Nucleophilic Aromatic Substitution Benzyne Mechanism

The benzyne mechanism (elimination-addition) is likely when the ring has no strong electron-withdrawing groups. It usually requires a powerful base or high temperatures. 

Step 1 Deprotonation adjacent to the leaving group gives a carbanion. 

Step 2 The carbanion expels the leaving group to give a benzyne intermediate. 

Step 3 The nucleophile attacks at either end of the reactive benzyne triple bond. 

With strong electron-withdrawing groups ortho or para, the addition-elimination mechanism is more likely. Without these activating groups, stronger conditions are required, and the benzyne mechanism is likely. 

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Mechanism 17-8 Nucleophilic Aromatic Substitution (Benzyne Mechanism) 789... 

The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution Benzyne... 

THE ELIMINATION-ADDITION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION BENZYNE... 

Elimination-addition mechanism for nucleophilic aromatic substitution. Benzyne... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

Although nucleophilic aromatic substitution by the elimination-addition mechanism is most commonly seen with very strong amide bases, it also occurs with bases such as hydroxide ion at high temperatures. A " C-labeling study revealed that hydrolysis of chlorobenzene proceeds by way of a benzyne intennediate. 

Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of HX to give a benzyne, followed by addition of a nucleophile. 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

Mechanism of nucleophilic aromatic substitution by elimination addition (the benzyne mechanism). 

After a new (and unusual) mechanism, such as the benzyne mechanism for nucleophilic aromatic substitution, is proposed, experiments are usually designed to test that mechanism. A classic experiment supporting the benzyne mechanism used a radioactive carbon label. Examination of the mechanism shown in Figure 17.6 shows that the carbon bonded to the leaving chlorine and the carbon ortho to it become equivalent in the benzyne intermediate. Consider what would happen if the carbon bonded to the chlorine were a radioactive isotope of carbon (l4C) rather than the normal isotope of carbon (I2C). If we follow the position of the radioactive carbon label through the mechanism of Figure 17.6, we find that the label should be equally distributed between the carbon attached to the amino group in the product and the carbon ortho to it. 

Nucleophilic aromatic substitutions have been studied in detail. Either of two mechanisms may be involved, depending on the reactants. One mechanism is similar to the electrophilic aromatic substitution mechanism, except that nucleophiles and carban-ions are involved rather than electrophiles and carbocations. The other mechanism involves benzyne, an interesting and unusual reactive intermediate. 

In summary, the benzyne mechanism operates when the halobenzene is unactivated toward nucleophilic aromatic substitution, and forcing conditions are used with a strong base. A two-step elimination forms a reactive benzyne intermediate. Nucleophilic attack, followed by protonation, gives the substituted product. 

Determine which nucleophilic aromatic substitutions are likely, and propose mechanisms for both the addition-elimination type and the benzyne type. Problems 17-52, 61, 62, G3, and GG... 

Notice the symmetry in this mechanism. Benzyne is formed from an ortho carbanion and it gives an ortho carbanion when it reacts with nucleophiles. The whole mechanism from bromobenzene to aniline involves an elimination to give benzyne followed by an addition of the nucleophile to the triple bond of benzyne. In many ways, this mechanism is the reverse of the normal addition-elimination mechanism for nucleophilic aromatic substitution and it is sometimes called the elimination-addition mechanism, the elimination step... 

We take up the aryl halides in a separate chapter because they differ so much from the alkyl halides in their preparation and properties. Aryl halides as a class are comparatively unreactive toward the nucleophilic substitution reactions so characteristic of the alkyl halides. The presence of certain other groups on the aromatic ring, however, greatly increases the reactivity of aryl halides in the absence of such groups, reaction can still be brought about by very basic reagents or high temperatures. We shall find that nucleophilic aromatic substitution can follow two very different paths the bimolecular displacement mechanism for activated aryl halides and the elimination-addition mechanismy which involves the remarkable intermediate called benzyne. 

This phenol synthesis is different from the nucleophilic aromatic substitutions discussed in the previous section because it takes place by an elimination addition mechanism rather than an addition/elimination. Strong base first causes the elimination of HX from halobenzene in an E2 reaction, yielding a highly reactive benzyne intermediate, and a nucleophile then adds to benzyne in a second step to give the product. The two steps are similar to those in other nucleophilic aromatic substitutions, but their order is reversed elimination before addition for the benzyne reaction rather than addition before elimination for the usual reaction. 

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