Nucleophilic substitution, aromatic anionic intermediates

Grignard reagent.80 Competition by nucleophilic aromatic substitution was not observed unless the only active position(s) was (were) substituted with a leaving group, as in the reaction of l-methoxy-2-nitro-naphthalene which gave 1 -alkyl-2-nitronaphthalenes in 73-95% yields.81 The use of Me3SiCH2MgCl (Peterson reagent) provides an entry to nitro-substituted benzyl anion intermediates, as shown in the example of Scheme 9.82... 

A nitro group is a strongly activating substituent in nucleophilic aromatic substitution where it stabilizes the key cyclohexadienyl anion intermediate... 

Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group. The more such substituents there are, the faster the reaction. As shown in Figure 16.18, only ortho and para electron-withdrawing substituents stabilize the anion intermediate through resonance a meta substituent offers no such resonance stabilization. Thus, p-ch oronitrobenzene and o-chloronitrobenzene react with hydroxide ion at 130 °C to yield substitution products, but m-chloronitrobenzene is inert to OH-. 

Such nucleophilic displacements are likely to be addition-elimination reactions, whether or not radical anions are also interposed as intermediates. The addition of methoxide ion to 2-nitrofuran in methanol or dimethyl sulfoxide affords a deep red salt of the anion 69 PMR shows the 5-proton has the greatest upfield shift, the 3- and 4-protons remaining vinylic in type.18 7 The similar additions in the thiophene series are less complete, presumably because oxygen is relatively electronegative and the furan aromaticity relatively low. Additional electronegative substituents increase the rate of addition and a second nitro group makes it necessary to use stopped flow techniques of rate measurement.141 In contrast, one acyl group (benzoyl or carboxy) does not stabilize an addition product and seldom promotes nucleophilic substitution by weaker nucleophiles such as ammonia. Whereas... 

Substitution of scheme a forms a well-documented class of reactions (see Costentin et al. 1999,2000, Costentin and Saveant 2000, Corsico and Rossi 2000, 2002, 2004, Adcock et al. 2001, Vanelle and Crozet 2002, Medebielle et al. 2002, Galli and Rappoport 2003, Rossi et al. 2003, Vanelle et al. 2004, and Bnden et al. 2005 and references therein). In contrast to conventional nucleophilic substitution, the nncleophile, Nu-, reacts not with the substrate, RX, to give a product but with the radical R. The latter emerges as a result of R-X bond cleavage. Snbstitnent X is very often a halogen atom, bnt other leaving groups can also be used (see section 7.8.1). In the majority of aromatic Sr I reactions, the anion-radical RX- (R=Ar) is the observable intermediate. It is depicted in scheme a. With aliphatic snbstrates, snbstitntion takes place rather than 8 2 or S l substitutions, and the concerted mechanism depicted in scheme b is feasible. 

Strong nucleophiles such as organolithium or organomagnesium derivatives do not react with substituted or unsubstituted phosphabenzene or arsabenzene (Y = P or As) by nucleophilic substitution as in the case of pyridines, but by addition to the heteroatom forming intermediate anions. These anions can then be converted into non-aromatic compounds by reaction with water yielding 1-alkyl-1,2-dihydro-derivatives, or they can be alkylated by an alkyl halide with the same or a different alkyl group, when two products may result a l,2-dialkyl-l,2-dihydro-derivative, or a 2 -derivative (Figure 17). The former products are kinetically controlled, whereas the latter compounds are thermodynamically controlled. 

This nuc( ophiiic aromatic substitution is in some ways anak ous to the nucleophilic acyl suhstitution of acid chlorides iSection 21.4i. In both caoca, the initial addition, step is favored hy the ability of the electiD-negattve atom (nitrogen or oxygen) to statMlize the anion intermediate. The intermediate then expels chloride ion to yield the substitution product. 

The reaction, a versatile synthetic tool, is initiated by generation of a radical anion. The designation Sr I indicates that the reaction is a nucleophilic substitution proceeding through a radical intermediate and that the rate-limiting step is unimolecular decay of the radical anion intermediate formed from the substrate (see a review by Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413-420). Sr I reactions occur with both aliphatic and aromatic compounds. 

These reactions are typical nucleophilic aromatic substitutions, similar to those we saw earlier for halobenzenes (Section 16.8). Reaction occurs by addition of the nucleophile to the C=N bond, followed by loss of halide ion from the anion intermediate. 

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