Ambident Nucleophilic Substitution: Understanding Non‐HSAB Behavior through Activation Strain and Conceptual DFT Analyses

Abstract

The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas‐phase SN2 reaction channels of archetypal ambident nucleophiles CN−, OCN−, and SCN− with CH3Cl (SN2@C) and SiH3Cl (SN2@Si), using DFT calculations. Our combined analyses highlight the inability of the HSAB principle to correctly predict the reactivity trends of these simple, model reactions. Instead, we have successfully traced reactivity trends to the canonical orbital‐interaction mechanism and the resulting nucleophile–substrate interaction energy. The HOMO–LUMO orbital interactions set the trend in both SN2@C and SN2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn–Sham molecular orbital analysis.

Predicting experimental electrophilicities from quantum and topological descriptors: A machine learning approach

“…This statement actually confirms the trend that descriptors following HSAB and Klopman-Salem principles were shown [98] to be inappropriate towards a structurally diverse set of compounds and especially for molecules with two or more reactive sites (ambident reagents), [99,100] leading to Mayr's conclusion that these theories should be abandoned. [101] The SHAP analysis can also be used as a feature selector for multilinear regressions (MRs).…”

High-Level Systematic Ab Initio Comparison of Carbon- and Silicon-Centered SN2 Reactions

“…41,47−50 Despite the interesting features of silicon-centered S N 2 reactions, these systems are less studied than the carboncentered analogues. In the case of the X − + SiH 3 Y-type reactions, mostly the Cl − + SiH 3 Cl (refs 41,[43][44][45][46][47][48][49][50]53,54,56) identity process is investigated in addition to the few studies on F − + SiH 3 F (refs 41,48,56). The theoretical studies on these reactions usually used density functional theory with triple-zeta basis sets to characterize the stationary points, [43][44][45][46][47]50,54,56 in some cases, 43,49,50 the energies are refined by the CCSD(T)/aug-cc-pVQZ level of theory.…”

On the Predictive Power of Chemical Concepts

“…[83] Applications of the HSAB principle to ambident reactants were heavily criticized due to notable failures occurring even for prototypical systems. [74,84] Although its now established roots in quantum chemistry allow for explicit calculations, the HSAB principle should not be mistaken as a universal tool for reactivity predictions. It may be regarded as one measure for reactivity in the context of all such concepts evaluated for a reactant.…”