Ab Initio Studies on the Tautomerism of Dioxo-Pyridazines and Their Anions as Novel Bioisosteres

Principal Investigator

Robin Allan

Department of Pharmacology,

University of Sydney

Substituted heterocycles 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 has 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 the dioxo-pyrdazines (six membered aromatic rings with adjacent nitrogen heteroatoms, 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 nine dioxo-pyridazines, and their conjugate bases, and to improve on the quality of previous 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 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 high level of theory in the gas phase and in the aqueous phase using semiempirical and ab initio solvation models. The work has been published. More accurate results will depend on further advances in computing technology, and the implementation of superior aqueous phase modelling.

What computational techniques are used?

The packages Gaussian94 and Molpro96 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) and MP2/6-311+G(2d,p). Higher level electron configuration was treated with



QCISD(T) theory, and a large basis set correction employed at MP2/ 6-311++G(3df,3pd). The ab initio Isodensity Polarised Continuum model in Gaussian94, and the semi-empirical AM1-SM2 and PM3-SM3 models in AMPAC were used to estimate solvation properties.


J. R. Greenwood, H. R. Capper, R. D. Allan, G. A. R. Johnston, Tautomerism of hydroxy-pyridazines: the N-Oxides, Proceedings, Third Electronic Computational Chemistry Confere nce. Journal of Molecular Structure (Theochem) 419 (1997) 97-111

J. R. Greenwood, H. R. Capper, R. D. Allan, G. A. R. Johnston, The tautomerism of pyridazinediones, Proceedings, Fourth Electronic Computational Chemistry Conference. Internet Journal of Chemistry http://www.ijc.com (1998) (in press)