NASH nucleophilic aromatic substitution

Nucleophilic displacements on unsubstituted aromatics usually do not occur since H is not a good leaving group. However, an example of nucleophilic aromatic substitution of hydrogen (NASH) has been reported on reacting aniline and azobenzene in the presence of base under aerobic conditions to generate 4-(phenylazo)diphenylamine, 9 (equation 13)115. 

The formation of substituted anilides from the reaction of amides with nitrobenzene is the first example of the direct formation of aromatic amide bonds via nucleophilic aromatic substitution for hydrogen. This reaction proceeds in high yield and regioselectivity, and does not require the use of halogenated materials or auxiliary leaving groups. Furthermore, these studies have demonstrated that the use of O2 as the terminal oxidant in NASH reactions can result in a highly selective and environmentally favorable route for the production of PNA and PPD. 

Flexsys found a solution to this problem in a class of reactions known as nucleophilic aromatic substitution of hydrogen (NASH). Through a series of experiments designed to probe the mechanism of NASH reactions, Flexsys achieved a breakthrough in understanding... 

Proposals for the mechanism of PPS formation include nucleophilic aromatic substitution (Sj Ar) (2radical-cation (27), and radical-anion processes (28,29). Some of the interesting features of the polymerization are that the initial reaction of the sodium sulfide-hydrate with NMP affords a soluble NaSH-sodium 4-(N-methylamino)butanoate mixture, and that polymers of higher molecular weight than pi edicted by the Caruthers equation are produced at low conversions. Mechanistic elucidation has been hampered by the harsh polymerization conditions and poor solubility of PPS in common organic solvents. A detailed mechanistic study of model compounds by Fahey provided strong evidence that the ionic S]s Ar mechanism predominates (30). Some of the evidence supporting the S s(Ar mechanism was the selective formation of phenylthiobenzenes, absence of disulfide production, kinetics behavior, the lack of influence of radical initiators and inhibitors, relative rate Hammet values, and activation parameters consistent with nucleophilic aromatic substitution. The radical-anion process was not completely discounted and may be a minor competing mechanism. 

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