Substitution SnAt, activating groups

The most practical method for the preparation of polyfarylcnc ether)s employs nucleophilic aromatic substitution (SnAi). Although nucleophilic substitution can occur via four principal mechanisms,49 the most important mechanism utilized for the synthesis of poly(arylene etlier)s has been SnAt, in which activating groups are present on the aromatic ring (Scheme 6.10). 

There are similarities between nucleophilic aromatic substitution (SnAt) and its more usual counterpart, electrophilic aromatic substitution. Each involves the formation of a resonance-stabilized intermediate, and each involves a temporary loss of aromaticity that is regained in the final step of the reaction. But the similarities are only so deep. The electrophilic reaction involves cationic intermediates the nucleophilic involves anionic intermediates. Use the differing effects of a nitro group, strongly deactivating in the electrophilic substitution and strongly activating in the nucleophilic substitution, to keep the two mechanisms distinct in your mind. 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

For the nucleophilic aromatic substitution reaction (SnAt) it has been discussed whether the addition of the nucleophile, the elimination of the leaving group is the rate limiting step or if this depends on the solvent. Taking the SnAt reaction between azide ion and 4-fluoronitrobenzene as an example, QM/MM calculations indicate that solvation effects cause the highest barrier for the elimination step. As a function of the solvent the experimental free energies of activation for these reactions are (values are given in kcal/mol) H2O 28.1/MeOH 27.5/MeCN ... 

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