Benzynes from aryl halides

The stereoelectronic influence on stability of benzynes is illustrated by the rates of benzyne generation via lithium halide elimination from aryl halides (Figure 10.16). 

The reaction proceeds by formation of the Grignard reagent from o bromofluorobenzene Because the order of reactivity of magnesium with aryl halides is Arl > ArBr > ArCl > ArF the Gngnard reagent has the structure shown and forms benzyne by loss of the salt FMgBr... 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Whether or not branching occurs at an intermediate, its existence may be demonstrated by running the reaction in the presence of a reagent designed to intercept that intermediate to yield a new and characteristic product. Observations at a qualitative level can be extremely informative (e.g. formation of cyclo-adducts when aryl halides are treated with a strong base in the presence of conjugated dienes to trap a benzyne intermediate) but even more information maybe obtained from quantitative experiments, especially when product analyses are coupled with rate measurements. 

In the original process using tin amides, transmetallation formed the amido intermediate. However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed. In the tin-free processes, reaction of palladium aryl halide complexes with amine and base generates palladium amide intermediates. One pathway for generation of the amido complex from amine and base would be reaction of the metal complex with the small concentration of amide that is present in the reaction mixtures. This pathway seems unlikely considering the two directly observed alternative pathways discussed below and the absence of benzyne and radical nucleophilic aromatic substitution products that would be generated from the reaction of alkali amide with aryl halides. 

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. 

Another reaction that cannot be an SN2, because of the impossibility of carrying it out on an aryl halide, is the displacement from the aryl bromide 7.187. The mechanism is an Sr jI reaction (see p. 147), involving an electron transfer from the enolate 7.186 to the halide 7.187. The radical anion 7.189 loses the bromide ion to give the aryl radical 7.190, and this couples with the radical 7.188 derived from the nucleophile to give the ketone 7.191.252 The m-mcthyl group shows that the reaction did not take place by way of a benzyne. 

Two mechanistic alternatives could explain these results. One possibility is that the aryl halide reacts with the incoming amino group by competitive "normal" (equation Figure 8.57) and "abnormal" (Figure 8.58) pathways. The second possibility is that both types of product result from an elimination-addition mechanism involving benzyne (86), an aromatic ring with a formal triple bond, as shown in Figure 8.59. 

On the basis of the labeling experiment, an alternative mechanism was proposed for the substitution reaction of aryl halides with strong base-the elimination-addition mechanism. In the first step, the elimination stage, amide anion removes a proton from the carbon on the ring adjacent to the one with the halogen. The product is an unstable intermediate known as benzyne. 

To the more usual homolytic fragmentation of aryl halides (from the excited state or from the radical anion, the well known SrnI reaction, for a recent example see the arylation of aromatics), the heterolytic version of the reaction which produces phenyl cations has more recently joined. A theroretic study on the photodissociation of fluorinated iodobenzenes has been published. The perfluoroallgrlation of various alkenes has been obtained by irradiation in the presence of iodoperfluorobutane. The formation of phenyl cations is exemplified in many arylation reactions and, in the case of o-chlorostannane, also a benzyne has been reported. In the field of polymer chemistry, iodonium salts are model cationic photoinitiators. In particular the truxene-acridine/diphenyl iodonium salt/9-vinylcarbazole combination is able to promote the ringopening polymerization of an epoxide, whereas the truxene AD/allq l halide/amine system is very efficient in initiating the radical photopolymerization of an acrylate. ... 

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). 

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