Ab Initio Studies on the Tautomerism of Dioxo Pyridazines and their Anions as Novel Bio Isosteres

Principal Investigator

Robin D. Allan

Department of Pharmacology

University of Sydney

Substituted heteroycles are potentially capable of existing in a number of different forms, called tautomers, depending on the positions at which labile protons prefer to reside on the structure. The problem of determining the tautomeric behaviour of heterocyclic compounds is a complex one, and many different methods have been employed. Ab initio methods are increasingly employed for this purpose. The determination of heterocyclic tautomerism is an extensive and interesting study in its own right, as well as having relevance to the study of the bioactivity and function of systems based on such heterocycles.

Our work has been to study the tautomerism of pyridazines, disubstituted with oxygen. Previous work has centred around low or medium level calculations on only one member of this class, maleic hydrazide. We have extended the work to include all dioxopyridazines, and their conjugate bases, and to improve on the quality of existing calculations, drawing on the best examples in the literature of methods applied to similar systems. Particular emphasis has been placed on probing the aqueous solution phase behaviour and acidities of these molecules, in addition to the gas-phase behaviour.


Jeremy R. Greenwood

Department of Pharmacology

University of Sydney


g50 - VPP

What are the results to date and the future of the work?

A full set of 132 possible conformers and tautomers have been examined, and promising structures studied at a high level of theory. The work is in press or in preperation for publication.

What computational techniques are used?

The packages Gaussian 94 and Molpro were used for gas phase calculations. Frequency analysis was performed at HF/6-31G(d). Geometry optimisation was performed at MP2/6-31G(d,p). Electron correlation was treated with calculations at QCISD(T)/6-31G(d,p). A large basis set correction at MP2/6-311++G(3df,3pd) was employed. The Gaussian 94 implementation of the isodensity polarised continuum model was used to estimate free energies in solution. The semi-empirical methods AM1-SM2 and PM3-SM3, implemented in the package AMPAC, were also employed for this purpose.


Greenwood, J.R., Capper, H.R., Allan, R.D., and Johnston, G.A.R. Tautomerism of hydroxy-pyridazines: the N-oxides , Proceedings of the Third Electronic Computational Chemistry Conference J.Molec.Struct(THEOCHEM),1997