

Jeremy,

   It always seems a bit self-serving to me to refer to one's own work,
however in this case it does seem particularly germane. We have explored
exactly the issues you are interested in for some heterocycles in JACS 115
(1993) 8810-8817. Although the paper is far more thorough, let me say in a
nutshell that (1) semiempirical methods are lousy for gas-phase energy
differences unless you get lucky, (2) remarkably high levels of ab initio
theory seem to be required if you want accurate relative energies for
tautomers with differently hybridized heteroatoms, and (3) solvation models
that account only for electrostatics (most continuum models) miss lots of the
specific interactions from the first shell that are important for polar
heterocycles, but explicit-solvent models (e.g., simulations) are terribly
expensive and have electrostatic terms of questionable utility. Our own
approach was to use our SM2 solvation model to correct gas-phase relative
free energies, and that seemed to work well.

   As for atomic charges, we have recently developed something we call Charge
Model 1 (a "Class IV" charge model) that maps semiempirical Mulliken charges
to new values that we have shown to be similar in quality to electrostatic
potential fitted charges from correlated, large-basis densities. This paper
is presently in press at the Journal of Computer-Aided Molecular Design.
Several heterocycles were included in the test set (although not quite so
complex as a pyridazindione) and none seemed to be particularly problematic.
I would be happy to send you a preprint if you are interested.

   Finally, from a practical standpoint, you are probably more interested in
doing calculations than reading about them. Both the SM2 solvation model and
the CM1 charge model (which can use either AM1 or PM3 wavefunctions,
incidentally) are available in our program AMSOL, which is distributed by
QCPE essentially for the medium cost (it may be about $200 at this point, I'm
afraid I don't recall--anyway, we don't get any money . . . ) The address
etc. for QCPE is in the CCL archives. Or, you could send e-mail to 
[email-masked].

Best regards,

Chris

-- 

Christopher J. Cramer
University of Minnesota
Department of Chemistry
207 Pleasant St. SE
Minneapolis, MN 55455-0431
(612) 624-0859
[email-masked]

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