Subject: Pyridazinedione response summary

From: Jeremy R Greenwood <[email-masked]>
Date: Tue, 27 Sep 1994 11:08:51 +1000 (EST)

Summary of responses to my query regarding the modelling of the tautomeric
structures of aminomethyl pyridazine-3,6-diones:

> 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?
 
Jeremy Greenwood

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From: "Raymond L. Roskwitakski" <[email-masked]>
Subject: Re: Modelling Pyridazindiones

Greetings Jeremy:

I have some references:

A prior pKa Calculations and Hydration of Organic Anions
William L. Jorgensen
J Am Chem Soc 1989 vol 111 pp. 4190-4197

Theoretical Examination of the S_N2 Reaction Involving Chloride Ion 
and Methyl Chloride in the Gas Phase and Aqueous Solution
Jayaraman Chandrasekhar, Scott Smith, William L. Jorgensen
J Am Chem Soc 1985 vol 107 pp. 154-163

Optimized Intermolecular Potential Functions for liquid Alcohols
William L. Jorgensen
J. Phys. Chem. 1986 vol 90 pp. 1276-1284

Relative Partion Coefficients for Organic Solutes from Fluid Simulations
William L. Jorgensen James M. Briggs
J. Phys. Chem. 1990 vol 94 pp. 1683-1686

Cis-Trans Energy Difference for the Peptidee Bond in the gas and
Aqueous Solution
William L. Jorgensen and Jiali Gao
J Am Chem Soc 1988 vol 110 pp. 4212-4216

I don't know where Jorgensen is now. You can ask for his address on CCL.
Best to talk with him to see if your problem can be handled well by this
method. It seems the best way to me, but then again I am not the in Monte
Carlo expert. He and Gao are.

Your problem is not trvial, since the energy curves of tatomers are shallow.
Inclusion of solvent effects makes sense to me, the gas phase results will
be confusing, because different computer methods will give different 
results because of the shallowness. 

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From: [email-masked]

I recently modeled a series of alpha hydroxy lactones and I could not get 
either AM1 or MM2 to produce the hydrogen bond that seemed to be 
important in these molecules.  I ended up using PC-Model and the results 
looked correct and match what physical characteristics that I know of.  

I wonder if there is a hydrogen bond between one of the NH groups and the 
alpha carbonyl in your system?

Sincerely

J. Born

[email-masked]
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From: "Raymond L. Roskwitakski" <[email-masked]>
Subject: RE: Modelling Pyridazindiones

Hi Jeremy:

In regard to part of your question:
[
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?
]

I suggest perturbative free energy calculations using monte carlo to simulate
the solvent. William Jorgenson, and Jiali Gao have done work in this.
I believe Jorgenson has a program for this called BOSS.

Hope this helps.

Raymond Roskwitalski, Jr.
[email-masked]

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>From [email-masked] Fri Sep  2 23:22:32 1994

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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>From [email-masked] Fri Sep  2 23:22:55 1994

Let me know the answers to your questions.  If you haven't seen it, the article
by George Shields in Journal of Computtational Chemistry deals with H-bonds which
might offer some hope to you.  I wish I knew the answers.  Also there was an
article by Cramer and/or Truhlar dealing with some sort of tautomerization.  I
think it was in JACS.  I'll hunt the references now.

  @@@@@@@@@@@      Yvonne Martin, Senior Project Leader
             @     Computer Assisted Molecular Design Project
   @@@@@@@@  @     D-47E, AP9A-LL
  @          @     Abbott Laboratories
  @          @     One Abbott Park Road
   @@@@@@@@@@      Abbott Park, IL 60064
                   Phone: 708 937-5362 FAX: 708 937-2625

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>From [email-masked] Fri Sep  2 22:15:19 1994

Hi Jeremy

For simulating solution (water) you can use two programs MOPAC93 (extended
version of MOPAC 6.0 including method COSMO (J.Chem.Soc.Perkin.Trans. 2, 799-805
(1993)) or AMSOL (extended version of AMPAC 3.0 program including SM1, SM2 and 
SM3 methods for estimation of solvation energy (only for water solution)). All 
this programs are available from
QCPE Catalogue.

