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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 S N 2 reaction channels of archetypal ambident nucleophiles CN − , OCN − , and SCN −  with CH 3 Cl (S N 2@C) and SiH 3 Cl (S N 2@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 S N 2@C and S N 2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn–Sham molecular orbital analysis.

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