ACD/pK_a DB

Technical Information, Page 4

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

Calculation of Steric Effects

In most cases steric effects have been taken into account by defining the ionization center as an ionizable functional group with a sufficiently large invariable skeleton. In cases where the variable substituents are in close proximity to ionizable groups, steric effects are calculated by the modified branching equations. For example, pK_a of N-monoalkylanilynium ions are calculated by the following equation:

pK_a = 4.85 + 0.27 • (nβ)^1.84 - 0.08 • (nγ)^2.36 + 0.01 • (nδ)^2.36 sd = 0.2

where nβ, nγ and nδ denote the numbers of atoms in second, third and fourth spheres of the N-alkyl substituent. The accuracy of the pK_a calculation for N-t-butyl anilynium is ± 0.1, whereas without this equation it would be ± 2!

Calculation of Charge Effects

In some cases charge effects have been taken into account by including the constant charged substituent into the definition of ionizable center. For example, the pK_a of carboxy groups in α-amino acids are calculated from the equation characterizing the -CH(NH₃⁺)COOH ionization center. In the cases when the charged substituent is variable its effect is calculated from the distance to ionization center.

Other Effects

ACD/pK_a warns you when other effects may appear which affect the experimentally observed pK_a values. These effects, if not properly taken into account, may cause a large discrepancy between the calculated and experimentally observed pK_a values.

A. Tautomeric Equilibria

For certain compounds, there is mixture of two or more structurally distinct species which are in rapid equilibrium. Normally proton transfer is involved in tautomeric equilibria. Some of the commonest instances of tautomerism are related to the following forms:

• Keto-enol
• Phenol-keto
• Nitroso-oxime
• Aliphatic nitro compounds
• Imine-enamine

If you are calculating pK_a values for species that contain these functional groups, you may want to use the ACD/Tautomers module of ACD/ChemSketch to check if other tautomeric forms exist. You may also set up your options to always predict the major tautomer:

For example, the hydroxytriazoliumonate species

Check for Tautomeric forms reveals that 3 tautomeric forms are possible:

B. Covalent Hydration

If the energy barrier to the addition of water across a double bond is relatively low, this can be a significant complicating factor in the accurate experimental determination of pK_a; thus, ACD/ pK_a is designed to flag known cases. For example, for pteridine, a pK_a calculation will automatically flag the species on the left as undergoing covalent hydration:

C. Vinylology

Another complicating factor in the calculation and measurement of pK_a is vinylology. Vinylology occurs due to resonance effects being transmitted through the double bond. In α, β-unsaturated ketones, nitriles, and esters, such as in the following structures

the γ-hydrogen acquires a level of acidity normally held by the position α to the carbonyl group. Due to vinylology, alkylation at the α-position competes with alkylation at the γ-position.

ACD/pK_a gives warning about vinylology, if an accurate enough prediction can not be made.