Subject: SCRF and pKa

From: Jeremy R Greenwood <[email-masked]>
Date: Wed, 4 Sep 1996 02:14:21 +1000 (EST)

Greetings all,

Two related and maybe naive questions on the difficult problem of aqueous 
phase calculations: 

I'm studying some acidic tautomeric heterocycles; while molecular 
dynamics methods or semi-empirical (e.g. SAM1) may be recommended, I'm 
interested in ab initio continuum methods, not least because I have 
them readily available.

1) Can someone point me in the direction of a study of, or give me an opinion 
of, the reliablity of the IPCM model vs. other (SCRF) methods for calculating 
solvation energies of species in dilute aqueous solution. I'm particularly 
interested in species for which hydrogen bonding is likely to be significant, 
and the comparative treatment of hydroxy vs. oxo tautomers. My preliminary
IPCM results consistantly indicate greater aqueous stabilisation of hydroxy 
vs. oxo tautomers, apparently in contradiction both with published results
>from other methods (FEP, Onsage, PCM) and generally accepted wisdom if I
understand correctly.

2) I'm interested in the state of the art for the ab initio calculation
of pKa. I'd greatly appreciate comments & suggestions for methodology, 
or pointers to recent literature. 

Empirical attempts within a given system to correlate dipole moments 
or point charges on acidic moieties calculated from one or other method 
with pKa could be a possible avenue. Is this tried?

A means of attacking pKa with SCRF I'm considering: in order to make 
most use of cancellation of systematic error, modelling the overall 
reaction:

    HA + OH-  ->  A- + H2O
   
Good estimates of the gas-phase deltaG of reaction should be calculable,
using Hartree-Fock frequencies and correllated theories with diffuse
functions for energies. An accurate estimate of deltaG in dilute aqueous 
solution at 298K should lead to pKa. How best to go from the former to the 
latter? 

IF (from question 1) the IPCM model (or other SCRF) gives reasonable 
relative aqueous solvation single point energies from gas phase geometries, 
could these be simply be used to correct the gas-phase free energies to 
determine an aqueous phase free energy of reaction and hence pKa with any 
degree of confidence?

Alternatively, as opposed to single point calculations, optimisation and 
frequency calculations could be performed with SCRF for aqueous solution, 
and from these, the free energy of reaction in solution derived and hence 
pKa. However, Gaussian94 only offers these calculations for the Onsager 
model using uncorrelated theories, and I have my doubts as to how well 
this would handle such systems.

Thanks for any suggestions in advance,

Jeremy