E. P. Serjeant

Prediction of pK a Values of Substituted Aliphatic Acids and Bases

Free energy changes produced by inserting substituents into organic molecules are approximately additive. Hence, the simplest way to use a linear free energy relationship for predicting the pK a of an aliphatic acid or amine where the pK a of the parent compound is known, is to add to it increments of pK a (∆pK a values) corresponding to the free energy changes produced by inserting the individual substituents. Finally, the total is adjusted by applying statistical factors or other corrections such as a decrease of 0.2 in the pK a value of an amine for every methyl group bound to the nitrogen, or an increase of 0.2 if the nitrogen atom forms part of a ring.

Prediction of p K a Values for Phenols, Aromatic Carboxylic Acids and Aromatic Amines

Within any class of substituted aromatic acid or base it is usually found that the acidic dissociation constant will vary in much the same way as that of the corresponding derivative in any other class. In most cases, these changes in acid strength, ∆pK a, produced by a substituent in a meta- or para-position can be predicted by the Hammett equation.

Recapitulation of the Main pK a Prediction Methods

When a pK a value is required, it may be possible to find the value at the required temperature and ionic strength in one of the compilations listed in Chapter 1. If the required value is not available, the ideal procedure would be to determine the value under the required conditions using procedures described by Albert and Serjeant (1971). If time does not permit or when a less accurately known value will suffice, a prediction based on methods described in this work can be made. It should be noted that the best predictions are those based on linear free energy relationships. In general, predictions are best which use the least number of substituent sigma constants and the least number of approximations. Ideally, pK a predictions should be based on a model compound as similar as possible in structure to the required compound.

Further Applications of Hammett and Taft Equations

The success of the method of prediction based on the additivity of increments of pK a values along chains in a molecule is not evidence of the correctness of the assumption that inductive effects are of overriding importance. Ring formation, by constraining the substituent in much closer proximity to the acidic or basic centre, leads to a stronger field effect than would be exerted by the same substituent attached at the free end of a chain, and may make a major contribution.

Methods of p K a Prediction

The extensive collections of pK a data currently available make it possible, without much difficulty, to predict from classes of compound and by analogy the pK a values of most acids or bases to within a few tenths of a pH unit.

Methods of pK a Prediction

The extensive collections of pK a data currently available make it possible, without much difficulty, to predict from classes of compound and by analogy the pK a values of most acids or bases to within a few tenths of a pH unit.

Methods of pKa Prediction

The extensive collections of pK a data currently available make it possible, without much difficulty, to predict from classes of compound and by analogy the pK a values of most acids or bases to within a few tenths of a pH unit.

Molecular Factors that Modify p K a Values

Qualitatively, factors that modify pK a values are well understood. They comprise mainly inductive, electrostatic and electron-delocalization (mesomeric) effects, together with contributions from hydrogen bonding, conformational differences and steric factors. Where a substituent tends to stabilize a cation more than the corresponding neutral molecule, or a neutral molecule more than the anion derived from it, the pK a of the acid will be raised. That is, the substituent will be acid-weakening or base-strengthening. Conversely, increased stabilization of an anion relative to the neutral species is acid-strengthening or base-weakening. Consideration of factors that modify the relative stabilities of these species can thus provide insights as to why pK a values vary but they do not permit calculations of the differences involved. It is nonetheless, useful to have even a qualitative indication of how substituents affect pK a values.

Some More Difficult Cases

Polycyclic molecules containing only one acidic or basic centre can be treated as monocyclic systems with the annelated rings as substituents. The latter may be paraffinic (or heteroparaffinic), aromatic, π-deficient or π-excessive heteroaromatic.

Examples where Prediction Presents Difficulties

It is important to recognize limitations to the possibility of predictions and to be on the alert for methods by which these inadequacies can be identified. This is often possible if data on appropriate model compounds are available.