Introduction
 

Chemical properties of molecules depend largely on whether they are ionized or not. Most organic molecules are capable of gaining and/or losing a proton in aqueous solutions. Proton transfer most frequently occurs between water and any ionizable atom of the organic molecule.

The molecule's response to protonation or deprotonation depends significantly on the site that was disturbed by proton transfer. Partial charge distribution in the molecule also varies with protonation of the acid/base active sites. Since the partial charge distribution is very sensitive to the protonation-deprotonation process (both near and far from the disturbed site), it can be used to determine the pK_a of a molecule.

Our pK_a prediction program is based on the calculation of partial charge of atoms in the molecule.

Acidic and basic molecules are ionized in aqueous solution. Acidic or basic character is assigned to the molecule according to Brönsted's rule. The ratio of the ionized and neutral forms depends on the pH, the temperature and the ion activity of the bulk phase. The ionization constant K_a is obtained from the activity ratio of conjugated base and conjugated acid multiplied with proton activity:

 

Definition of pK_a
 

The pK_a value is obtained from the ionization constant of a molecule using the following definition:

 
When the pH of the solution is equal with pK_a, the concentrations of the dissociated and undissociated species are equal. 

Definition of the acidic/basic prefix of pK_a

Definition of the basic prefix

Protonated positive ions are considered as protonated basic sites , therefore "basic" prefix is used for them. The neutral basic sites are predefined in the pK_a calculator, they also have the "basic" prefix., e.g. if the submitted molecule is CH₃NH₂ or CH₃NH₃^+,, they get "basic" prefix and pK_a=10.08.

Definition of the acidic prefix

Deprotonated negative ions are considered as deprotonated acidic sites , therefore "acidic" prefix is used for them. The neutral acidic sites are predefined in the pK_a calculator, they also have "acidic" prefix, e.g. if submitted molecule is CH₃COOH or CH₃COO^- , they get "acidic" prefix and pK_a=4.54.

Multiprotic molecules

 

When a molecule contains more than one ionizable atom, it is called a multiprotic compound. For these types of molecules we need to distinguish between micro and macro acidic dissociation constants. The micro acidic dissociation constant is obtained from the equilibrium concentration of the conjugated acid-base pairs. The macro acidic dissociation constant is obtained from the global mass and charge conservation law. When a molecule has N ionizable sites, the total number of microspecies in the solution is 2^N.

Example case

 

To better understand the difference between micro and macro constants we consider ionization equilibrium of a triprotic acid AH₃. Referring to the different deprotonation sites of the AH₃ molecule we introduce the upper indexes of the protons:

 

The ionization process of the AH¹H²H³ molecule in aqueous solution is described with 12 equilibrium reactions. Microspecies and their charge are summarized in Table 1.

 

Tab. 1 Microspecies of AH₃ and their charge 

The AH₃ molecule has three macro acidic constants since it is a triprotic acid. Macro acidic constants K₁, K₂, and K₃ are obtained from the concentration of the microspecies:

 

And the three macro pK_a values of the AH₃ molecule that would be obtained with routine laboratory measurements are as follows: 

pK_a,1=-log₁₀(K₁) 
pK_a,2=-log₁₀(K₂) 
pK_a,3=-log₁₀(K₃) 

Examples
 

The following examples show the different acidic/basic processes and related calculations.

Example #1

 

Example #2

Imides and amides can have either acidic or basic character. The extent of amide/imide ionization at a given pH is determined by two acid dissociation constants: pK_a,1 is assigned to the deprotonation step  RNH  RN^- + H⁺ and pK_a,2 is assigned to the protonation step RNH₂⁺ RNH + H⁺ .

The ratio of anionic and cationic species depends on pK_a,1, pK_a,2 and the pH: 

 

If 2*pH - (pK_a,1 + pK_a,2) > 0 than deprotonation of amide/imide is favored and the molecule is said to have an acidic character. 
If 2*pH - (pK_a,1 + pK_a,2) < 0 than protonation of amide/imide is favored and it is considered to have a basic character. 

Chemists often want to know the ionization state of organic compounds at pH 7.4. In general, the macro pK_as of amide/imide compounds are calculated and their acidic or basic character determined with the above formulas at pH 7.4.