A modification of the Hammett equation for predicting ionisation constants of p-vinyl phenols

Currently there are several compounds used as drugs or studied as new chemical entities, which have an electron withdrawing group connected to a vinylic double bond in a phenolic or catecholic core structure. These compounds share a common feature – current computational methods utilizing the Hammett type equation for the prediction of ionisation constants fail to give accurate prediction of pK_a's for compounds containing the vinylic moiety. The hypothesis was that the effect of electron-withdrawing substituents on the pK_a of p-vinyl phenols is due to the delocalized electronic structure of these compounds. Thus, this effect should be additive for multiple substituents attached to the vinylic double bond and quantifiable by LFER-based methods. The aim of this study was to produce an improved equation with a reduced tendency to underestimate the effect of the double bond on the ionisation of the phenolic hydroxyl. To this end a set of 19 para-substituted vinyl phenols was used. The ionisation constants were measured potentiometrically, and a training set of 10 compounds was selected to build a regression model (r² = 0.987 and S.E. = 0.09). The average error with an external test set of six compounds was 0.19 for our model and 1.27 for the ACD-labs 7.0. Thus, we have been able to significantly improve the existing model for prediction of the ionisation constants of substituted p-vinyl phenols.