ACD/pK_a DB

Technical Information

• Varieties of pK_a 
• Microscopic vs. Macroscopic pK_a Constants 
• How Does ACD/pK_a DB Predict pK_a Values?  
• Calculations 

General Definition of 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 equilibrium acid ionization constant, K_a, expresses the ratio of concentrations for the reaction:

where, by convention, it is assumed that the concentration of water is constant, and it is absorbed into the K_a definition.

The acid ionization constant varies by orders of magnitude. For example at 25°C:

acetic acid
phenol

It is easier to refer to such extreme numbers on a logarithmic scale and, again by convention, "p" is used to denote the negative logarithm (base 10):

The K_a values of the compounds above are then easily converted to pK_a values:

acetic acid
phenol

There is an essential difference between interpreting the pK_a values for molecules vs. ions. A molecule which loses a proton ionizes:

An ion which loses a proton, however, de-ionizes:

Note that there is no intrinsic reason to rule out pK_a values less than 0 or greater than 14. For example, sulfuric acid, , has a negative pK_a for the loss of its first proton:

pKa < 0

although normally experiments can only measure pK_a between 1 and 13.

Ionization Centers

The determination of pK_a depends on the presence of heteroatoms such as oxygen or nitrogen. Although in principle a pK_a value could be calculated for any atomic center, including carbon, in practice the extrapolation is poor for systems which have a very low amount of ionization. For example, the C-H bonds in methane have such highly covalent character that

has a vanishingly small probability of occurring. Some C-H bonds do have measurable ionic character, and these are calculated by ACD/pK_a DB. For example, the C-H bond of the methylene group at the 2-position in 1,3-cyclopentanedione is highly polarized; its pK_a is predicted to be about 8.9:

Normally, however, a heteroatom is part of the ionization center, and ACD/pK_a DB is designed to test for the presence of heteroatoms which are capable of forming bonds with sufficient ionic character to have measurable pK_a values, thus enabling reasonable prediction of pK_a for related compounds.

Automatic Protonation vs. Fixed Form

The pK_a software has been designed to do three types of calculation, which are discussed in more detail below:

• Apparent constants: the algorithm automatically protonates the sketched-in molecule. You can specify whether you want the approximated or exact values.
• Microconstants of the current form: the algorithm accepts the molecule sketched in "as is" and tries to add a proton.
• Single pK_a values: ionization at each dissociation center is calculated while the rest of the molecule is considered neutral.

We recommend the use of exact (or, for large molecules, approximated) apparent constants.

Apparent Constants

The "apparent constant" of the pK_a mimics the experimental situation by "adding" protons to the molecule in the same order the molecule would normally be protonated in the solution.

For example, sketching the neutral glycine molecule H₂N-CH₂-COOH and specifying the "apparent constant" will give two values: 9.64 and 2.43. Note that these values are calculated for the actual ionization equilibria:

You can choose between "approximated" and "exact" forms of this calculation; the difference lies in the type of algorithm used. If two or more dissociated groups in the structure have close experimental pK_a values, they interfere with each other so that the calculated values lie farther apart than what the experimentally-observed values actually do. With an "exact" calculation, this interference phenomenon is taken into consideration every time. With an "approximated" calculation, this is taken into account only for strictly identical groups. For example, for 2-methylbutanedioic acid, which contains two similar but not identical carboxyl groups, the approximated apparent pK_a values have an uncertainty of 0.23 and 0.19 and differ from experimental values by 0.37 and 0.44, whereas the exact apparent pK_a values disagree with the experimentally-measured pK_a values by 0.08 and 0.10.

Microconstants of Current Form

The "microconstants of current form" is a method of calculation, which accepts the input structure exactly as it is, and tries to remove a proton from it.

For example, sketching the neutral glycine molecule H2N-CH2-COOH and specifying "microconstants of current form" will give two results: "not calculated" and 4.14. These are for:

On the other hand, if the input structure had specifically shown an ammonium group, H₃N⁺-, the current form calculation would have reported these two pK_a values:

Single pK_a Values

The "single pK_a" is close to the pK_a values as synthetic chemists view them. If there are two acidic sites in the molecule, a chemist needs to know the relative acid pK_a values. It could be done by calculating the pK_a for each ionization site while the rest of the molecule is considered neutral. While this does not reproduce the actual experimentally measured titration results of a bi-acid in a strong base titrated with an acid, single "pK_a" indicates the relative ease of ionization at each center. So:

Thus, for this case we see that the carboxy-group is more acidic than the hydroxy-group. For a di-basic compound the following pK_a constants will be calculated using this method:

    (pK_a = 7.81)

   (pK_a = 5.90)

Here, the amino-group is more basic than the pyridine.

So, "single pK_a" method predicts the pK_a for each site, leaving the rest of the molecule neutral.