On tautomerism and substituent effect in 8-hydroxyquinoline-derived medicine molecules

The 8-hydroxyquinoline (8HQ) molecule and its four derivatives used as medicines: chloroxine, clioquinol, iodoquinol, and nitroxoline (8HQ substituted in the benzene ring by 5,7-dichloro-, 5-chloro-7-iodo-, 5,7-diiodo-, and 7-nitro-, respectively), were studied using the DFT/B3LYP/6-311G** method. Three forms of each molecule were considered: (OH center dot center dot center dot N) with the intramolecular OH center dot center dot center dot N hydrogen bond, (OH;N) with the broken intramolecular hydrogen bond, and (NH), the tautomer with the H-atom attached to the pyridine N-atom. Regardless of the substitution, the (OH center dot center dot center dot N) form, with the intramolecular OH center dot center dot center dot N hydrogen bond, was the most stable form. Breaking the intramolecular bond led to the formation of (OH;N), which was less stable by at least 25 kJ/mol. The NH tautomer was higher in energy than the (OH center dot center dot center dot N) tautomer by at least 40 kJ/mol. Based on AIM analysis, it was found that the intramolecular OH center dot center dot center dot N bond was the weakest in 8HQ stronger in chloroxine, clioquinol and iodoquinol, and it was the strongest in nitroxolin. The benzene ring aromaticity decreased from 8HQ through halogenosubstituted 8HQ to nitroxoline, which was in line with the decrease of the pi-electron population in the benzene ring. The sum of aromaticities of the two rings was largest for the (OH center dot center dot center dot N) tautomers, significantly lower for the (OH;N) tautomers, and the smallest for (NH) tautomers. From the electron population in sigma and pi valence orbitals of the two quinoline rings it appears that, for the benzene ring, the halogens acted as sigma-electron withdrawing and pi-electron donating substituents, whereas NO2 was a sigma- and pi-electron withdrawing substituent. The sigma substituent effect almost solely influenced the substitution site, i.e., the benzene ring, whereas the pi substituent effect was extended to the pyridine ring. Here, we also present changes in the sigma and pi-electron populations resulting from tautomerization and breaking of the intramolecular OH center dot center dot center dot N hydrogen bonds. (C) 2010 Elsevier B.V. All rights reserved.