Computational studies of intramolecular hydrogen-bonding interactions and proton transfer in the tautomers of 1,4-dihydroxy-5,8-naphthoquinone imine:a model for 5-iminoduanomycin

Intramolecular hydrogen bonding interactions in 1,4-dihydroxy-5,8-naphthoqu inone imine (1a), its tautomers (2a-4a), and the rotamers of 1a-4a, and the utility of the SAM1 semiempirical method, in comparison to ab initio Hartr ee-Fock (HF) (as well as AM1 and PM3) methods, for the study of such intera ctions were evaluated. The (NH)-H-...-O hydrogen bonds can be characterized as strong and were found to be stronger than, or comparable to, the streng th of the (OH)-H-...-O hydrogen bonds. This finding is in contrast with an earlier report based on NMR experimental data on 5-iminodaunomycin (II) in which the (OH)-H-...-O hydrogen bonds were reported to be the strongest (G. L. Tong, D.W. Henry, E.M. Acton, J. Med. Chem., 22 (1979) 36; J.W. Lown, H. H. Chen, J.A. Plambeck, Biochem. Pharma., 28 (1979) 2563). The relative sta bilities of the tautomers (all local minima) predicted by SAM1 and HF/6-31G ** were: 4a > 2a > 1a > 3a; 4a > 1a > 2a > 3a, respectively). 2a and 3a wer e not found to be saddle points whereas the structures analogous to 2a and 3a in the naphthazarin system were reported to be so. All the methods used predicted the imidine form (4a) to be the most stable tautomer. The above f indings suggest the interpretation of the experimental data on the biochemi cal reactivity of II should be re-examined. The SAM1 barrier energies for t automerization by intramolecular proton transfer were substantially lower t han, or comparable to the HF/6-31G** ones. The SAM1 trend in stability of t he tautomers and some of the SAM1 barrier energies and other hydrogen-bond parameters are found to be qualitatively more in line with preliminary DFT results, and thus, the SAM1 trend in stability is probably correct. However , the overall accuracy of the HF/6-31G** and the SAM1 methods for the study of hydrogen bonding in these systems appears to be unsatisfactory. (C) 199 9 Elsevier Science B.V. All rights reserved.