolo[3,4-c ]quinoline (2), 1-hydroxy-1H -pyrazolo[4,3-c ]isoquinoline (3) and 1-hydroxy-1H -pyrazolo[4,3-c ]quinoline (4) show remarkable differences in properties and reactivity, both between each other and compared with the simpler parent compound 1-hydroxypyrazole (0), despite their great structural similarity. Ab initio calculations were performed with a view to investigating their preferred tautomeric forms and proton affinities in gas phase and in aqueous solution. Theories used include B3LYP density functional theory with the 6-311+G(d,p) basis set, and complete basis set (CBS) methods. Free energies of solvation were calculated using the Jaguar PB-SCRF solvation method at B3LYP/6-311+G(d,p), and relative pKas estimated via the Boltzmann distributions and literature values for scaling and correcting these methods. The results suggest differences in affinity and order of protonation, and most strikingly, the contribution of N -oxide tautomers in certain cases, which have not generally been reported for 1-hydroxypyrazoles. The results are compared to experimental pKa measurements, empirical pKa estimates, n.m.r. data, and the crystal structure of 0.