Farewell to the HSAB Treatment of Ambident Reactivity

Abstract

The concept of hard and soft acids and bases (HSAB) proved to be useful for rationalizing stability constants of metal complexes. Its application to organic reactions, particularly ambident reactivity, has led to exotic blossoms. By attempting to rationalize all the observed regioselectivities by favorable soft-soft and hard-hard as well as unfavorable hard-soft interactions, older treatments of ambident reactivity, which correctly differentiated between thermodynamic and kinetic control as well as between different coordination states of ionic substrates, have been replaced. By ignoring conflicting experimental results and even referring to untraceable experimental data, the HSAB treatment of ambident reactivity has gained undeserved popularity. In this Review we demonstrate that the HSAB as well as the related Klopman-Salem model do not even correctly predict the behavior of the prototypes of ambident nucleophiles and, therefore, are rather misleading instead of useful guides. An alternative treatment of ambident reactivity based on Marcus theory will be presented.

Nucleophilic properties of purine bases: inherent reactivity versus reaction conditions

“…It was later combined with empirical HSAB principle. Recently, this approach has been criticized by Mayr et al [88]. They argue that the number of cases where empirical HSAB approach fails is almost equal to that of its successes.…”

Alkylation of potassium ethyl acetoacetate: HSAB versus Marcus theory

“…These facts outline a fundamental argument against the applicability of the Marcus analysis to the reaction under investigation. We slightly disagree with Mayr et al who supposed that the source of inapplicability of the Marcus analysis is neglecting the different force constants in alkyl halides [11].…”

“…Mayr et al reconsidered the papers where the alkylation reactions of typical ambident nucleophiles: NCS À , NC À , NO 2 À , NCO À , RCHNO 2 À , amide anions, and benzene sulfinate have been investigated. They concluded that not even the site of alkylation is correctly predicted by the HSAB theory, and suggested another approach to ambident reactivity [11]. This approach differentiates between thermodynamically and kinetically controlled reactions.…”

“…It was pointed out [11] that, unlike many other enolate anions, the alkylation of EAE À cannot be elucidated on the basis of the qualitative Marcus analysis. On the other hand, the HSAB theory explains the above reaction in the following way: Ethyl chloride, with the hard leaving group, reacts preferentially with the harder oxygen, whereas ethyl iodide, with the soft leaving group, reacts preferentially with the softer carbon.…”

“…Such a concept has been widely accepted by many researchers, but has also been criticised [9][10][11]. It was put forward that, in spite of the fact that different reaction conditions dictate different reaction products, the HSAB theory does not make difference between thermodynamic and kinetic control [9,10].…”