If you want use ab initio calculations see papers Schlegel at al. JACS 104, 5347
(1982) about tautomerisation of 2-Pyridone and 4-Pyridone, or Cieplak at al.
Int. J. Quantum Chem. 14, 65 (1987)

Reference for semi-empirical calculations of 2- and 4-pyridones: Katritzky and 
Szafran, J. Mol. Struct. (TCHEOCHEM)

Stanislaw Oldziej
Faculty of Chemistry
University of Gdansk
POLAND
e-mail:[email-masked]

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>From [email-masked] Fri Sep  2 20:54:48 1994

Dear Jeremy:

Interesting problem.  I'm surely no expert in this field, but
based on limited experience you might wish to consider MP2/6-31G* 
optimizations.  The system is pretty small, so I think this would be
possible with gaussian-92 running on (say) an IBM550 or greater.
You will need lots of disk space; 2 Gb should do.  

If the MP2 optimization is not affordable, the other approach (which
makes sense to do anyway) is a series of opts with increasing basis 
sets to see how your results change from one to the next.  Start with 
6-31G* then 6-31+G* then 6-31++G* ... etc.  You might also look at DH 
basis sets.

The energy differences between tautomers is often quite small and
correlation seems like something you definitely want to include,
so follow the HF opts with some kind of correlated single points.
You also could follow the MP2/6-31G* opts (if you do them) with
higher basis-set correlated single points calcs.  I will avoid the 
whole religious issue of which correlation method would be best 
for your system.

I have no idea whether density functional is appropriate for this
kind of system.  Semi-empirical is a complete waste of time, IMHO.

Finally, I gather the formula is C4H4N2O2.  What is your experimental
evidence for the hydroxy form?  Is it the diol or the mono-ol?  What
is the pKa?  Pyridones (sometimes called 2-hydroxy pyridines) can
be drawn as hydroxy compounds, but in fact they exist as the lactams.
The proton is on the nitrogen.  So if you actually have the alcohol
form, then somehow this system's extra nitrogen atom has switched
the tautomeric preference.  That would be interesting to understand.
(I freely confess I don't understand tautomerization very well.)

J: Actually the formula of the structures I'm dealing with is
J: C5H7N3O2, containing an aminomethyl substitution. The literature
J: sugests that in gas, liquid, and solid phases, for pyridazine-3,6-diones,
J: the oxo/hydroxy (mono-ol, mono-one) tautomers are preferred. This
J: is indeed interesting, and somewhat different from other hydroxy-
J: nitrogen heterocycles. Pyridazine-3,6-dione itself is strongly acidic,
J: pKa = 1.00

I would love to learn more about your system, and of course look 
forward to your summary!

/ Mark
([email-masked])

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>From [email-masked] Fri Sep  2 21:13:36 1994

Dear Dr.Jeremy Greenwood,

>Which semi-empirical technique is most likely to give me reasonably
>accurate structures and energies for this ring system? 
I think PM3 gives better 'total energies' than AM1 or MNDO, however,
do not know about the structures.

>Is there an appropriate (not too computationally expensive) technique
>for simulating solution behaviour, reliable for predicting zwitterionic
>and tautomeric structure?
If you are using MOPAC93 please add EPS=78.4 to the keyword line.

>I would like to be able to predict qualitatively if not quantitatively,
>which proton(s) are the most acidic. 
How about removing one H-atom from the molecule, adding CHARGE=-1 and
EPS=78.4 to the keyword line. If you repeat this and evaluate each
'heat of formation' data, you could say which state is stable, it 
means the most acidic proton.

Hope this help.

     ____/   ___/  ___/ Yoshihisa INOUE (^_^)   the Green Cross Corp.
    /       /     /     2-25-1 Shodai-Ohtani,Hirakata,Osaka 573 JAPAN
   / _ /   /     /         tel: +81-720-56-9328
  /   /   /     /          fax: +81-720-68-9597
_____/ _____/_____/     E-mail: [email-masked]

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>From [email-masked] Sat Sep  3 00:36:35 1994

To answer one point of many in your question:  AMSOL is capable of modelling
solution behavior.  It is even possible to compute zwitterions in the gas 
phase:  I just saw a poster on the topic at the Washington ACS meeting for
glycine. (intramolecular proton transfer).  The authors published this in
JACSS, at the end of '93, I believe.

There have been many discussions on computing partial charges on this mailer:
you should check the archives!

Good luck!
Irene Newhouse

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