Nucleophilic Substitution Involving Benzyne Intermediates

A very different mechanism for these reactions was put forward by Roberts and co-workers. Summarizing the various reactions reported in the literature, Roberts noted the following  

The amino group was always found either on the carbon atom from which the leaving group departed or, at most, one carbon atom away. 

Neither the starting materials (aryl halides) nor the products (aryla-mines) appeared to isomerize under the reaction conditions. 

Particularly noteworthy is the use of quotation marks around the word prove in the statement by Roberts (reference 234) that the above facts strongly indicate but do not prove that benzyne is the intermediate in the [reaction]. Therefore, other reaction mechanisms will be considered in order to determine whether a more satisfactory formulation can be found.  

Use of halobenzenes labeled with deuterium on one of the positions ortho to the halogen gave further insight into the reaction. If the reaction occurs in 

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One of the characteristics of reactions involving benzyne intermediates is that the nucleophile can bond to the same carbon to which the leaving group was bonded, or it can bond to the carbon adjacent to the one to which the leaving group was bonded. This often results in the formation of isomeric products when substituted aromatic halides are used. For example, the reaction of yo-bromotoluene with sodium dimethyl-amide in dimethylamine as the solvent gives a 50 50 mixture of the meta and para... 

In Chapter 16, we will look at the reactions of substituted benzenes. First we will study reactions that change the nature of the substituent on the benzene ring and we will see how the nature of the substituent affects both the reactivity of the ring and the placement of any incoming substituent. Then we will look at three types of reactions that can be used to synthesize substituted benzenes other than those discussed in Chapter 15— reactions of arene diazonium salts, nucleophilic aromatic substitution reactions, and reactions that involve benzyne intermediates. You will then have the opportunity to design syntheses of compounds that contain benzene rings. 

Figure 8-5. Reactions of halobenzene derivatives with nucleophiles, a) Unactivated compounds are extremely inert and only react by mechanisms that involve the formation of benzynes. b) The presence of the electron-withdrawing nitro group, which can stabilise an anionic intermediate by the delocalisation of the charge onto the electronegative oxygen atoms, allows facile nucleophilic substitutions.

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 earlier chapters we revealed how some reactive intermediates can be prepared, usually under special conditions rather different from those of the reaction under study, as a reassurance that some of these unlikely looking species can have real existence. Intermediates of this kind include the carboca-tion in the S l reaction (Chapter 17), the cations and anions in electrophilic (Chapter 22) and nucleophilic (Chapter 23) aromatic substitutions, and the enols and enolates in various reactions of carbonyl compounds (Chapters 21 and 26-29). We have also used labelling in this chapter to show that symmetrical intermediates are probably involved in, for example, nucleophilic aromatic substitution with a benzyne intermediate (Chapter 23). 

Nucleophilic aromatic substitution reactions and substitution reactions proceeding through benzyne intermediates take place by different routes. In the first reaction, the substitution takes place by an addition, followed by an elimination. In the second case, the substitution involves an elimination, followed by an addition. Virtually all substitutions are equivalent to an addition and an elimination (in either order). 

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. 

Benzene rings with substituents other than halo, nitro, sulfonic acid, alkyl, and acyl can be prepared by first synthesizing one of these substituted benzenes and then chemically changing the substituent. The kinds of substituents that can be placed on benzene rings are greatly expanded by reactions of arene dia-zonium salts, nucleophilic aromatic substitution reactions, and reactions involving a benzyne intermediate. The relative positions of two substituents on a benzene ring are indicated either by numbers or by the prefixes ortho, meta, and para. 

As noted in Chapter 9, conventional nucleophilic substitution reactions of the type described for aliphatic compounds don t occur at sp hybrid carbon atoms. The formation of aryl cations is disfavored because they are unstable, and attack from the backside of the C-halogen bond is rendered impossible by the ring structure. So the substitution of aryl halides is much more difficult, and the mechanism of the S).j2Ar reaction is quite different, involving addition followed by elimination—a two-step process. For example, although substitution of chlorobenzene by hydroxyl ion is possible, conditions are harsh (350 °C, high pressure), and even then, yields are low. The reaction (Figure 13.13) probably involves a benzyne intermediate (see Sections 10.9 and 13.6). 

The central question here is whether the reaction is a synchronous Sn2 displacement or involves addition of the nucleophile to form an intermediate of some stability. The emphasis in this chapter will be largely on this problem. The final category is that of reactions involving a benzyne intermediate. These substitutions frequently involve rearrangements as shown below. 

The preceding explanation would seem to explain most of the data in Table 8.21, but there is one apparent discrepancy. We might have expected the methoxy substituent to be electron-donating, but it gives the same product orientation as does trifluoromethyl. This intuitive expectation of the substituent effect of methoxy is based primarily on its influence on electrophilic aromatic substitution (SeAr) and on nucleophilic aromatic substitution (SwAr) reactions, both of which involve attachment of a species to an aromatic ring to form a cr complex. In contrast, the carbanionic intermediates presumed to be formed in the benzyne reaction have the nonbonded pair of electrons in... 

The latter reagent allowed the substitution on some poorly activated substrates, such as 0- and w-dichlorobenzene, to give, although in moderate yields, o- and m-chloroanisole, respectively. This shows that the reaction involves direct attack of the nucleophile at the reaction center, not a benzyne-type mechanism These intermediates cannot be detected in liquid-liquid PTC where the water associated to the anion in the organic phase assists the cleavage of the bond between the leaving-group and the aromatic carbon atom... 

Halogens on aromatic rings can be replaced by a variety of other substituents. There are two general pathways (and a few more which are rare and will not be considered here) by which the substitution can be effected. The first involves loss of halogen and a proton on the adjacent carbon (an elimination reaction, vide infra) to produce an intermediate (called benzyne), which subsequently adds a nucleophile. The overall result is substitution. 

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