Vicarious nucleophilic substitution of hydrogen. Mechanism and orientation

Abstract

Hydrogens located at activated positions in electrophilic arenes, e.g. ortho and para hydrogens in nitrobenzenes, can be replaced with a nucleophile moiety provided there is at least one nucleofuge X connected to the nucleophilic centre. As the group really leaving in this hydrogen substitution process is not the hydride anion but X, the reaction has been named vicarious nucleophilic substitution of hydrogen (VNS). The concepts on the mechanism of the reaction and their experimental background are presented. Reactivity and orientation-the fundamental questions concerning synthetical applications of VNS-are discussed in light of the supposed mechanistic picture.

Synthesis of α-(Nitroaryl)benzylphosphonates via Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes

“…We have already shown that orientation of the VNS reaction that also proceeds via formation of the σ H adduct depends on the conditions. Under conditions assuring equilibration of the σ H adducts formation, substitution proceeds mostly in the para position (thermodynamic control) . Thus, in order to afford selectively or dominantly substitution in the para position it is necessary to create conditions that ensure equilibration of the σ H adducts formation.…”

Oxidative Nucleophilic Substitution of Hydrogen versus Ring-Opening in the Reaction of 4-R-2-Nitrothiophenes with Amines. The Crucial Effect of 4-Alkyl Groups

“…Actually, nucleophilic substitution of hydrogen is a general method for the introduction of carbon as well as heteroatom substituents via direct replacement of hydrogen in electron-deficient aromatic or heteroaromatic rings. − The reaction proceeds via an initial addition of the nucleophile to the electron-deficient ring in a position occupied by a hydrogen atom to give an anionic σ H -adduct which can be converted into the final product in one of several ways. In particular, when the carbanion contains a leaving group X at the side chain, a base-induced β-elimination of HX from the σ H -adduct gives products of vicarious nucleophilic substitution (VNS) . On the other hand, oxidation of the σ H -adduct (e.g., with an external oxidant) gives ONSH …”

Elucidation of the Vicarious Nucleophilic Substitution of Hydrogen Mechanism via Studies of Competition between Substitution of Hydrogen, Deuterium, and Fluorine

“…That the steady-state approximation also applies with k′ 2 .k′ -1 for the S N Ar pathway is an assumption that reflects the most commonly reported situation for mononitroactivated arenes. 11 In eqs 4 and 5, 1 and C-2 refer to the fluoronitroaromatic and the carbanion at hand, respectively, while P H and P F represent the products of the hydrogen and fluorine substitutions, respectively; i.e., we will express the product distribution as [P H ] ) [3] and…”