Quantitative Scale for the Nitronium Cation-Donating Ability of Electrophilic Nitrating Reagents

Electrophilic nitration is a fundamental transformation in organic synthesis; however, traditional mineral acid-based methods suffer from harsh conditions and limited substrate scope, motivating the development of organic electrophilic nitrating reagents. Here, we present a comprehensive computational investigation of the nitronium cation donating ability (NC+DA) of more than 50 reagents, including alkyl nitrates, nitric anhydrides, N-nitropyridinium salts, N-nitropyrazoles, N-nitroamides, pyridazinone derivatives, and other heterocyclic systems. The results enable the establishment a systematic NC+DA scale and reveal detailed structure-reactivity relationships influenced by electronic and steric factors. Guided by this scale, several potential N-nitroamide-type reagents with lower NC+DA values than existing nitroamides were designed. This work provides a quantitative framework for understanding and predicting the reactivity of organic electrophilic nitrating reagents and offers a rational basis for the design of next-generation electrophilic nitrating reagents for synthetic applications.