Subject: Re: CCL:pKa calculation

From: [email-masked] (Per-Ola Norrby)
Date: Tue, 26 Nov 1996 07:43:19 +0100

>I have calculated the energy (HF) of a set of protonated molecules and compared
>them with the ones of non protonated species. After inclusion of vibrational
>and thermal corrections you can get a figure which can be refered as 'proton
>affinity' of the studied molecule. I want to know if there is any relationship
>between this proton affinity and pKa of the molecule. Any comment in this
>regard will be appreciated.
>
>Thanx in advance
>
>--
>Emad

        Dear Emad,

        What you have here is a "gas phase pKa".  If you want the aqueous
pKa, you have to perform the calculations in solvent.  Some solvation
models are available, I'm not sure I really trust them, but you could try.

        Also, trying to calculate any kind of absolute pKa requires very
high levels, in my experience HF is not nearly good enough.  Something that
COULD be fairly reliable is calculating RELATIVE pKa from an isodesmic
comparison, eg:

        R3N  +  NH4+  <->  R3NH+  +  NH3

        Thus you could calculate values relative to one standard, this
should be good enough for most applications.  I recommend the book "Ab
initio molecular orbital theory" by Hehre, Radom, Schleyer, and Pople.
With an isodesmic comparison, you MIGHT get away with adding solvent
contributions as single point calculations for all species in the above
equation.  In my experience, the most reliable published methods for this
are the SMx models, available in many programs with semi-empirical
calculations, ie AM1-SM2 or PM3-SM3.  If you want to do it at the ab initio
level (not necessarily better), you could look into Tomasi's PCM-method.

        Regards,

        Per-Ola Norrby

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
 *  Per-Ola Norrby
 *  The Royal Danish School of Pharmacy, Dept. of Med. Chem.
 *  Universitetsparken 2, DK 2100 Copenhagen, Denmark
 *  tel. +45-35376777-506, +45-35370850    fax +45-35372209
 *  Internet: [email-masked], http://compchem.dfh.dk/

---

From: A J Turner <[email-masked]>
Date: Tue, 26 Nov 1996 07:51:11 +0000 (GMT)

Hi!

Whilst what you are saying is very interesting as far as it goes, it takes
no account of the entropic change on solvation.

The only method of which I am aware that will do this would be QM/MM
FEPT. This can be done at all levels of ab-initio theory - if you have a
big enough computer!  Hoever - I am begining to believe that it will give
reasonable results at AM1 level - and thus be do-able for small systems
- on a work-station.

Best wishes

Alex

 -------------------------------------------------------------------
|Alexander J Turner         [email-masked]                  |
|Post Graduate              |http://www.bath.ac.uk/~chpajt/home.html|
|School of Chemistry        |+144 1225 8262826 ext 5137             |
|University of Bath         |                                       |
|Bath, Avon, U.K.           |Field: QM/MM modeling                  |
 -------------------------------------------------------------------