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

Abstract

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⋯N) with the intramolecular OH⋯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⋯N) form, with the intramolecular OH⋯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⋯N) tautomer by at least 40 kJ/mol. Based on AIM analysis, it was found that the intramolecular OH⋯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 π-electron population in the benzene ring. The sum of aromaticities of the two rings was largest for the (OH⋯N) tautomers, significantly lower for the (OH;N) tautomers, and the smallest for (NH) tautomers. From the electron population in σ and π valence orbitals of the two quinoline rings it appears that, for the benzene ring, the halogens acted as σ-electron withdrawing and π-electron donating substituents, whereas NO₂ was a σ- and π-electron withdrawing substituent. The σ substituent effect almost solely influenced the substitution site, i.e., the benzene ring, whereas the π substituent effect was extended to the pyridine ring. Here, we also present changes in the σ and π-electron populations resulting from tautomerization and breaking of the intramolecular OH⋯N hydrogen bonds.