I Lab Services 

4.19 pK

a

This module calculates acid base ionization constants (pK

a

 values) for organic and some 

inorganic chemical compounds in the system at the equilibrium state under standard conditions 

(25 C and zero ionic strength in aqueous solutions), the algorithm of this calculation mimics the 

experimental order of protonation of the drawn molecule and determines the pK

a

 values which 

can be experimentally measured in aqueous solution.  Each calculation is provided with its  95% 

confidence limits and, when available, literature references.  The accuracy of calculations for 

simple structures is usually better than  0.2 pK

a

 units (for complex structures it is better than  0.5 

pK

a

 units). 

The resultant dialog box displays the query structure and the calculated pK

a

 values.  The 

calculated pK

a

 values of a stepwise equilibrium are reported.  The following scheme gives an 

estimate of the meaning of each of the calculated constants for the reactions: 

(1) HL/L + H 

(2) H2L/HL + H   

and 

(3) H3L/H2L + H 

More details can be found in the sections that follow. 

4.19.1 Limitations 

The ACD/pK

a

 algorithm will refuse to predict pK

a

 values for structures which:  

Contain more than 255 atoms (note that the program refuses to predict pK

a

 for some 

cyclic compounds having less than 255 atoms due to the fact that the program uses a 

cycle breaking algorithm that increases the number of atoms); 

Do not contain an ionization center; 

Contain atoms of non typical valence; 

Contain atoms other than C, H, O, S, P, N, F, Cl, Br, I, Se, Si, Ge, Pb, Sn, As, and B; 

Contain two or more fragments; 

Contain more than 20 ionization centers; 

Contain d block or f block metal atoms; or 

Contain textual abbreviations which cannot be transformed to structural fragments. 

4.19.2  What is ACD/pK

a

? 

The pK

a

 is a measure of the tendency of a molecule or ion to keep a proton, H

+

, at its ionization 

center(s).  It is related to ionization capabilities of chemical species.  The more likely ionization 

occurs, the more likely a species will be taken up into aqueous solution, because water is a very 

polar solvent (dielectric constant, 

20

 = 80).  If a molecule does not readily ionize, then it will tend 

to stay in a non polar solvent such as cyclohexane (

20

 = 2) or octanol (

20

 = 10).  In biological 

terms, pK

a

 is thus an important concept in determining whether a molecule will be taken up by 

aqueous tissue components or the lipid membranes.  It is also closely related to the concepts of 

pH (the acidity of solution) and logP (the partition coefficient between immiscible liquids). 

The equilibrium acid ionization constant, K

a

, expresses the ratio of concentrations for the 

reaction: 

HA + H

2

O 

 H

3

O

+

 + A

K

a

 = [H

3

O

+

] [A

] / [HA]  

where, by convention, it is assumed that the concentration of water is constant, and it is absorbed 

into the K

a

 definition. 

ACD/I Lab via ChemSketch  

User's Guide 

49