Can we predict ambident regioselectivity using the chemical hardness?

The hard/soft acid/base (HSAB) principle is a cornerstone in our understanding of chemical reactivity preferences. Motivated by the success of the original ("global") version of this rule, a "local" counterpart was readily proposed to account for regioselectivity preferences, in particular, in ambident reactions. However, ample experimental evidence indicates that the local HSAB principle often fails to provide meaningful predictions. Here we examine the assumptions behind the standard proof of the local HSAB rule, showing that it is based on a flawed premise. By solving this issue, we show that it is critical to consider not only the charge transferred between the different reacting centers but also the charge reorganization within the non-reacting parts of the molecule. We propose different reorganization models and derive the corresponding regioselectivity rules for each.