Estimating Dissociated Structures in EPI

Acids are a common example of molecules that can exist in both neutral or ionized species depending on the pH of the environment and pKa of the molecule.  An example molecule is salicyclic acid (2-hydroxybenzoic acid) as shown below:

The structure on the left is the non-ionized species and the structure on the right is the ionized (dissociated) species.  The SMILES notation of each could be:

    Non-Ionized SMILES:  Oc1ccccc1C(=O)O

    Ionized SMILES:  Oc1ccccc1C(=O)[O-]

Currently, the SMILES interpreter in all EPI Suite programs will automatically convert the ionized SMILES (Oc1ccccc1C(=O)[O-]) to the non-ionized SMILES (Oc1ccccc1C(=O)O) which yields estimates for the non-ionized species only.

How To Generate EPI Program Estimates for the Ionized Species

The KOWWIN Program estimates the log octanol-water partition coefficient of a molecule.  With the exception of a few zwitterionic structures (such as amino acids) and ion-pair structures (such as sodium salts), KOWWIN estimates the log Kow of the neutral (non-ionized) molecule.  KOWWIN (and other individual EPI programs) are not currently programmed to generate estimates over a range of pH values.

However, KOWWIN is capable of yielding estimates for the ionized species for various acids such as carboxylic acids. The method is to enter the acid as either the sodium (Na), potassium (K) or lithium (Li) salt of the structure.  Sodium salts  comprise the bulk of available experimental data for these salts, but in terms of KOWWIN estimation, it makes no difference which of the three salts (Na, K, Li) is entered for estimation results.  Using the sodium salt of salicylic acid as an example:

SMILES:  Oc1ccccc1C(=O)[O-].[Na+] or  Oc1ccccc1C(=O)O[Na]

In KOWWIN, Oc1ccccc1C(=O)[O-].[Na+]  estimates the ion-pair log Kow of sodium salicylate which is effectively the value for the ionized species of salicylic acid:

Salicyclic Acid (CAS 69-72-7), Oc1ccccc1C(=O)O

... Experimental logKow = 2.26 (neutral species)

... KOWWIN estimate = 2.24 (neutral species)

Sodium Salicylate (CAS 54-21-7), Oc1ccccc1C(=O)[O-].[Na+]

... Experimental logKow = -1.43

... KOWWIN estimate = -1.49

Salicylic acid has a pKa of 2.97 (EPI Suite PhysProp Database).  The experimentally measured log Kow of salicylic acid at pH of 6.5-8.0 (where it will exist primarily in the ionized species) is reported to range from -1.22 to -1.66 (Sangster Database) which is very similar to the experimental values for sodium salicylate.  The same result occurs for a variety of other ionized acid measurements and corresponding measurements for the sodium salts.

Therefore, the ionized log Kow of an acid can be approximated by entering the sodium, potassium or lithium salt of the molecule in the KOWWIN program.