Subject: Modelling Pyridazindiones

From: Jeremy R Greenwood <[email-masked]>
Date: Fri, 2 Sep 1994 11:18:54 +1000 (EST)

As a newcomer to the field and to this list, please forgive any naivety.

I am currently attempting to model structures containing the unusual
heterocycle pyridazine-3,6-dione, which displays multiple lactam-lactim
tautomerism. Experimental evidence suggests that the oxo-hydroxy
tautomer is most stable.

I've been using MOPAC, however I don't know if I can trust the results
(based on W.Fabian, J. Molecular Structure (Theochem), 200 (1990), 295).
Which semi-empirical technique is most likely to give me reasonably
accurate structures and energies for this ring system? If I have
to resort to ab initio calculations, what is the minimum level
of theory necessary to handle this ring?

Secondly, the structures I am modelling are most likely zwitterionic
in physiological solution, as they contain an amino group in addition
to the acidic pyridazindione. Is there any point in modelling zwitterions
on MOPAC or Gaussian 92 in the gas phase and trying to extrapolate
to solution behaviour? Is there an appropriate (not too computationally
expensive) technique for simulating solution behaviour, reliable for
predicting zwitterionic and tautomeric structure, or does one have to
resort to coordinating water molecules etc.? 

Thirdly, the atomic charges returned by various semi-empirical methods
vary widely for these structures. I would like to be able to predict
qualitatively if not quantitatively, which proton(s) are the most acidic. 
I realise that this may once again depend on aqueous behaviour rather 
than gas-phase, and hence be rather a tall order. Any suggestions?

Thanks in advance,

Jeremy Greenwood <[email-masked]>
Department of Pharmacology, University of Sydney NSW 2006, Australia